Speech and gait abnormalities in motor subtypes of de-novo Parkinson's disease.

AIM To investigate the presence and relationship of temporal speech and gait parameters in patients with postural instability/gait disorder (PIGD) and tremor-dominant (TD) motor subtypes of Parkinson's disease (PD). METHODS Speech samples and instrumented walkway system assessments were acquired from a total of 60 de-novo PD patients (40 in TD and 20 in PIGD subtype) and 40 matched healthy controls. Objective acoustic vocal assessment of seven distinct speech timing dimensions was related to instrumental gait measures including velocity, cadence, and stride length. RESULTS Compared to controls, PIGD subtype showed greater consonant timing abnormalities by prolonged voice onset time (VOT) while also shorter stride length during both normal walking and dual task, while decreased velocity and cadence only during dual task. Speaking rate was faster in PIGD than TD subtype. In PIGD subtype, prolonged VOT correlated with slower gait velocity (r = -0.56, p = 0.01) and shorter stride length (r = -0.59, p = 0.008) during normal walking, whereas relationships were also found between decreased cadence in dual task and irregular alternating motion rates (r = -0.48, p = 0.04) and prolonged pauses (r = -0.50, p = 0.03). No correlation between speech and gait was detected in TD subtype. CONCLUSION Our findings suggest that speech and gait rhythm disorder share similar underlying pathomechanisms specific for PIGD subtype

Motor symptoms in Parkinson's disease: A unified framework

Parkinson’s disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (akinesia and bradykinesia, tremor and rigidity), PD patients show additional motor deficits, including: gait disturbance, impaired handwriting, grip force and speech deficits, among others. Some of these motor symptoms (e.g., deficits of gait, speech, and handwriting) have similar clinical profiles, neural substrates, and respond similarly to dopaminergic medication and deep brain stimulation (DBS). Here, we provide an extensive review of the clinical characteristics and neural substrates of each of these motor symptoms, to highlight precisely how PD and its medical and surgical treatments impact motor symptoms. In conclusion, we offer a unified framework for understanding the range of motor symptoms in PD. We argue that various motor symptoms in PD reflect dysfunction of neural structures responsible for action selection, motor sequencing, and coordination and execution of movement

Analysis of a distinct speech disorder seen in chronic manganese toxicity following Ephedrone abuse

INTRODUCTION: In the last fifteen years a new cause of chronic manganese toxicity has been recognized. It follows recreational intravenous injections of Ephedrone, synthesized from a cold remedies contained pseudoephedrine. Potassium permanganate is used as an oxidant. It presents with severe parkinsonism-dystonia and a characteristic dysarthria. OBJECTIVES: We performed a focus perceptual study of dysarthria in Ephedrone induced parkinsonism and compared the findings with the speech disorders seen in Parkinson's disease (PD) and Progressive Supranuclear Palsy (PSP). METHODS: A digital voice recording, perceptual speech analysis (Darley, 1975) [18], serial neurological assessment and Brain Magnetic Resonance (MR) imaging were performed at the Lviv regional Clinical Hospital. The results were analysed at the Institute of Neurology in London. RESULTS: Dysarthria developed after 8.5 ± 3.2 months of daily intravenous Ephedrone abuse and was an initial symptom in a third of cases. It was characterised by a robotic-flat prosody, whispering or continuous phonation, an inability to regulate pitch and volume, frozen lip articulation, a variable degree of dystonic tightness, difficulties in speech initiation and palladia, There was no nasality and swallowing was normal. In some patients speech deteriorated even after the discontinuation of Ephedrone. MR imaging, performed soon after drug cessation showed T1 signal hyperintesity in striatum and pallidum, especially in the Globus Pallidum interna. CONCLUSION: Ephedrone induced chronic manganese toxicity can lead to a mixed hypokinetic-dystonic dysarthria with a distinct dystonic pattern. Perceptual speech analysis can be a helpful ancillary investigation in the differential diagnosis of parkinsonism, and may permit the recognition of chronic manganese toxicity

