26 research outputs found

    Neuroplasticity following pallidal stimulation for dystonia.

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    Dystonia is a disabling condition characterised by involuntary muscle spasms and abnormal postures. Its pathophysiology is incompletely understood but most lines of evidence point to an underlying defect of basal ganglia function leading to abnormal corticomotor output. Various abnormalities have been shown, including abnormal neuronal activity in basal ganglia output nuclei, defective neural inhibition at the spinal, brainstem, cortical level and sensorimotor misprocessing. More recently, increased neural plasticity has been found in dystonia patients in response to transcranial magnetic stimulation (TMS) protocols which induce motor cortex plasticity. Excessive plasticity might contribute to dystonia by promoting or reinforcing abnormal patterns of connectivity. The most significant advance in the treatment of generalised dystonia has been the development of globus pallidus internus (GPi) deep brain stimulation (DBS). Interestingly its beneficial effects are progressive over weeks to months rather than immediate. A plasticity effect has been implicated but physiological evidence has been lacking. Furthermore it is unknown what impact GPi DBS has on the underlying pathophysiology such as defective inhibition or excessive plasticity. The aim of the present work was to examine the impact of GPi DBS on underlying pathophysiological features such as disinhibition and abnormal motor cortical plasticity. In this thesis, studies in a consecutive series of dystonia patients, mainly those with primary generalised dystonia, who underwent bilateral GPi DBS, are presented. Patients were studied in a prospective, longitudinal manner with both clinical assessment of dystonia using a validated rating scale and electrophysiological studies including blink reflex excitability and forearm H-reflex reciprocal inhibition. In addition, once stable improvement had been achieved, the impact of GPi DBS on motor cortex plasticity was studied using TMS paired associative stimulation (PAS). The clinical study of these patients confirmed the therapeutic efficacy of GPi DBS and provided direct evidence of the superiority of the posteroventral globus pallidus as the optimal target. The longitudinal studies of blink and H-reflex, showed progressive normalisation of brainstem and spinal excitability, which correlated with the time-course of clinical improvement. These data provide the first evidence of reversal of underlying dystonia pathophysiology by GPi DBS and are compatible with progressive long-term neural reorganisation (plasticity) playing a role in the mechanism of action of GPi DBS. Furthermore, the result of TMS PAS experiments demonstrated that GPi DBS reduces the short-term plasticity of the motor cortex, the magnitude of this effect also correlated with therapeutic effect. This result is compatible with the concept that excessive plasticity promotes dystonia and reversal of these abnormalities may be another mechanism by which GPi DBS acts. In conclusion, work presented in this thesis provides the first electrophysiological correlates of clinical improvement in dystonia after GPi DBS, which collectively supports the notion that both long and short-term plasticity within the central nervous system are involved in the mechanism of GPi DBS action

    Deep Brain Stimulation (DBS) Applications

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    The issue is dedicated to applications of Deep Brain Stimulation and, in this issue, we would like to highlight the new developments that are taking place in the field. These include the application of new technology to existing indications, as well as ‘new’ indications. We would also like to highlight the most recent clinical evidence from international multicentre trials. The issue will include articles relating to movement disorders, pain, psychiatric indications, as well as emerging indications that are not yet accompanied by clinical evidence. We look forward to your expert contribution to this exciting issue

    Oscillatory activity in the basal ganglia - is it relevant to movement disorders therapy?

