Wearable Sensors in the Evaluation of Gait and Balance in Neurological Disorders

The aging population and the increased prevalence of neurological diseases have raised the issue of gait and balance disorders as a major public concern worldwide. Indeed, gait and balance disorders are responsible for a high healthcare and economic burden on society, thus, requiring new solutions to prevent harmful consequences. Recently, wearable sensors have provided new challenges and opportunities to address this issue through innovative diagnostic and therapeutic strategies. Accordingly, the book “Wearable Sensors in the Evaluation of Gait and Balance in Neurological Disorders” collects the most up-to-date information about the objective evaluation of gait and balance disorders, by means of wearable biosensors, in patients with various types of neurological diseases, including Parkinson’s disease, multiple sclerosis, stroke, traumatic brain injury, and cerebellar ataxia. By adopting wearable technologies, the sixteen original research articles and reviews included in this book offer an updated overview of the most recent approaches for the objective evaluation of gait and balance disorders

Unveiling the impact of neuromotor disorders on speech: a structured approach combining biomechanical fundamentals and statistical machine learning

Speech has been shown to convey clinically useful information in the study of Neurodegenerative Disorders (NDs), such as Parkinson’s Disease (PD). Traditionally the use of speech as an exploratory tool in People with Parkinson’s (PwP) has focused on the estimation of acoustic characteristics and their study at face value, analysing the physio-acoustical markers and using them as features for the differentiation between Healthy Controls (HC) and PwP. The present work takes a step further, given the intricate interoperation between neuromotor activity, responsible for both planning and driving the system, and the production of the acoustic speech signal; by the study of speech, this relationship may be properly exploited and analysed, providing a non-invasive method for the diagnosis, analysis, and observation of NDs. This work aims to introduce a working model that is capable of linking both domains and serves as a projection tool to provide insights about a speaker’s neuromotor state. This is based on a review of the neurophysiological background of the structure and function of the nervous system, and a review of the main nervous system dysfunctions involved in PD and other related neuromotor disorders. The role of the respiratory, phonatory, and articulatory systems is reviewed in the production of voice and speech under normal and pathological circumstances. This setting might allow for speech to be considered a useful trait within the precision medicine framework, as it provides a personal biometric marker that is innate and easy to elicit, can be recorded remotely with inexpensive equipment, is non-invasive, cost-effective, and easy to process. The problem can be divided into two main categories: firstly, a binary detection task distinguishing between healthy controls and individuals with NDs based on the projection model and phonatory estimates; secondly, a progression and tracking task providing a set of quantitative indices that enable clinically interpretable scores. This study aims to define a set of features and models that help to characterise hypokinetic dysarthria (HD). These incorporate the neuroscientific knowhow semantically and quantitatively to be used in clinical decision support tools that provide mechanistic insight on the processes involved in speech production, incorporating into the algorithmic element neuromotor considerations that add to better interpretability, consequently leading to improved clinical decisions and diagnosis. An overview of the acoustic signal processing algorithms for use in speech articulation and phonation system inversion regarding neuromotor disorder assessment is provided. An algorithmic methodology for model inversion and exploration has been proposed for the functional characterization and system inversion of each subsystem involved under the neuro-biomechanical foundations exposed before. A description of the vocal fold biomechanics using the glottal source, and formant dynamics provides the base for specific mapping to articulation kinematics. The statistical methods used in performance evaluation are based on three-way comparisons and transversal and longitudinal assessment by classical hypothesis testing. Three related experimental studies are shown to empirically illustrate the potential of phonation and articulation analysis: the characterization of PD from glottal biomechanics based on the amplitude distributions of the glottal flow and on the vocal fold body stiffness in assessing the efficiency of transcranial magnetic stimulation, and the description of PD dysarthria through an articulation projection model. The results from the biomechanical analysis of phonation showed that the behaviour of glottal source amplitude distributions from PD and healthy controls using three-way comparisons and hierarchical clustering were essentially distinguishable from those from normative young participants with the best accuracy scores produced by SVM classifiers of 94.8% (males) and 92.2% (females). Nevertheless, PD participants were barely separable from age-matched controls, possibly pointing to confounding factors due to age. The outcomes from using vocal fold stiffness in assessing the efficiency of transcranial magnetic stimulation showed mixed results, as some PD participants reflected clear improvements in phonation stability after stimulation, whereas some others did not. Some cases of sham controls experienced also minor improvements of unknown origin, possibly expressing a placebo effect. The overall results on the efficiency of stimulation showed an accuracy global score of 67% over the 18 cases studied. The results from articulation projection modelling showed the possibility of formulating personalised models for PD and control participants to transform acoustic formant dynamics into articulation kinematics. This might open the possibility of characterising PD dysarthria based on speech audio records. The most remarkable findings of the study include the determination of the glottal source amplitude distribution behaviour of normative and PD participants; the impact of age effects in phonation as a confounding factor in neuromotor disorder characterization; the importance of ensuring that the classification of speech dysarthria is based on principles that can be explained and interpreted; the need of taking into account the effects of medication when framing new classification experiments; the potential of using EEG-band decomposition to analyse vocal fold stiffness correlates, as well as the possibility of using these descriptions in longitudinal monitoring of treatment efficiency; the feasibility of establishing a relationship between acoustic and kinematic variables by projection model inversion; and the potential of these descriptions for estimating neuromotor activities in midbrain related to phonation and articulation activity. The most important outcome to be brought forth from the thesis is that the methodology used throughout the project uses a bottom-up approach based on speech model inversion at the acoustical, biomechanical, and neuromotor levels allowing to estimate glottal signals, biomechanical correlates, and neuromotor activity from speech alone, establishing a common neuromechanical characterisation framework on its own