Multimodal response to levodopa treatment in advanced and late Parkinson’s disease

Parkinson’s disease (PD) is a progressive age-dependent neurodegenerative disease. Life expectancy increasing and a better knowledge in PD treatment management, including the advent of device-aided therapies, are likely to increase the number of patients who can reach an advanced disease stage and eventually enter the late stage (LS) of the disease in the next decades. LSPD is a recently recognized disease stage, in which patients are severely disable and dependent on activities of daily life (ADLs) due to the presence of poor treatment responsive motor and non-motor symptoms (NMS) thus highly impacting caregiver’s burden and social/health care system. Hence an operational clinical criteria to identify LSPD patients has been recently proposed suggesting adopt a Schwab and England activity of daily life score (S&E) < 50 in the MED ON condition. LSPD patients’ treatment management is challenging. Treatment-related adverse effects (AEs) are frequent and few evidence in terms of phamacological and non-pharmacological treatment efficacy are available as they are barely included in clinical or research studies and even the participation into routine hospital-based visits can be an unsurmountable limit. At the same time, even if general PD disease severity milestones have been described, we do not know how LSPD patients specifically progress, if they do evolve and if there are clinical markers or biomarkers of poor outcome that could be useful to focus specific therapeutic interventions for this specific disease stage. We aimed to deeply characterize the clinical phenotype, needs along with clinical markers or biomarkers of poor outcome of LSPD patients. As levodopa (L-dopa) is the mainstay of PD treatment and a simplification of treatment regimen in later disease stages has been suggested, we also aimed to investigate the real effect of L-dopa on motor symptoms and NMS among LSPD patients, if compared to advanced stage patients. Among NMS, we focused our work particularly on speech impairment, exploring speech response to L-dopa among LSPD patients and to fine stimulation parameters adjustment, in combination with L-dopa, in advanced PD patients submitted to deep brain stimulation (DBS). Participants were LSPD (Schwab and England ADL Scale [S&E] 3 in “MED ON” state) and advanced stage PD patients previously submitted to DBS. Cross-sectional data were obtained by means of a comprehensive clinical assessment including a L-dopa challenge test with a suprathreshold dose. A subgroup of thirteen LSPD patients underwent a neuroimaging study in order to study neuromelanin (NM) substantia nigra (SN) area changes in the latest disease stage if compared to previous ones. Automated analysis of speech were used to study the effect of a supramaximal L-dopa dose in twenty-four LSPD patients as well as L-dopa and frequency stimulation adjustment in twenty deep brain stimulated patients. Longitudinal data were collected only for LSPD patients. Descriptive, regression and survival curves analysis were performed. Fifty LSPD patients (female 46%) were included. Mean age was 77.5 ± 5.9 years and mean disease duration was 15.5± 6.5 years. At baseline, 76% had L-dopa-induced motor complications (MCs), mainly non-troublesome, 68%were demented, 54% had psychosis and 68% depression. Caregiver distress was high. L-dopa responsiveness was mild (18% ± 12 of improvement on MDS-UPDRS-III) and present only for appendicular signs, being tremor and rigidity the most responsive ones, while axial signs did not change. The clinical significance of this better motor response was marginal according to the Clinical Global Improvement Scale and the change in the S&E between OFF and ON state. The magnitude of L-dopa response correlated with the acute appearance of dyskinesias and the severity of MCs. After one-year, 20% of the patients were dead, 18% institutionalized in nursing home and 6% passed to a HY 5. MDS-UPDRS-motor mean score worsened 7.2 ± 10.3 points, corresponding to a 15.7% (±23.0) increase, with no difference between tremor-dominant versus akinetic-rigid phenotype or PD patients with/without dementia (PDD/non-PDD) at baseline. However, there was heterogeneity between patients in terms of disease progression, as 12 patients (37.5%) had a motor deterioration ≤ 3 points and 14 (43%) ≤ 5 points with concomitant worsening of the MDS-UPDRS-II (Motor Aspects of Experiences of Daily Living), of 2.1±4.1. Conversely, eleven cases (32%) did not deteriorate and, in fact, 10 of these improved between 1-6 points at the MDS-UPDRS-III. Overall NMS worsened, mostly in cognition/mood, urinary and gastrointestinal domains. Conversely, MCs improved despite similar L-dopa equivalent dose. Functional independence and quality of life worsened. Dysphagia severity at baseline predicted a poor combined outcome (death, being institutionalized or developing HY 5) (Hazard ratio 2.3, 95% CI 1.12- 4.4; p = 0.01) or death alone (Hazard ratio of 2.9, 95% CI 1.12- 8.6, p=0.04), whereas magnitude of L-dopa response of LSPD patients did not. SN area evaluated by NM-sensitive magnetic resonance imaging (MRI), resulted able to differentiate LSPD patients from both de novo PD patients and controls, though not founding statistical differences between LSPD patients and patients with two-five year disease duration. Performing an indirect comparison of the effect of L-dopa on motor symptoms and NMS among twenty LSPD patients and twenty-two, not-matched, advanced PD patients, a milder response on motor symptoms (11% vs. 37% of improvement on MDS-UPDRS-III) and an absence of response on NMS, namely anxiety, fatigue and pain, were found among LSPD patients, with concomitant higher frequency of drug-related AEs. Indeed orthostatic hypotension (OH) or drowsiness occurred among 35% of LSPD patients versus 13% of advanced PD patients, who still presented a benefit from L-dopa intake on pain and anxiety, while fatigue did not change. Scales applicability and blood pressure assessment while standing resulted challenging among LSPD patients with consequent missing data on depression, anxiety, pain and OH identification and possible underestimation of those symptoms. No effect of L-dopa was found on speech and voice by means of both automated analysis and clinical evaluation in LSPD patients. Respiratory support for speech and voice stability were the most affected speech and voice features among LSPD patients. Among axial symptoms, speech seemed to be the most L-dopa unresponsive one. Speech unresponsiveness to L-dopa was confirmed also among subthalamic (STN)-DBS treated patients with both mild and severe dysarthria, at least in combination with stimulation. Conversely, PD patients with severe dysarthria under chronic STN-DBS treatment showed a benefit of lowering frequency of stimulation from 130 Hz (High frequency stimulation [HFS]) to 60Hz (low frequency stimulation [LFS]), with concomitant increment of voltage, in order to keep constant the total energy delivered. Indeed speech intelligibility and articulatory diadochokinesis presented an acute improvement passing from HFS to LFS, as assessed by automated speech analysis and such a benefit, when present and clinically meaningful, lasted during six months with no motor worsening, though requiring medication adjustment. The present study provides further evidence to better delineate a recently recognized and poorly described PD stage. An extensive cross-sectional and longitudinal observation is proposed. LSPD patients clearly differ from previous stages in terms of both clinical features, needs, therapeutic response and drugs’ tolerability profile. Over one year, a heterogeneous disease progression of motor symptoms is still present and it seems even steeper if compared to previous stages, while functional independence globally worsened. As well as mild motor improvements are still possible with treatment adjustment, it is also possible to identify a clinical phenotype of LSPD patients who are likely to have a better response to L-dopa if compared to the other ones. Clinical assessment and therapeutic interventions for swallowing problems should be a priority. PDD or living in a nursing home remain other indicators of poor outcome. In the next few years the number of LSPD patients who have been previously submitted to device-aided therapies is expected to increase, bringing new clinical scenarios, such as the fine parameters adjustment of invasive treatment for challenging motor and NMS and the difficult management or eventual interruption of those treatments among elderly and frail LSPD patients. Overall, future research and fund allocations should be specifically oriented on LSPD patients, usually not included or considered in clinical trials or research studies, and on L-dopa not-responsive aspects and caregivers’ need

