Clinical Research Directory

Passive Versus Active Music Therapy Parkinson's Disease

The purpose of this pilot study is to identify the effects of active versus passive music therapy on functional ability and psychophysiological responses to goal-directed exercise in people with Parkinson's disease.

Probing Gut-Brain Communication in Parkinson's Disease

Administering transcutaneous vagus nerve stimulation in patients with Parkinson's disease to see how it affects stomach and brain activity.

Real-world Patient Experiences With Inbrija®

Parkinson's disease can cause OFF episodes, when medication effects wear off and symptoms return, affecting movement, daily activities, comfort, and wellbeing. This study aims to explore the experiences of people with Parkinson's disease who are prescribed Inbrija® as part of their usual care. Through a mixed-methods approach, the study will examine how OFF episodes affect patients, what influences their decision to use Inbrija®, and whether patient-reported outcomes related to symptoms, daily functioning, and quality of life change during the first 3 months of treatment. The study is planned to be conducted at approximately 7 sites in Austria, Germany, and Sweden and will enroll up to 120 participants receiving Inbrija® in routine clinical practice.

Artificial Intelligence-based Parkinson's Disease Risk Assessment (AI-PRA) Study

The study aims to provide initial proof-of-concept validation data of an artificial intelligence-based model to estimate individual Parkinson's disease risk using demographic, clinical, genetic information and digital biomarker data collected via a smartwatch and a mobile application.

Bayesian Optimization of DBS for Gait

This project aims to establish the feasibility of Bayesian optimization for tuning deep brain stimulation (DBS) to treat gait symptoms in Parkinson's disease (PD) patients. Our primary question is: Can Bayesian optimization of DBS achieve reproducible results within a feasible number of gait measurements? PD patients will be enrolled who have DBS of the subthalamic nucleus (STN) or globus pallidus (GP) in whom at least 3 months have passed since activation of their neurostimulators, for stabilization of clinical stimulator settings. We will apply Bayesian optimization to derive DBS settings which maximally lengthen step length relative to the OFF DBS state.

Acute Effects of Capacitive-Resistive Radiofrequency Therapy in People With Parkinson's Disease

This study will investigate the immediate and short-term effects of capacitive-resistive radiofrequency therapy (TECAR) applied to the lower limbs in people with Parkinson's disease. The main aim is to determine which of four different TECAR application protocols produces the greatest improvement in muscle stiffness and walking function. Twenty participants with Parkinson's disease will receive four different TECAR protocols in four separate sessions. The protocols will include capacitive treatment, resistive treatment, and two combinations of capacitive and resistive treatment. Each participant will receive all four protocols, and the order in which they are applied will be randomized. Sessions will be separated by a 7-day washout period. Muscle stiffness will be measured using the MyotonPRO device. Walking and functional mobility will also be assessed using the Timed Up and Go test and the 10-Metre Walk Test. Joint range of motion and lower-limb musculoskeletal pain will also be evaluated. Measurements will be performed immediately before treatment, immediately after treatment, and 48 hours after each session. The study will also record any discomfort or adverse events associated with TECAR therapy to evaluate the safety and tolerability of the different treatment protocols.

GBPDC: Gut-Brain in PD Consortium Master Protocol

The purpose of this research study is to identify the role that the gut-brain axis, the group of nerves that connect the brain and gut, plays in Parkinson's disease (PD). The National Institute of Diabetes and Digestive and Kidney Diseases is sponsoring this research study. During this study, specific groups of participants, also known as "cohorts", will be identified based on the severity of their PD. There will also be a cohort enrolling participants who do not have Parkinson's and a cohort enrolling participants that are at risk for developing PD. Each of these cohorts will be compared to the others to assess the differences in the gut-brain connection. Participants in this study will: * meet with a medical provider * answer questionnaires * give samples of blood, stool, and saliva * have X-rays taken while swallowing different foods (swallowing study) * have X-rays taken to see how long it takes markers to move through their colon (colon transit study) * have a flexible sigmoidoscopy, where a doctor looks inside the lower part of the colon and takes small tissue samples (biopsies) from the mucosa (lining) * have samples taken of their skin * have an anorectal manometry and a balloon expulsion test, where a small tube and balloon are placed in the rectum to measure muscle function. Participation in the study will last up to 24 months (2 years).