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    Chronic high frequency stimulation of the basal ganglia can be a highly effective intervention for movement disorders in patients. In the past decade, therapeutic benefits have been seen with stimulation of the subthalamic nucleus and globus pallidus interna for Parkinson's disease (PD) and dystonia, respectively. These procedures have allowed direct recording of basal ganglia activity and have suggested that abnormal synchronisation of neurons in these nuclei may contribute to motor impairment. This thesis explores the possible correlation between synchronised activity in the basal ganglia, as evidenced by oscillations in local field potentials, and movement disorders. In Chapter 3, we demonstrate the correlation between synchronization at frequencies under 10 Hz in the globus pallidus interna and dystonic EMG. This low frequency activity is shown to be locked to neuronal activity within GPi in patients with dystonia (Chapter 4). Deep brain stimulation is thought to suppress spontaneous pathological activity in the basal ganglia. Equally, however, it must also suppress any residual physiological activity in these nuclei. In Chapter 5, we demonstrate that the basal ganglia are involved in the processing of simple limb movements in the human, by separating the effects of deep brain stimulation on pathological and physiological activities based on baseline task performance. An impairment of motor performance was seen during high frequency stimulation in those patients with the best task performance at baseline. This deleterious effect, however, should be distinguished from the effect of direct stimulation at 20 Hz in Parkinson's disease. Oscillatory activity at around 20 Hz is thought to be a core feature in Parkinson's disease. In Chapter 6, we demonstrate that the excessive synchronization imposed by stimulation of the subthalamic nucleus at 20 Hz slows movement, in those patients with the best task performance at baseline. This supports the notion that synchronization around 20 Hz may be causally linked to bradykinesia. Last, the therapeutic effectiveness of DBS therapy for patients with PD partially relies on the accurate localisation of the motor region of the subthalamic nucleus. In Chapter 7, we propose an alternative method for the localization of this region using the spontaneous pathological 20 Hz activity to be found in this nucleus. The findings of these studies provide evidence that basal ganglia oscillatory activities of differing frequencies contribute to movement disorders

    Biofeedback Based Physical Rehabilitation in Parkinson's Disease Aimed at Self-Enhancement

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    Parkinson’s disease (PD) is a progressive neuromotor disorder that results in a progressive deterioration of balance and motor abilities with a consequent increase of the risk of falls and a reduction of quality of life. Physical therapy revealed to be fit for the symptomatic treatment of the disease and the adoption of biofeedback signals showed to be effective in prolonging the benefits of the therapy. Thus, this doctoral project has been designed to assess the benefits that wearable technologies for biofeedback generation could have in physical therapy. To further improve the developed biofeedback-based system, the assessment of new methods for the objective evaluation of balance control was included into the study. The dissertation is divided into three different set of studies, respectively aimed at: 1) presenting new wearable systems specifically designed for biofeedback-based rehabilitation; 2) assessing proprioceptive impairments in PD subjects through the adoption of a robotic platform to destabilize the base of support; 3) discussing new methods for the evaluation of balance preceding the execution of voluntary movements. The efficacy of the main proposed solution was assessed in a 6-months RCT study by comparison of subjects with PD trained with the biofeedback system and patients that received usual care. Both clinical and instrumental outcomes supported the higher efficacy of the biofeedback-based approach. The developed instrumented tests showed good sensitivity in discriminating patients and in detecting changes induced by physical therapy. The results reported in this thesis lead to the conclusion that the adoption of biofeedback based physical rehabilitation systems is promising in the treatment of Parkinson’s disease. The availability of a set of fast, easy-to-manage tests for the evaluation of balance and motor control might be useful in the design of home-delivered, user-tailored exercises for both healthy elderly and neurological subjects

    An entropy-based investigation of underpinnings and impact of oscillations in a model of PD