Effects of deep brain stimulation on speech in patients with Parkinson’s disease and dystonia

Disorders affecting the basal ganglia can have a severe effect on speech motor control. The effect can vary depending on the pathophysiology of the basal ganglia disease but in general terms it can be classified as hypokinetic or hyperkinetic dysarthria. Despite the role of basal ganglia on speech, there is a marked discrepancy between the effect of medical and surgical treatments on limb and speech motor control. This is compounded by the complex nature of speech and communication in general, and the lack of animal models of speech motor control. The emergence of deep brain stimulation of basal ganglia structures gives us the opportunity to record systematically the effects on speech and attempt some assumptions on the role of basal ganglia on speech motor control. The aim of the present work was to examine the impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) and globus pallidus internus (GPi-DBS) for dystonia on speech motor control. A consecutive series of PD and dystonia patients who underwent DBS was evaluated. Patients were studied in a prospective longitudinal manner with both clinical assessment of their speech intelligibility and acoustical analysis of their speech. The role of pre-operative clinical factors and electrical parameters of stimulation, mainly electrode positioning and voltage amplitude was systematically examined. In addition, for selected patients, tongue movements were studied using electropalatography. Aerodynamic aspects of speech were also studied. The impact of speech therapy was assessed in a subgroup of patients. The clinical evaluation of speech intelligibility one and three years post STN-DBS in PD patients showed a deterioration of speech, partly related to medially placed electrodes and high amplitude of stimulation. Pre-operative predictive factors included low speech intelligibility before surgery and longer disease duration. Articulation rather than voice was most frequently affected with a distinct dysarthria type emerging, mainly hyperkinetic-dystonic, rather than hypokinetic. Traditionally effective therapy for PD dysarthria had little to no benefit following STN-DBS. Speech following GPi-DBS for dystonia did not significantly change after one year of stimulation. A subgroup of patients showed hypokinetic features, mainly reduced voice volume and fast rate of speech more typical of Parkinsonian speech. Speech changes in both STN-DBS and GPi-DBS were apparent after six months of stimulation. This progressive deterioration of speech and the critical role of the electrical parameters of stimulation suggest a long-term effect of electrical stimulation of basal ganglia on speech motor control

Voice tremor in Parkinson's disease (PD) :identification, characterisation and relationship with speech, voice and disease variables

Phd ThesisVoice tremor is associated with Parkinson’s disease (PD), however little is known about the precise characteristics of PD voice tremor, optimum methods of evaluation or possible relationships with other speech, voice, and disease variables. The question of possible differences between voice tremor in people with PD (pwPD) and neurologically healthy ageing people has not been addressed. Thirty pwPD ‘off-medication’ and twenty eight age-sex matched neurologically healthy controls were evaluated for voice tremor features using acoustic measurement, auditory perceptual voice rating, and nasendoscopic vocal tract examination. Speech intelligibility, severity of voice impairment, voice disability and disease variables (duration, disability, motor symptom severity, phenotype) were measured and examined for relationship with acoustic voice tremor measures. Results showed that pwPD were more likely to show greater auditory perceived voice instability and a greater magnitude of frequency and amplitude tremor in comparison to controls, however without statistical significance. PwPD had a higher rate of amplitude tremor than controls (p<0.05). Judged from ‘silent’ video recordings of nasendoscopic examination, pwPD had a greater amount of tremor in the palate, tongue, and global larynx (vertical dimension) than controls during rest breathing, sustained /s/, /a/ and /i/ (p<0.05). Acoustic voice tremor did not relate significantly to other speech and voice variables. PwPD had a significantly higher voice disability than controls (p<0.05), though this was independent of voice tremor. The magnitude of frequency tremor was positively associated with disease duration (p<0.05). A lower rate of amplitude tremor was associated with an increase in motor symptoms severity (p<0.05). Acoustic voice tremor did not relate in any significant way to PD disability or phenotype. ii PD voice tremor is characterised by auditory perceived instability and tremor, a mean amplitude tremor of 4.94 Hz, and tremor in vocal tract structures. Acoustic analysis and nasendoscopy proved valuable adjunctive tools for characterising voice tremor. Voice tremor is not present in all people with PD, but does appear to increase with disease duration. However pwPD examined here represent a relatively mild group with relatively short disease duration. Further work will look at people with more severe disease symptomatology and longer duration

