Clinical Research Directory

Analysis of Cutaneous Phosphorylated Alpha-Synuclein to Identify Patients at Risk of Progressing From Essential Tremor to Parkinson's Disease

Background and Rationale Essential tremor (ET) affects over 6 million Americans and approximately 5% of adults over age 60. Patients with ET have a 10-20 times higher risk of developing Parkinson's disease (PD) compared to age-matched populations, with approximately 1% converting to PD annually. Post-mortem studies reveal Lewy body pathology in some ET patients, suggesting a subset may have prodromal PD. Current diagnostic tools (DaTscan, SYNTap) are either insufficiently sensitive for early disease, too expensive, or too invasive for routine screening. The Syn-One Test offers a minimally invasive approach to detect phosphorylated α-synuclein (P-SYN) pathology in skin biopsies. Primary Objectives 1. Identify which ET patients have P-SYN pathology indicative of prodromal PD 2. Predict which patients are most likely to phenoconvert to PD

Deep Brain Stimulation Surgery for Movement Disorders

Background: \- Deep brain stimulation (DBS) is an approved surgery for certain movement disorders, like Parkinson's disease, that do not respond well to other treatments. DBS uses a battery-powered device called a neurostimulator (like a pacemaker) that is placed under the skin in the chest. It is used to stimulate the areas of the brain that affect movement. Stimulating these areas helps to block the nerve signals that cause abnormal movements. Researchers also want to record the brain function of people with movement disorders during the surgery. Objectives: * To study how DBS surgery affects Parkinson s disease, dystonia, and tremor. * To obtain information on brain and nerve cell function during DBS surgery. Eligibility: \- People at least 18 years of age who have movement disorders, like Parkinson's disease, essential tremor, and dystonia. Design: * Researchers will screen patients with physical and neurological exams to decide whether they can have the surgery. Patients will also have a medical history, blood tests, imaging studies, and other tests. Before the surgery, participants will practice movement and memory tests. * During surgery, the stimulator will be placed to provide the right amount of stimulation for the brain. Patients will perform the movement and memory tests that they practiced earlier. * After surgery, participants will recover in the hospital. They will have a followup visit within 4 weeks to turn on and adjust the stimulator. The stimulator has to be programmed and adjusted over weeks to months to find the best settings. * Participants will return for followup visits at 1, 2, and 3 months after surgery. Researchers will test their movement, memory, and general quality of life. Each visit will last about 2 hours.