Assessment of the Safety, Immunogenicity, and Pharmacodynamics of TRB-001 in Patients With Early Idiopathic Parkinson's Disease

This is a randomized, placebo-controlled, double-blind, dose-finding phase 1b study with the purpose to assess the safety, immunogenicity and pharmacodynamics of TRB-001 in early idiopathic Parkinson's Disease patients.

Effects of Repetitive Transcranial Magnetic Stimulation (rTMS)-Primed Self-controlled Practice in People With Parkinson's Disease

Parkinson's disease (PD) is commonly associated with impaired motor learning and reduced motivation, both of which can negatively influence rehabilitation outcomes. Prior cross-sectional evidence suggests that providing individuals with PD self-controlled access to training parameters enhances motor learning, increases motivation, and facilitates cognitive processing. However, the effects of self-controlled practice implemented across repeated training sessions remain underexplored. Moreover, given that dysfunction of fronto-striatal circuits in PD may limit the neuroplastic response to motor training alone, adjunctive neuromodulatory priming approaches such as repetitive transcranial magnetic stimulation (rTMS) may be required to optimize therapeutic efficacy. To date, it remains unclear whether rTMS priming combined with self-controlled motor training yields superior clinical benefits, and whether stimulation of different cortical targets produces differential effects. In particular, the dorsolateral prefrontal cortex (DLPFC), a key region involved in cognitive control and motivation, may offer distinct therapeutic effects compared with stimulation of the primary motor cortex (M1). This study aims to investigate the effects of rTMS priming over the DLPFC or M1, followed by self-controlled motor training, in individuals with PD, and to compare these effects with a sham stimulation condition. This single-blinded, randomized control trial will recruit 90 individuals with PD, who will be matched into 45 pairs and randomly assigned to one of three stimulation conditions: DLPFC, M1, or sham. Within each pair, one participant will be allocated to a self-controlled practice condition, and the other to a yoked (paired-control) condition that receives identical training content determined by their matched counterpart. Each participant will undergo 12 intervention sessions. In each session, rTMS will be applied first as a priming intervention, followed immediately by 45 minutes of standardized physical therapy-based motor training. For the DLPFC group, stimulation will target the left DLPFC; for the M1 group, stimulation will be applied over the M1 contralateral to the more affected limb; and for the sham condition, the coil will be rotated 90 degrees to mimic stimulation without effective cortical activation. During the training phase, participants in the self-controlled condition will be allowed to select aspects of their practice content, whereas yoked participants will follow the corresponding selections made by their matched partner. The primary outcome measure is the Unified Parkinson's Disease Rating Scale (UPDRS). Secondary outcomes include assessments of cognitive function, apathy, non-motor symptoms, gait performance, balance, functional mobility, falls efficacy, and quality of life. Neurophysiological outcomes will be assessed using single- and paired-pulse TMS to evaluate corticospinal excitability and cortico-cortical connectivity, particularly between DLPFC and M1 networks. All assessments will be conducted in the medication-on state by blinded evaluators at baseline, immediately post-intervention, and at one-month follow-up. Data will be analyzed using mixed-effects repeated-measures ANOVA to examine group-by-time interactions and intervention effects. This study seeks to determine whether rTMS priming over cognitive-control versus motor networks differentially enhances the efficacy of self-controlled motor training, and whether such combined interventions can induce sustained improvements in motor and non-motor outcomes in PD.

MRI-Guided Temporal Interference Stimulation for Parkinson's Disease

This study aims to evaluate the efficacy and safety of tTIS treatment in patients with Parkinson's disease (PD). The study will enroll eligible PD patients and randomly assign them to two groups: Group A will first receive combined GPi and STN stimulation, followed by GPi stimulation one week later; Group B will first receive GPi stimulation, followed by combined GPi and STN stimulation one week later. The MDS-UPDRS Part III will be assessed at pre-stimulation baseline, immediately after stimulation, and at 30 and 60 minutes post-stimulation for each session, in order to evaluate and compare the therapeutic effects of tTIS targeting GPi alone versus combined GPi and STN stimulation on motor symptoms in PD patients, and to assess the differential efficacy of tTIS at different targets among PD patients with varying symptoms.