Development of Markerless Systems for Automatic Analysis of Movements and Facial Expressions: Applications in Neurophysiology

This project is focused on the development of markerless methods for studying facial expressions and movements in neurology, focusing on Parkinson’s disease (PD) and disorders of consciousness (DOC). PD is a neurodegenerative illness that affects around 2% of the population over 65 years old. Impairments of voice/speech are among the main signs of PD. This set of impairments is called hypokinetic dysarthria, because of the reduced range of movements involved in speech. This reduction can be visible also in other facial muscles, leading to a hypomimia. Despite the high percentage of patients that suffer from dysarthria and hypomimia, only a few of them undergo speech therapy with the aim to improve the dynamic of articulatory/facial movements. The main reason is the lack of low cost methodologies that could be implemented at home. DOC after coma are Vegetative State (VS), characterized by the absence of self-awareness and awareness of the environment, and Minimally Conscious State (MCS), in which certain behaviors are sufficiently reproducible to be distinguished from reflex responses. The differential diagnosis between VS and MCS can be hard and prone to a high rate of misdiagnosis (~40%). This differential diagnosis is mainly based on neuro-behavioral scales. A key role to plan the rehabilitation in DOC patients is played by the first diagnosis after coma. In fact, MCS patients are more prone to a consciousness recovery than VS patients. Concerning PD the aim is the development of contactless systems that could be used to study symptoms related to speech and facial movements/expressions. The methods proposed here, based on acoustical analysis and video processing techniques could support patients during speech therapy also at home. Concerning DOC patients the project is focused on the assessment of reflex and cognitive responses to standardized stimuli. This would allow objectifying the perceptual analysis performed by clinicians

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

Pathophysiological mechanisms in Parkinson`s Disease and Dystonia – converging aetiologies

In this thesis I used a range of experimental approaches including genetics, enzyme activity measurements, histology and imaging to explore converging pathophysiological mechanisms of Parkinson`s disease and dystonia, two conditions with frequent clinical overlap. First, based on a combined retro- and prospective cohort of patients, using a combination of lysosomal enzyme activity measurements in peripheral blood and brain samples, as well as a target gene approach, I provide first evidence of reduced levels of enzyme activity in Glucocerebrosidase and the presence of GBA mutations, indicating lysosomal abnormality, in a relevant proportion of patients with dystonia of previously unknown origin. Second, based on a retrospective cohort of patients, I detail that a relevant proportion of genetically confirmed mitochondrial disease patients present with a movement disorder phenotype - predominantly dystonia and parkinsonism. Analysing volumetric MRI data, I describe a patterned cerebellar atrophy in these particular patients. This also includes the first cases of isolated dystonia due to mitochondrial disease, adding the latter as a potential aetiology for dystonia of unknown origin. Third, I used a combination of post-GWAS population genetic approaches and tissue-based experiments to explore in how far the strong association between advancing age and Parkinson ́s disease is mediated via telomere length. Although the initial finding of an association between genetically determined telomere length and PD risk did not replicate in independent cohorts, I provide evidence that telomere length in human putamen physiologically shortens with advancing age and 3 is regulated differently than in other brain regions. This is unique in the human brain, implying a particular age-related vulnerability of the striatum, part of the nigro-striatal network, crucially involved in PD pathophysiology. I conclude by discussing the above findings in light of the current literature, expand on their relevance and possible direction of future experiments