Oscillation-specific nodal alterations in early to middle stages Parkinsons disease.

Background: Different oscillations of brain networks could carry different dimensions of brain integration. We aimed to investigate oscillation-specific nodal alterations in patients with Parkinsons disease (PD) across early stage to middle stage by using graph theory-based analysis. Methods: Eighty-eight PD patients including 39 PD patients in the early stage (EPD) and 49 patients in the middle stage (MPD) and 36 controls were recruited in the present study. Graph theory-based network analyses from three oscillation frequencies (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; slow-3: 0.073-0.198 Hz) were analyzed. Nodal metrics (e.g. nodal degree centrality, betweenness centrality and nodal efficiency) were calculated. Results: Our results showed that (1) a divergent effect of oscillation frequencies on nodal metrics, especially on nodal degree centrality and nodal efficiency, that the anteroventral neocortex and subcortex had high nodal metrics within low oscillation frequencies while the posterolateral neocortex had high values within the relative high oscillation frequency was observed, which visually showed that network was perturbed in PD; (2) PD patients in early stage relatively preserved nodal properties while MPD patients showed widespread abnormalities, which was consistently detected within all three oscillation frequencies; (3) the involvement of basal ganglia could be specifically observed within slow-5 oscillation frequency in MPD patients; (4) logistic regression and receiver operating characteristic curve analyses demonstrated that some of those oscillation-specific nodal alterations had the ability to well discriminate PD patients from controls or MPD from EPD patients at the individual level; (5) occipital disruption within high frequency (slow-3) made a significant influence on motor impairment which was dominated by akinesia and rigidity. Conclusions: Coupling various oscillations could provide potentially useful information for large-scale network and progressive oscillation-specific nodal alterations were observed in PD patients across early to middle stages

Rest tremor in Parkinson's disease: body distribution and time of appearance

Objective To assess body distribution and timing of appearance of rest tremor in Parkinson's disease. Methods Information was obtained by a computerized database containing historical information collected at the first visit and data collected during the subsequent follow-up visits. Information on rest tremor developed during the follow-up could be therefore obtained by our own observation in a proportion of patients. Results Among 289 patients, rest tremor was reported at disease onset in 65.4% of cases and detected at last follow-up examination in 74.4% of patients. Analysis of patients who did not report rest tremor at disease onset indicated that 26% of such patients (9% in the overall population) manifested rest tremor over the disease course. Rest tremor spread to new sites in 39% of patients who manifested rest tremor at disease onset. Regardless of tremor presentation at disease onset or during the follow-up, upper limb was the most frequent tremor localization. Over the follow-up, rest tremor developed faster in the upper limb than in other body sites. The risk of developing rest tremor during the follow-up was not affected by sex, side of motor symptom onset and site of tremor presentation. However, age of disease onset > 63 years was associated with an increased risk of rest tremor spread. Conclusions This study provides new information about body distribution and timing of rest tremor appearance during the course of early stages of Parkinson's disease that may help clinicians in patients' counselling

Force platform recordings in the diagnosis of primary orthostatic tremor

Primary orthostatic tremor (OT) consists of rhythmical muscle contractions at a frequency of around 16 Hz, causing discomfort and/or unsteadiness while standing. Diagnosis has hitherto relied on recording Electromyography (EMG) from affected muscles. The main aim of this study was to see if the characteristic postural tremor in OT can be identified with force platforms. We also quantified postural sway in OT patients to assess their degree of objective unsteadiness. Finally, we investigated the time relations between bursts of activity in the various affected muscle groups. Subjects stood on a force platform with concurrent multichannel surface EMG recordings from the lower limbs. Seven patients with clinical and EMG diagnosis of OT were examined and the force platform data compared with those of 21 other neurological patients with postural tremor and eight normal controls. All OT patients had high frequency peaks in power spectra of posturography and EMG recordings (12–16 Hz). No such high frequency activity was evident in patients with Parkinson's disease, cerebellar degenerations, essential tremor or in healthy controls. Additionally, OT patients showed increased sway at low frequencies relative to normal controls, suggesting that the unsteadiness reported by OT patients is at least partly due to increased postural sway. Examination of EMG timing showed fixed patterns of muscle activation when maintaining a quiet stance within but not across OT patients. These data show a high correlation between EMG and posturography and confirm that OT may be diagnosed using short epochs of force platform recordings