Neuroimaging of fetal cell therapy in Parkinson’s disease

Parkinson’s disease is the second most common neurodegenerative disease characterised by the elevated formation of α-synuclein-immunopositive intraneuronal proteinaceous inclusions (Lewy pathology) and the progressive loss of neuromelanin-laden dopaminergic cells of the substantia nigra pars compacta, resulting in the loss of striatal dopaminergic terminals and emergence of cardinal motor features including bradykinesia, rigidity, tremor and postural instability. Dopaminomimetic agents provide effective symptomatic relief in the early stages of illness, yet due to the inherently progressive nature of the disease and the induction of debilitating side effects their efficacy is eventually lost. Cellular restorative strategies involving intrastriatal transplantation of human fetal ventral mesencephalic (hfVM) tissue gained traction from the early 1990’s, when several multi-disciplinary teams reported drastic motoric improvements concomitant with graft-derived dopaminergic re-innervation. However, outcomes of double-blind randomised controlled trials and the presentation of novel dyskinetic movements persisting in the “off-state” called for substantial revision of cell delivery strategies. The current thesis utilises positron emission tomography to examine the effects of hfVM implantation under the Transeuro protocol on dopaminergic ([18F]FDOPA, [11C]PE2I) and serotonergic ([11C]DASB) systems in patients with Parkinson’s disease and elucidate the neural underpinnings of its clinical impact. The main findings are; 1) implanted hfVM tissue led to increases in putamenal dopamine synthesis and storage capacity, dopamine and serotonin transporter density as compared to non-transplanted patients; 2) modification to surgical procedures provided inhomogenous and inconsistent re-innervation; 3) hfVM transplantation was associated with clinical improvements in measures of bradykinesia, rigidity and tremor; 4) graft-related changes in posterior putamenal dopamine and serotonin transporter density predicted symptomatic relief of bradykinesia and tremor; 5) heterogeneity of posterior putamenal re-innervation may impact upon potential clinical benefit; 6) graft-induced dyskinesia was associated with greater post-operative increases in dopamine transporter expression in the anterior putamen; 7) there was no evidence that graft-induced dyskinesia was related to serotonergic hyperinnervation. The novel findings presented in this thesis have major implications for cell-based restorative strategies beyond the hfVM era and will likely foster informed [re]consideration of many aspects of therapeutic delivery and trial design. For its ability to provide mechanistic insight in vivo, neuroimaging may continue to play a central role in the optimisation of future interventions.Open Acces

Proceedings of the 3rd international conference on disability, virtual reality and associated technologies (ICDVRAT 2000)

The proceedings of the conferenc

Multimodal Therapy of Upper Gastrointestinal Malignancies

Recent decades have seen remarkable advances in the treatment of upper gastrointestinal malignancies, i.e., adenocarcinoma and squamous cell carcinoma as well as gastrointestinal stromal and other rare tumors of the esophagus and stomach. While, historically, surgical resection has been the sole treatment for these tumors, multimodal therapies have meanwhile proven their efficacy. At present, pre- and postoperative chemotherapy and radiotherapy, targeted drug therapy, and stage-specific surgical approaches are all indispensable cornerstones of an individualized treatment for upper gastrointestinal malignancies. With such multimodal treatment, better outcomes comprising improved quality of life and prolonged survival have been achieved for patients. However, for many tumor entities and stages, the ideal combination and sequence of treatments is still being evaluated in clinical trials. Moreover, the value of novel approaches such as immunotherapy or robotic surgery remains a matter of research. In this Special Issue of Cancers, up-to-date original research, short communications, and comprehensive review articles on all modalities playing a role in the treatment of upper gastrointestinal malignancies have been published

Unravelling the progression of unfolded protein Rresponse in a model system of familial Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia disorders and, yet, there is no preventative or curative treatment. It is associated with the progressive loss of memory and cognition and clinically divided into sporadic and familial forms. Familial Alzheimer’s disease (FAD) has predominantly a genetic predisposition with inherited mutations in the amyloid-β precursor protein (APP) and presinilin genes, which promote APP processing through the amyloidogenic pathway. This results in the release of the Aβ peptide, a major neurotoxic agent in AD progression. Accumulation of unfolded and misfolded disease-specific proteins (including Aβ and tau proteins) in neuronal cells perturbs endoplasmic reticulum (ER) homeostasis, leading to the onset of a cellular stress cascade called unfolded protein response (UPR), markers of which are upregulated in AD brain specimens. This suggests a possible role for ER stress in activation and the pathogenesis of AD. The research aimed to investigate the dynamic response of the UPR in an experimental model system of the disease combined with a computational model. For this purpose human neuroblastoma cell lines overexpressing the wild-type (APPWT) and two mutant forms of APP (APPMUT) associated with FAD were generated. Gene expression analysis of UPR markers revealed that overexpression of APP induces preconditioning of ER stress in all cell lines but with a stronger response in FAD-associated mutants. The progression sequence of UPR in APPWT and APPMUT was investigated in a time-course manner following the application of chemical stress. The results revealed that APPMUT exhibited the highest global response to chemically induced stress with a similar pattern. A computational model of the mammalian UPR was then generated and used to understand the dynamics of UPR. The model was able to reproduce our experimental data, which included pre-existing genetic factors (mutations in APP-associated with FAD) and a mimic of environmental triggers (induction of stress) consequently triggering the stress response. It suggested a different protein load and magnitude of transcriptional activation upon stress among the three cell lines. This was followed by in silico case studies exploring the effect of drugs targeting different branches of the UPR. This study proposes a novel multidisciplinary platform that could be further used for the development of therapeutics for AD. As the familial and sporadic form of the disease have similar neuropathological characteristics, drugs efficacious for FAD will also be beneficial for the most common form of AD.Open Acces