Effects of Microelectrode-based Brain Stimulation in Humans

The currently available treatments of Parkinson's disease (PD) and Essential Tremor (ET) are inadequate and accompanied by adverse side effects making the treatment much less effective. This includes treatments with pharmaceuticals as well as electrical brain stimulation (DBS; Deep Brain Stimulation). To address this challenge, we have systematically worked to identify and overcome the shortcomings with current brain stimulation. Essential has been to achieve an understanding of the mechanisms behind the ubiquitous tissue reactions (often referred to as "foreign body reactions"), with loss of nerve cells near implanted electrodes and how to accomplish minimal tissue reactions/damage, which is necessary to enable therapeutically efficient low-intensity stimulation at precise locations. A further challenge relates to individual differences at the level of neuronal networks, making the exact sites in the brain that cause therapeutic and adverse side effects when stimulated not known in advance and thus requiring individual determination. Our strategy has therefore been to develop highly biocompatible microelectrodes (thinner than a human hair and highly flexible) and a guiding investigational device for controlled insertion of a cluster of such microelectrodes in deep target tissue. This enables individualized selection of appropriate stimulation sites. This technique, termed by us "High Definition Brain Stimulation" (HDBS), proved remarkably successful in animal models of both Parkinson's disease and pain by reliably providing powerful symptom relief without noticeable adverse side effects. For this first in human (FIH) investigation of microelectrode-based brain stimulation, we have systematically minimized all identified and foreseeable risks through optimization of the microelectrodes, the design of the investigational device for HDBS and development of simple minimally invasive surgical insertion methods. Extensive monitored safety tests in animals have confirmed the picture of negligeable tissue reactions/damage and absence of bleeding in the target area. Biological safety is also ensured by using only well-established materials documented for chronic implantation in the brain, established sterilization methods, identified safe stimulation intensities, and that the insertion procedures are adapted to well-established precision neurosurgical instruments and routines. The study is an early (FIH) feasibility clinical investigation which will be conducted in up to 12 patients with Parkinson's disease and/or Essential Tremor who are already scheduled for implantation of established DBS. The HDBS device will be inserted into awake patients in the same track as planned for the established DBS electrode. The evaluation will follow a protocol that includes stimulation of predetermined subsets of microelectrodes at up to 4 predetermined levels (depth) in the brain. The stimulation intensity for each subgroup is gradually increased until either a therapeutic effect or an undesirable side effect has been achieved. If an unacceptable effect is elicited, stimulation is immediately interrupted and a new subset of electrodes will be tested. After completion of the evaluation, the HDBS cluster electrode is removed and the implantation of an established permanent DBS electrode is completed. The evaluation will take up to 2.5 hours per patient. The patient's verbal responses, gestures, changes (if any) in tremors, rigidity, speech ability (such as slurring) or facial expressions before, during and after stimulation will be linked to the stimulation parameters (stimulation intensity, subgroup of microelectrodes, depth in the brain and time of reaction) and documented in writing and through video recordings. The analysis will only be made on anonymized data. The primary objective of this early feasibility, FIH, clinical investigation is to clarify whether HDBS (High Definition Brain Stimulation), through individualized stimulation of appropriate subgroups of implanted biocompatible microelectrodes, can provide a powerful therapeutic effect with minimal negative side effects also in humans. In addition, it is intended to simultaneously obtain important information that can be used by the neurosurgeon to improve the subsequent placement of the already scheduled permanent DBS electrode in the individual patient and thereby improve the treatment. Consequently, the secondary objective is to clarify whether HDBS can be used by the neurosurgeon to improve the placement of a permanent DBS electrode. The project paves the way for permanent HDBS with completely new opportunities for powerful, sustainable therapy with minimal side-effects in Parkinson's disease, Essential Tremor and other intractable neurologic disorders. Moreover, the HDBS technology enables new and potent opportunities for brain research.

The Encora X1™ in a Real World Observational Study

This research is a post-market study designed to evaluate the long-term, real-world impact of the Encora X1™ on your daily life. The Encora X1™ is a FDA-cleared, wrist-worn, non-invasive neurostimulator device that delivers personalized mechanical stimulation to aid in the relief of hand tremors in adults with essential tremor. A non-invasive device is a device that stays outside of the body. It is not implanted and does not penetrate the skin. Neurostimulation means that the device uses targeted electrical or magnetic pulses to stimulate activity in the nervous system. This study aims to understand how it improves your ability to perform daily activities and your overall satisfaction with the device over a 36-month period. Your feedback will help researchers understand how the device is used over a long period of time in a home environment and improve the delivery of care for individuals with Essential Tremor.

Identifying Markers of Disease Subtypes and Disease Progression in the Syndrome of Essential Tremor

The goal of this observational study is to learn about epidemiology, biologic markers, disease subtypes and possible prognostic factors in essential tremor (ET) patients. The main question\[s\] it aims to answer are: * The prevalence of ET-plus compared to ET in a prospectively collected ET population. * To assess in detail the heterogenous group of ET patients using comprehensive clinical (motor and non-motor scales, questionnaires), imaging \[magnetic resonance imaging (MRI), sonography of substantia nigra and cerebral vessels\], neurophysiological (tremor analysis, digital spiral drawing) and laboratory markers (sGFAP, sNfL, routine laboratory parameters). * To assess possible non-invasive markers of neurodegeneration in ET patients (optic coherence tomography, alpha-synuclein in olfactory mucosa) Participants will be asked to undergo the above mention evaluation at baseline and at follow-up approx. 5 years later. Researchers will compare the findings within the ET group to independently existing cohorts of healthy controls and/or patients with other movement disorders like Parkinson's disease.

Tapping Test and the Archimedean Spiral for the Differential Diagnosis of Tremor. Machine Learning Approach

In clinical practice, it is sometimes difficult to establish whether a patient's tremor is due to Parkinson's disease or essential tremor. The distinction is crucial as the health implications differ significantly between the two conditions. Therefore, the present study aims to develop a diagnostic method based on machine learning techniques to help differentiate whether a patient's tremor is due to one condition or the other. To achieve this, 110 patients with tremor, correctly diagnosed with either Parkinson's disease or essential tremor, will participate. They will undergo two diagnostic tests (tapping test and Archimedean spiral) to capture data that can be processed using machine learning techniques.