Digital Patient Engagement in Technology-Supported Neurorehabilitation

The goal of this observational study is to investigate digital patient engagement and its psychosocial correlates and potential predictors among adults aged 18-85 years with neurological disorders who are undergoing technology-supported neurorehabilitation using robotic systems for upper-limb training and/or virtual reality-based technologies. Specifically, the study will examine the roles of hope and the quality of the patient-healthcare professional relationship as the potential predictors of engagement with rehabilitation technologies. It will also explore the contribution of disease-management self-efficacy, technology anxiety, and sociodemographic, clinical, functional, and rehabilitation-related characteristics. Finally, the study will examine whether digital patient engagement predicts the perceived psychosocial impact of rehabilitation technologies, behavioural intention to continue using them, and overall satisfaction with the rehabilitation pathway. Participants will: * continue their standard neurorehabilitation pathway without any modification to routine clinical procedures; * complete a computerized self-report questionnaire via the Qualtrics digital platform at a single time point after completing at least three rehabilitation sessions using the technologies under study. No experimental intervention, comparison group, or follow-up assessment is planned.

Comparison of Benzhexol and Procyclidine for Tremor in Tremor-Predominant Parkinson's Disease

The goal of this clinical trial is to compare benzhexol and procyclidine for improving tremor in adults with tremor-predominant Parkinson's disease who are taking levodopa. Researchers will compare the two medicines to determine whether benzhexol provides similar improvement in tremor to procyclidine and to assess their side effects. Participants will be randomly assigned to receive either benzhexol or procyclidine in addition to their usual levodopa treatment. Motor symptoms and side effects will be assessed before treatment and at 2 weeks, 3 months, and 6 months.

Synthetic Vasomotion for Glymphatic Enhancement

The goal of this pilot clinical trial is to learn whether a week-long study combining controlled breathing procedures, intermittent exposure to a low-concentration carbon dioxide gas mixture, and noninvasive vagus nerve stimulation can be carried out safely and comfortably in adults with early-stage Parkinson's disease and age-matched healthy adults. The study will also explore how these procedures affect physiological signals related to breathing, cardiovascular and autonomic function, brain activity, and physiological processes thought to be related to fluid movement in and around the brain. The main questions the study aims to answer are: * Can participants safely and comfortably complete the study procedures and at-home monitoring? * Do physiological responses differ when intermittent hypercapnia is paired with active noninvasive vagus nerve stimulation compared with sham stimulation? * Are changes measured during the intervention visits related to overnight physiological measurements and changes in blood-based biomarkers? Researchers will compare active and sham noninvasive vagus nerve stimulation within the same participants. Both conditions will be paired with guided breathing and intermittent hypercapnia, in which participants briefly breathe a controlled gas mixture containing 5% carbon dioxide. Participants will: * Complete an intake and baseline visit and several nights of at-home physiological monitoring. * Complete two intervention visits in randomized order, one using active vagus nerve stimulation and one using sham stimulation. * Complete guided breathing and intermittent hypercapnia procedures while respiratory, cardiovascular, and other physiological signals are monitored. * Provide blood samples before and after intervention procedures for exploratory biomarker measurements. This is an exploratory pilot study. It is not intended to diagnose, treat, or prevent Parkinson's disease or any other medical condition.

Idiopathic Parkinson's Disease: Interest of an Early Group-Based Cognitive Rehabilitation Program (LIFECOG-PD)

Current pharmacological treatments have not demonstrated significant improvement in cognitive impairment in Parkinson's disease (PD). Given the high prevalence and serious impact of cognitive impairment in PD, there is a pressing need for non-pharmacological interventions with demonstrated functional benefits. Cognitive rehabilitation is a structured program designed to help improve or compensate for patients' cognitive abilities by providing an approach tailored to each patient's individual needs and goals. Neuropsychologists from French Parkinson's Disease expert centers have developed a new cognitive rehabilitation program called LifeCOG-PD, for PD patients with a subjective cognitive complaint or a mild cognitive impairment (MCI), delivered at the hospital in seven 90-minute sessions conducted in groups of 3-4 participants. This program, combining psychoeducation, practical strategies, and personalized goal setting, aims to maintain patients' daily autonomy, enhance quality of life, and delay the cognitive impact of the disease. By evaluating feasibility, acceptability and functional outcomes, this study will contribute critical data to inform future PD management guidelines to help support autonomy and cognitive resilience in PD.