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    The involvement of the basal ganglia in motor control has been highlighted in studies of Parkinson’s disease (PD) and other movement disorders. The loss of dopaminergic neurons in the substantia nigra pars compacta and subsequent decrease of the dopamine level in the basal ganglia is recognized as the hallmark of PD. The classical view of the architecture of the dopamine depleted basal ganglia-thalamo-cortical circuit identifies changes in firing rates as the probable cause for the motor impairments in PD. Yet, more recent findings have shown that disturbances in other intrinsic dynamical properties of these networks may also contribute to motor deficits. Electrophysiological recordings in the basal ganglia of deep brain stimulation (DBS) patients (when OFF stimulation) have found pathological oscillations at beta frequency (13-30 Hz). This abnormal oscillatory activity has also been found in basal ganglia nuclei of animal models of PD. Additionally, the beta frequency oscillations were found to decrease when the patients are on dopamine replacement therapies and as they initiate movement. Beta frequency oscillations have been identified in the firing of single neurons and in the coupling of discharges between neurons. Within the framework of information theory, we proposed a time series model to analyse and relate the effects of changes in the dynamics of individual factors – such as alterations in firing rates, oscillations and synchrony (or auto and cross-correlations) caused by dopamine depletion – on the coding capacity (i.e., entropy) of a network. We estimated the entropy of a neural network based on the probabilities of current spiking conditioned on the observation of firing rate and spiking history of the current neuron and of neighbouring neurons. Moreover, we could estimate entropies for each of these factors separately, in healthy and dopamine depleted conditions, and assess their relative contribution to the decrease of coding capacity in disease. Furthermore, the causal characteristics of the model made it possible to compare the synaptic connectivity of neuronal populations in health with that in disease, by measuring the amount of directed information transferred between populations. We employed the model to study the external globus pallidus (GPe) network in control and 6-hydroxydopamine (6-OHDA) lesioned rats – a model for PD. We found a significant decrease in the coding capacity in lesioned animals, compared to controls, and that this decrease was predominantly on account of a reduction in the GPe firing rates. Although to a lesser extent, the amplification of the oscillatory activity (mainly in the beta frequency range) observed in the lesioned animals had also a significant impact on the reduction of their coding capacity. The higher synchrony found in the 6-OHDA rats had the least effect. We also found that the levels of coding capacity in the GPe were restored to levels close to control when the lesioned animals were treated with the dopamine agonist apomorphine. In addition, we detected a stronger coupling between the subthalamic nucleus (STN) and the GPe in the dopamine depleted rats, pointing to an abnormally exaggerated transfer of information within this network. We have shown that the GPe and the STN-GPe networks in the dopamine depleted rat exhibit information processing irregularities. We believe these deficits in processing and relaying information may also be present in other structures of the basal ganglia-thalamo-cortical circuit and that they may underlie the motor impairment in PD

    Deep Brain Stimulation (DBS) Applications

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    Neuromagnetic investigations of mechanisms and effects of STN-DBS and medication in Parkinson's disease

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    Parkinson’s disease (PD) is a neurodegenerative disorder cardinally marked by motor symptoms, but also sensory symptoms and several other non-motor symptoms. PD patients are typically treated with dopaminergic medication for several years. Many patients eventually experience bouts of periods where medication might not be able to effectively control symptoms as well as experience side-effects of long-term dopaminergic treatments. Deep brain stimulation (DBS) is an option as the next therapeutic recourse for such patients. DBS treatment essentially involves placement of stimulating electrodes in the subthalamic nucleus (STN) or the globus pallidus internum (GPi) along with an implanted pulse generator (IPG) in the sub-clavicular space. STN-DBS alleviates motor symptoms and leads to substantial improvements in quality of life for PD patients. Although DBS is known to improve several classes of symptoms, the effect mechanism of DBS is still not clear. While there is a lack of electrophysiological investigation of sensory processing and the effects of treatments in PD altogether, the electrophysiological studies of the cortical dynamics during motor tasks and at rest lack consensus.We recorded magnetoencephalography (MEG) and electromyography (EMG) from PD patients in three studies: (i) at rest, (ii) during median nerve stimulation, and (iii) while performing phasic contractions (hand gripping). The three studies focused on cortical oscillatory dynamics at rest, during somatosensory processing and during movement, respectively. The measurements were conducted in DBS-treated, untreated (DBS washout) and dopaminergic-medicated states. While both treatments (DBS and dopaminergic medication) ameliorated motor symptoms similarly in all studies, they showed differentiated effects on: (i) increased sensorimotor cortical low-gamma spectral power (31-45 Hz) (but no changes in beta power (13-30 Hz)) at rest only during DBS, (ii) somatosensory processing with higher gamma augmentation (31-45 Hz, 20-60 ms) in the dopaminergic-medicated state compared to DBS-treated and untreated states, and (iii) hand gripping with increased motor-related beta corticomuscular coherence (CMC, 13-30 Hz) during dopaminergic medication in contrast to increased gamma power (31-45 Hz) during DBS.Firstly, we infer from the three studies that DBS and dopaminergic medication employ partially different anatomo-functional pathways and functional strategies when improving PD symptoms. Secondly, we suggest that treatments act on pathological oscillatory dynamics differently at cortical and sub-cortical levels and may do so through more sophisticated mechanisms than mere suppression of the pathological spectral power in a particular band. And thirdly, we urge exploring effect mechanisms of PD treatments beyond the motor system. The effects of dopaminergic medication on early somatosensory processing has opened the door for exploring the effects of treatments and studying their mechanisms using electrophysiology, especially in higher order sensory deficits. Integration of such research findings into a holistic view on mechanisms of treatments could pave way for better disease management paradigms. 