RWE Study Utilizing the Cala Trio Device in Patients With Essential Tremor

The study objective is to evaluate hand tremor relief in the treated hand following stimulation with the Cala Trio Device in adults with essential tremor, and healthcare resource utilization and total healthcare costs over a 12-month period.

Stereotactic Radiosurgery in the Treatment of Essential Tremor

The goal of this interventional study is to evaluate the effectiveness of treatment using stereotactic radiosurgery in the treatment of essential tremor in adult patients

Coordinated Reset Deep Brain Stimulation for Essential Tremor

Deep brain stimulation (DBS) is a surgical procedure for the treatment of Essential Tremor (ET). A novel approach to current DBS approaches is called coordinated reset DBS (CR-DBS) which uses different patterns of stimulation at lower currents and can address the limitations of traditional DBS that uses continuous high amplitude, high frequency stimulation. This study will evaluate the feasibility, safety and short-term efficacy of thalamic CR-DBS in upper extremity ET. The goal of this study is to evaluate the safety and short-term efficacy of thalamic CR- DBS in ET, including the acute (during CR-DBS) and carryover (following DBS cessation) effects, and compare these to those induced by clinically optimized T-DBS. To achieve our goal, a low-risk, two-phase clinical study will be conducted in patients with upper extremity (UE) ET. The first aim is to identify the spatial location and peak frequency of tremor related oscillatory activities in VIM (Phase I). The second aim is to compare the acute effects of thalamic CR-DBS to clinically optimized T-DBS (Phase II).

Boston Scientific Registry of Deep Brain Stimulation for Treatment of Essential Tremor (ET)

To compile characteristics of real-world outcomes for Boston Scientific Corporation's commercially approved Deep Brain Stimulation (DBS) Systems, when used according to the applicable Directions for Use, for the treatment of Essential Tremor.

Radiofrequency (RF) Ablation Prospective Outcomes Study for Central Nervous System - RAPID for CNS

The objective of this study is to compile real-world outcomes of Boston Scientific commercially approved radiofrequency (RF) ablation systems used in the central nervous system (CNS) for use in functional neurosurgery.

Intraoperative Microelectrode Recordings Using MAVEN Compared to Standard Recording Apparatuses

The purpose of this research is to determine if the electrophysiologic data collected from standard-of-care microelectrode recordings during human deep brain stimulation (DBS) surgery will be the same using the MAVEN device compared with the standard Alpha Omega device with either a tungsten standard-of-care microelectrode (for microelectrode recordings), or a carbon-fiber microelectrode (for neurotransmitter recordings). The number of microelectrodes used for both the tungsten and the carbon-fiber version will be the same as the standard-of-care.

Deep Brain Stimulation (DBS) Retrospective Outcomes Study

The primary objective of this study is to characterize real-world clinical outcomes of Deep Brain Stimulation (DBS) using retrospective review of de-identified patient records.

Essential 3 - Decentralized, Phase 3 Study Evaluating the Safety and Efficacy of Ulixacaltamide in Essential Tremor (ET)

The goal of this clinical study is to compare ulixacaltamide and placebo treatment in essential tremor. The main question it aims to answer is: • Is ulixacaltamide a safe and efficacious treatment for patients with essential tremor? Participants will be asked to participate in one of two clinical studies where they will be treated with either ulixacaltamide or placebo for a period of up to 12 weeks. After the controlled study completion, they will be eligible to participate in a long-term, open-label safety study (LTSS) and be treated with ulixacaltamide. Participants are eligible to enroll directly into the LTSS if they previously participated in an essential tremor trial, received sponsor invitation after being deemed ineligible for the controlled study, or following enrollment closure of the controlled study.

A Study of Wearable Device in Essential Tremor Patients

The purpose of this research is to observe the daily loss of benefit from DBS therapy by performing a standardized set of tasks throughout the day while wearing an Apple Watch to collect movement and other physiological data.