Effect of Motor Imagery Added to Rehabilitation on Balance and Kinesiophobia in Patients With Parkinson's Disease

Parkinson's Disease (PD) is a progressive brain disorder that affects movement and balance. It can cause slowed movements, stiffness, tremor, balance problems, and an increased risk of falling. Many individuals with PD develop fear of movement, also referred to as kinesiophobia, and fear of falling. This condition may lead to avoidance of physical activity, which can further worsen balance and movement abilities. This study aims to determine whether adding Motor Imagery (MI) to a standard rehabilitation program can improve balance and reduce fear of movement in individuals with PD. MI is a mental practice technique in which an individual rehearses movements cognitively without actual physical execution. For example, a person may imagine standing up, walking, or climbing stairs. Although the movement is not physically performed, the brain regions involved in movement are activated. MI is safe, does not require special equipment, and may help improve motor control. Eligible participants will be randomly assigned to one of two groups. One group will receive standard physical therapy and rehabilitation exercises, while the other group will receive the same therapy combined with additional MI training. The rehabilitation program will last six weeks. The study will primarily evaluate whether this combined approach improves balance and reduces fear of movement. In addition, the potential effects of the intervention on fall risk, functional mobility and performance, fear of falling, activities of daily living, and motor function will also be examined. Assessments will be performed at the beginning of the study, at the end of treatment, and again at 12 weeks. Researchers hope to determine whether combining MI with conventional rehabilitation provides greater benefits than conventional rehabilitation alone and may help improve rehabilitation strategies for people living with PD.

Evaluation of the Effects of Levodopa-Benserazide Drug Combination on Periodontal Status in Patients With Parkinson's Disease

The aim of this study is to evaluate the effects of Levodopa-Benserazide drug combination on periodontal status and salivary cytokine levels in patients with Parkinson's disease. The study includes four groups: Parkinson's patients with periodontitis, periodontally healthy Parkinson's patients, participants without Parkinson's with periodontitis, and periodontally healthy participants without Parkinson's. Clinical periodontal parameters (Plaque Index, Gingival Index, Bleeding on Probing, Pocket Depth, and Clinical Attachment Loss) will be recorded. Unstimulated saliva samples will be collected to analyze the levels of TNF-alpha, RANTES, IL-10, IL-13, Total Oxidant Status (TOS), Total Antioxidant Status (TAS), and Malondialdehyde (MDA).

VG081821AC Tablets for Early to Mid-stage Parkinson's Disease

This study is testing a new oral medication called VG081821AC to see if it can help improve movement symptoms in people with early to mid-stage Parkinson's disease. VG081821AC works by blocking a protein in the brain called the adenosine A2A receptor, which may help improve motor function without using levodopa. The main goal is to measure changes in movement symptoms using a standard rating scale called the MDS-UPDRS Part III (Motor Examination). This scale evaluates how well participants can move, walk, and perform daily activities. The study will compare the scores before and after 12 weeks of treatment to see if VG081821AC improves movement symptoms better than the placebo. Currently, levodopa is the most common treatment for Parkinson's disease, but it can cause side effects over time. If VG081821AC works well, it could offer a new treatment option for people in the early to mid-stages of Parkinson's disease who want to delay or avoid starting levodopa. A total of 152 adults (aged 18-80 years) will be enrolled in this trial in China. Participants will be randomly assigned (like flipping a coin) to one of four groups: * VG081821AC 25 mg (taken twice daily) * VG081821AC 50 mg (taken twice daily) * VG081821AC 75 mg (taken twice daily) * Placebo (a pill with no active drug, taken twice daily) Participants will visit the study center 8 times to have their movement symptoms, safety, and overall health checked.

Anodic Stimulation in Parkinson's Disease

Randomized, double-blind, crossover design, interventional study to assess the differences between mixed cathodic/anodic, pure cathodic, and pure anodic stimulation with respect to efficacy, side effect thresholds, symptom control, and quality of life in Parkinson's Disease patients implanted with Boston Scientific Cartesia directional DBS leads in the bilateral STN.