Cognitive Behavioral Therapy in Movement Disorders. A Review

In addition to motor symptoms, patients with movement disorders often complain of psychiatric disturbances, including mood, anxiety, and impulse-control disorders and psychosis. These abnormalities are often misdiagnosed and left untreated, thus resulting in a worse prognosis and lower quality of life. Besides the use of standard pharmacological treatments, psychiatric abnormalities can be treated by means of nonpharmacological approaches. These approaches include various types of psychological therapies, the most widely used being cognitive behavioral therapy (CBT). We reviewed all articles, conducted until 2014, that contained primary data derived from clinical trials and case reports on the effect of CBT in the most common movement disorders. One randomized, controlled study and several uncontrolled studies on the efficacy of CBT in Parkinson's disease (PD) have shown a short-term benefit of depression and anxiety. In Tourette's syndrome (TS), CBT has been assessed in a number of large controlled clinical trials that have demonstrated an improvement in psychiatric disturbances and tics. There are no controlled studies on the efficacy of CBT in other types of movement disorders, such as dystonia, Huntington's disease, and essential tremor. Only a limited number of studies have evaluated the efficacy of CBT in the management of psychiatric disorders in movement disorders. The evidence available suggests that CBT is useful in TS and probably useful in PD. We recommend the planning of randomized, controlled clinical trials to investigate the effects of CBT and group CBT in the treatment of psychiatric disturbances in movement disorders

Investigation of intraoperative accelerometer data recording for safer and improved target selection for deep brain stimulation

Background: Deep Brain Stimulation (DBS) is a well established surgical treatment for Parkinson’s Disease (PD) and Essential Tremor (ET). Electrical leads are surgically implanted in the deeply seated structures in the brain and chronically stimulated. The location of the lead with respect to the anatomy is very important for optimal treatment. Therefore, clinicians carefully plan the surgery, record electrophysiological signals from the region of interest and perform stimulation tests to identify the best location to permanently place the leads. Nevertheless, there are certain aspects of the surgery that can still be improved. Firstly, therapeutic effects of stimulation are estimated by visually evaluating changes in tremor or passively moving patient's limb to evaluate changes in rigidity. These methods are subjective and depend heavily on the experience of the evaluator. Secondly, a significant amount of patient data is collected before and during the surgery like various CT and MR images, surgical planning information, electrophysiological recordings and results of stimulation tests. These are not fully utilized at the time of choosing the position for lead placement as they are either not available or acquired on separate systems or in the form of paper notes only. Thirdly, studies have shown that the current target structures to implant the leads (Subthalamic Nucleus (STN) for PD and Ventral Intermediate Nucleus (VIM) for ET) may not be the only ones responsible for the therapeutic effects. The objective of this doctoral work is to develop new methods that help clinicians subdue the above limitations which could in the long term improve the DBS therapy. Method: After a thorough review of the existing literature, specifically customized solutions were designed for the shortcomings described above. A new method to quantitatively evaluate tremor during DBS surgery using acceleration sensor was developed. The method was then adapted to measure acceleration of passive movements and to evaluate changes in rigidity through it. Data from 30 DBS surgeries was collected by applying these methods in two clinical studies: one in Centre Hospitalier Universitaire, Clermont-Ferrand, France and another multi-center study in Universitäspital Basel and Inselspital Bern in Switzerland. To study the role of different anatomical structures in the therapeutic and adverse effects of stimulation, the data collected during the study was analysed using two methods. The first classical approach was to classify the data based on the anatomical structure in which the stimulating contact of the electrode was located. The second advanced approach was to use patient-specific Finite Element Method (FEM) simulations of the Electric Field (EF) to estimate the spatial distribution of stimulation in the structures surrounding the electrode. Such simulations of the adverse effect inducing stimulation current amplitudes are used to visualize the boundaries of safe stimulation and identify structures that could be responsible for these effects. In addition, the patient-specific simulations are also used to develop a new method called "Improvement Maps" to generate 2D and 3D visualization of intraoperative stimulation test results with the patient images and surgical planning. This visualization summarized the stimulation test results by dividing the explored area into multiple regions based on the improvement in symptoms as measured by the accelerometric methods. Results: The accelerometric method successfully measured changes in tremor and rigidity. Standard deviation, signal energy and spectral amplitude of dominant frequency correlated with changes in the symptoms. Symptom suppressing stimulation current amplitudes identified through quantitative methods were lower than those identified through the subjective methods. Comparison of anatomical targets using the accelerometric data showed that to suppress rigidity in PD patients, stimulation current needed was marginally higher for Fields of Forel (FF) and Zona Incerta (ZI) compared to STN. On the other hand, the adverse effect occurrence rate was significantly lower in ZI and FF, indicating them to be better targets compared to STN. Similarly, for ET patients, other thalamic nuclei like the Intermediolateral (InL) and Ventro-Oral (VO) as well as the Pre-Lemniscal Radiations (PLR) are as efficient in suppressing tremor as the VIM but have lower occurrence of adverse effects. Volumetric analysis of spatial distribution of stimulation agreed with these results suggesting that the structures other than the VIM could also play a role in therapeutic effects of stimulation. The visualization of the adverse effect simulations clearly show the structures which could be responsible for such effects e.g. stimulation in the internal capsula induced pyramidal effects. These findings concur with the published literature. With regard to the improvement maps, the clinicians found them intuitive and easy to use to identify the optimal position for lead placement. If the maps were available during the surgery, the clinicians' choice of lead placement would have been different. Conclusion: This doctoral work has shown that modern techniques like quantitative symptom evaluation and electric field simulations can suppress the existing drawbacks of the DBS surgery. Furthermore, these methods along with 3D visualization of data can simplify tasks for clinicians of optimizing lead placement. Better placement of the DBS lead can potentially reduce adverse effects and increase battery life of implanted pulse generator, resulting in better therapy for patients