    Effects of deep brain stimulation of the subthalamic nucleus and the pedunculopontine nucleus on cognitive function in Parkinson's disease

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    The general aim of this thesis was to investigate the cognitive effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the pedunclopontine nucleus (PPN) in Parkinson’s disease (PD). In Study 1, acute STN stimulation did not induce impulsivity on a probabilistic decisionmaking task, suggesting STN-DBS induced impulsivity may occur in tasks involving conflict, reward or time pressure. This study has clarified that the inhibitory deficits associated with STN-DBS are situation and task specific, which makes it clear why new cases of post-operative impulse control disorders are only reported in some patients. In Study 2, the STN-DBS induced decline in verbal fluency (VF), greater for semantic than phonemic fluency, was found to be a surgical rather than an acute stimulation effect, mainly due to reduced switching but no change in cluster size. Therefore, future work in identifying the mechanisms of the STN-DBS induced VF decline should focus on surgical rather than stimulation effects. In Study 3, patients failed to benefit from corrective feedback to enhance their learning relative to a trial-and-error version when performing visual conditional associative learning tasks (VCLT) with STN-DBS on versus off. STN-DBS seemed to influence proactive interference resolution on the VCLTs. These results have implications for the use of adjunct interventions such as speech therapy or physiotherapy following STN-DBS surgery. In Study 4, PPN-DBS surgery did not have an impact on most aspects of cognition assessed and the only consistent decline was in switching category VF. For the two patients who developed dementia after PPN-DBS surgery, resuming low frequency stimulation improved working memory and attention. The findings from these studies provide further evidence and clarity regarding the cognitive sequel of STN-DBS and PPN-DBS for PD and confirm that the former can be a good treatment of choice for mid to late-stage Parkinson’s disease without the risk of major cognitive adverse effects

    Diagnosis and Treatment of Parkinson's Disease

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    Parkinson's disease is diagnosed by history and physical examination and there are no laboratory investigations available to aid the diagnosis of Parkinson's disease. Confirmation of diagnosis of Parkinson's disease thus remains a difficulty. This book brings forth an update of most recent developments made in terms of biomarkers and various imaging techniques with potential use for diagnosing Parkinson's disease. A detailed discussion about the differential diagnosis of Parkinson's disease also follows as Parkinson's disease may be difficult to differentiate from other mimicking conditions at times. As Parkinson's disease affects many systems of human body, a multimodality treatment of this condition is necessary to improve the quality of life of patients. This book provides detailed information on the currently available variety of treatments for Parkinson's disease including pharmacotherapy, physical therapy and surgical treatments of Parkinson's disease. Postoperative care of patients of Parkinson's disease has also been discussed in an organized manner in this text. Clinicians dealing with day to day problems caused by Parkinson's disease as well as other healthcare workers can use beneficial treatment outlines provided in this book
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