Motor Network Physiology

The brain networks controlling movement are complex, involving multiple areas of the brain. Some neurological disorders, like Parkinson's disease (PD) and essential tremor (ET), cause abnormalities in these brain networks. Deep brain stimulation is a treatment that is used to treat these types of neurological diseases and is thought to help patients by modulating brain networks responsible for movement. Levodopa medication is also used to modulate this brain networks in patients with PD. The overall objective is to develop a unified theory of basal ganglia thalamocortical (BGTC) circuit dynamics that accounts for disease symptomatology, movement, and their inter-relationship. The underlying hypothesis, is that the rigidity and bradykinesia of PD are fundamentally related to excessive functional coupling across nodes in the BGTC motor circuit impeding effective information flow. In this research, the investigator will take advantage of the unique opportunity provided by awake deep brain stimulation surgery to learn more about how the brain functions in a diseased state and how deep brain stimulation changes these networks to make movement more normal. The investigator will simultaneously assess cortical and subcortical electrophysiology in relation to clinical symptoms and behavioral measures and in response to deep brain stimulation, cortical stimulation, and pharmacologic therapy in patients undergoing Deep Brain Stimulation (DBS) implantation surgery.

Magnetoencephalography (MEG) Pilot Study

The purpose of this research is to learn more about how the brain works in people with essential tremor, and how it changes after treatment with High-Intensity Focused Ultrasound (HiFU). Essential tremor is a movement disorder that causes shaking, usually in the hands, and can make everyday tasks difficult. HiFU is a treatment that uses focused sound waves to target a small area in the brain involved in tremor. In this study, the investigators aim to understand how this treatment affects the brain's networks by using safe, non-invasive tests such as brain imaging, brain wave recordings, and movement assessments.

The Efficacy of Aldehyde Dehydrogenase Enzyme in Essential Tremor Patients: A Single-Center Study

This is a sponsor-initiated, single-arm, single-center clinical trial designed to evaluate the efficacy and safety of an ALDH-containing food supplement (PICOZYME ET) in patients with Essential Tremor (ET). Participants will consume the investigational product daily for three months, and clinical outcomes will be assessed using the Clinical Rating Scale for Tremor (CRST) and the Activities of Daily Living (ADL) scale. Additional exploratory analyses will evaluate changes in metabolic biomarkers and brain function via imaging and blood tests.

Elucidating the Temporality of Structural and Functional Connectivity Changes in Essential Tremor After Successful Deep Brain Stimulation to the Dentato-rubro-thalamic Tract

The purpose of this study is to elucidate the structural connectivity of the dentato-rubro-thalamic tract (DRTt) and to detect functional network changes due to DRTt stimulation

Clinical and Physiological Studies of Tremor Syndromes

Background: Researchers have some data on how the brain controls movement and why some people have tremor. But the causes of tremor are not fully known. Researchers want to study people with tremor to learn about changes in the brain and possible causes of tremor. Objective: To better understand how the brain controls movement, learn more about tremor, and train movement disorder specialists. Eligibility: People ages 18 and older with a diagnosed tremor syndrome Healthy volunteers ages 18 and older Design: Participants will be screened with: * Medical history * Physical exam * Urine tests * Clinical rating scales * Health questions * They may have electromyography (EMG) or accelerometry. Sensors or electrodes taped to the skin measure movement. Participation lasts up to 1 year. Some participants will have a visit to examine their tremor more. They may have rating scales, EMG, and drawing and writing tests. Participants will be in 1 or more substudies. These will require up to 7 visits. Visits could include the following: * EMG with accelerometry * Small electrodes taped on the body give small electric shocks that stimulate nerves. * MRI: Participants lie on a table that slides into a cylinder that takes pictures of the body while they do simple tasks. * Small electrodes on the scalp record brain waves. * A cone with detectors on the head measures brain activity while participants do tasks. * A wire coil held on the scalp gives an electrical current that affects brain activity. * Tests for thinking, memory, smell, hearing, or vision * Electrodes on the head give a weak electrical current that affects brain activity. * Photographs or videos of movement Participant data may be shared with other researchers.