Free-living monitoring of Parkinson’s disease: lessons from the field

Wearable technology comprises miniaturized sensors (e.g. accelerometers) worn on the body and/or paired with mobile devices (e.g. smart phones) allowing continuous patient monitoring in unsupervised, habitual environments (termed free-living). Wearable technologies are revolutionising approaches to healthcare due to their utility, accessibility and affordability. They are positioned to transform Parkinson’s disease (PD) management through provision of individualised, comprehensive, and representative data. This is particularly relevant in PD where symptoms are often triggered by task and free-living environmental challenges that cannot be replicated with sufficient veracity elsewhere. This review concerns use of wearable technology in free-living environments for people with PD. It outlines the potential advantages of wearable technologies and evidence for these to accurately detect and measure clinically relevant features including motor symptoms, falls risk, freezing of gait, gait, functional mobility and physical activity. Technological limitations and challenges are highlighted and advances concerning broader aspects are discussed. Recommendations to overcome key challenges are made. To date there is no fully validated system to monitor clinical features or activities in free living environments. Robust accuracy and validity metrics for some features have been reported, and wearable technology may be used in these cases with a degree of confidence. Utility and acceptability appears reasonable, although testing has largely been informal. Key recommendations include adopting a multi-disciplinary approach for standardising definitions, protocols and outcomes. Robust validation of developed algorithms and sensor-based metrics is required along with testing of utility. These advances are required before widespread clinical adoption of wearable technology can be realise

Feasibility of diffusion and probabilistic white matter analysis in patients implanted with a deep brain stimulator.

Deep brain stimulation (DBS) for Parkinson\u27s disease (PD) is an established advanced therapy that produces therapeutic effects through high frequency stimulation. Although this therapeutic option leads to improved clinical outcomes, the mechanisms of the underlying efficacy of this treatment are not well understood. Therefore, investigation of DBS and its postoperative effects on brain architecture is of great interest. Diffusion weighted imaging (DWI) is an advanced imaging technique, which has the ability to estimate the structure of white matter fibers; however, clinical application of DWI after DBS implantation is challenging due to the strong susceptibility artifacts caused by implanted devices. This study aims to evaluate the feasibility of generating meaningful white matter reconstructions after DBS implantation; and to subsequently quantify the degree to which these tracts are affected by post-operative device-related artifacts. DWI was safely performed before and after implanting electrodes for DBS in 9 PD patients. Differences within each subject between pre- and post-implantation FA, MD, and RD values for 123 regions of interest (ROIs) were calculated. While differences were noted globally, they were larger in regions directly affected by the artifact. White matter tracts were generated from each ROI with probabilistic tractography, revealing significant differences in the reconstruction of several white matter structures after DBS. Tracts pertinent to PD, such as regions of the substantia nigra and nigrostriatal tracts, were largely unaffected. The aim of this study was to demonstrate the feasibility and clinical applicability of acquiring and processing DWI post-operatively in PD patients after DBS implantation. The presence of global differences provides an impetus for acquiring DWI shortly after implantation to establish a new baseline against which longitudinal changes in brain connectivity in DBS patients can be compared. Understanding that post-operative fiber tracking in patients is feasible on a clinically-relevant scale has significant implications for increasing our current understanding of the pathophysiology of movement disorders, and may provide insights into better defining the pathophysiology and therapeutic effects of DBS