Stereotactic Radiosurgery for Essential Tremor and Parkinsonian Tremor

The purpose of this study is to determine the changes in quality of life and degree of tremor for patients with essential tremor or Parkinsonian tremor who are treated by stereotactic radiosurgery (SRS). This is a questionnaire-based study. Please see Detailed Description below for more information.

Neurofeedback Using Implanted Deep Brain Stimulation Electrodes

Deep brain stimulation (DBS) has become a gold-standard symptomatic treatment option for Parkinson's disease (PD) and is also explored for a variety of other neurological disorders. The implantation of electrodes into deep brain areas has not only enabled the application of electrical stimuli, but has also provided researchers and clinicians with an unprecedented window to investigate aberrant neuronal activity right at the core of pathological brain circuits. Local field potentials (LFP) have already been readily investigated through externalised DBS electrode wires prior to internalisation and connection to an implantable neurostimulator. In the case of PD, motor symptoms have been evidenced to correlate with exaggerated beta oscillatory activity (13-35 Hz) in the LFP recorded from the subthalamic nucleus (STN). Firstly, beta activity recorded in the STN at rest in patients withdrawn from their medication has been correlated with the Unified Parkinson's Disease Rating Scale (UPDRS) across patients. Secondly, a reduction of signal power in the beta-band was correlated with clinical improvements of motor symptoms. Thirdly, the two main therapeutic strategies, the administration of L-Dopa, and high-frequency DBS both lead to a suppression of beta-synchronicity in the STN. Furthermore, beta-oscillations show fast and movement-dependent modulation over time and can serve as a biomarker and feedback signal to control the delivery of DBS. The investigators recently implemented deep brain electrical neurofeedback to provide real-time visual neurofeedback of pathological STN oscillations through externalised DBS electrodes and showed that PD patients were able to volitionally control and reduce subthalamic activity within a single 1 hour session. Moreover, neurofeedback-learnt strategies accelerated movements and could be retained in the short- and mid-term. Only recently, a newly developed neurostimulator, the Percept™ PC (Medtronic Neurological Division, Minneapolis, MN, USA), has been clinically approved, which can not only apply electrical impulses, but also enable the measurement and transmission of brain activity. This neurostimulator is now the first choice for implantations at the University Hospital Zurich and is used for a variety of neurological disorders. The investigators' goal is to investigate whether neurofeedback through a fully implanted deep brain stimulation device is possible and can lead to a better control of pathological oscillations as well as symptom mitigation. Having shown that endogenous control over deep brain oscillations is possible, the investigators will also test this novel therapeutic approach for pathologies other than PD that are also treated with DBS. Neurofeedback using implanted DBS electrodes will have the advantage of enabling longer and multiple-day training sessions, which the investigators hypothesise to have a larger impact on control over pathological deep brain oscillations and neurological symptoms, as such a fully implanted neurofeedback system no longer requires the externalisation of DBS wires and is as such no longer limited to the first two days after electrode implantation. All in all, the investigators will not exceed a total streaming time of 7 hours per patients (7 d of battery time), which the investigators deem justifiable with respect to a battery life of \> 5 years. This proposed research is highly significant as it will help our understanding of various neurological diseases that are highly prevalent in society (PD being, for instance, the second most common neurodegenerative disorder after Alzheimer's disease) and might culminate in novel, endogenous treatment strategies. The overall risk for patients is minimal to non-existent, as stimulation parameters are unaffected and the intended changes in brain activity are self-induced while DBS stimulation is off.

3-D Tractography FUS Ablation for Essential Tremor

The investigators propose to advance Vim-FUSA (Ventral Intermediate Nucleus - Focused Ultrasound Ablation) with the support of 3-D tractography, a neuroimaging technique to visually represent nerve tracts within the brain. The investigators hypothesize that 3-D tractography Vim-FUSA will improve the Vim ablation compared to standard Vim-FUSA and prove safe and feasible in the clinical setting. The investigators also hypothesize that intraoperative magnetic resonance (i-MR) monitoring will differentiate ablated tissue from immediate perilesional edema and accurately predict the Vim-FUSA clinical outcomes.

Physiology, Imaging and Modeling of Essential Tremor

This project aims to investigate novel ways to deliver brain stimulation to Essential Tremor (ET) patients by introducing software changes to their existing devices. The study team aims to investigate safety and efficacy of these new stimulation parameters in patients with ET.