Sensor-Based Optimization of Therapy for Parkinson's Disease Patients With Motor Fluctuations

Although numerous tools have been developed in recent years with the enhancement of new technologies precision and the reduction of their size, still few medical devices are used in clinical routine in Parkinson's Disease. Knowledge about Parkinson's Disease motor symptoms has been widely improved especially thanks to objective monitoring of movements. However, patients are mostly observed in defined environment during scripted activities, which is per se distinct from the real life conditions. Besides, experts may agree on the limitations of the diary that is supposed to reflect the patient's status at home, while outpatients' visits may also not correctly enable the neurologist to catch up the everyday life condition of the patient. In order to overcome some of these issues, we hypothesize that the implementation of body-worn sensors at home monitoring could provide promising solutions. Yet, important information is missing: there is no previous randomized trial studying the additional value of body-worn sensors to improve motor symptoms, quality of life and ability to perform everyday life activities for example. To our knowledge, our study proposal is the first one to adjust therapy of patients with Parkinson's Disease based on the reports of body-worn sensors monitoring. If the efficacy and reliability of at home monitoring with sensors is proven, new healthcare guidelines could arise with the objective of a better and continuous patient's follow-up, remotely from the outpatient's visit.

Effects of a Multicomponent Protocol With Emphasis on Muscle Power Training on Bradykinesia in Individuals With Parkinson's Disease

Parkinson's disease (PD) is a chronic progressive neurological disorder that involves both motor and non-motor symptoms, culminating in functional decline and disability. One of the main symptoms of PD is bradykinesia and its deleterious effect on functionality. Muscle weakness has also been reported as an important symptom of PD, and muscle power may be even more affected and related to these symptoms. Typical conventional physical therapy treatment includes mobility exercises, strength training, gait training, and balance training, and it presents numerous benefits associated with the reduction of motor symptoms of PD. Physical therapy with power training has also been studied as an alternative to improve the ability to perform activities of daily living in other populations. However, the literature that includes power training in physiotherapeutic approaches for people with PD is scarce. Power training may minimize the problems arising from changes in motor function in older adults with PD; however, there is still a lack of evidence using this modality in the different subtypes of the disease. Knowing that motor function is associated with functional capacity and disease severity, physical therapy becomes an important treatment resource with exercises to improve muscle power. Therefore, the objective of this study is to investigate the effect of a multicomponent protocol with an emphasis on muscle power training concerning bradykinesia in individuals with rigid-akinetic type PD. A Randomized Clinical Trial will be conducted, in which individuals diagnosed with Parkinson's disease, rigid-akinetic type, classified from 1 to 3 on the Hoehn and Yahr Scale, aged between 50 and 85 years, and who sign the Informed Consent Form will participate. The individuals will be randomized into two treatment groups: G1 - traditional multicomponent training, G2 - multicomponent training with an emphasis on muscle power and G3 - control group. Assessments will be conducted at four time points for all participants: before (T0), during (T1 - 6 weeks), immediately after intervention (T3 - 12 weeks), and follow-up (T4 - 16 weeks). The assessments will consist of the analysis of: 1) motor function through the adapted Unified Parkinson's Disease Rating Scale (UPDRS III) (bradykinesia as the primary outcome); 2) mobility of the posterior chain of the trunk and lower limbs using the Wells Bench; 3) body composition by Dual-Energy X-ray Absorptiometry (DXA); 4) rigidity of the leg extensor muscles assessed by ultrasound elastography; 5) muscle power of knee extensors using a linear potentiometer (Peak Power, CEFISE); 6) functional capacity through the CounterMovement Jump - CMJ and the Sit-to-Stand Five Times Test (TSLCV); and 7) postural assessment using the NeuroPostureApp. Treatment sessions will occur twice a week for 12 weeks, lasting 60 minutes each, totaling 24 sessions for each intervention. Group 1 will perform an exercise protocol that includes warm-up, mobility, muscle strength, and flexibility. Group 2 will perform the same exercise protocol, with the caveat that, whenever feasible, exercises will be executed in the muscle power modality (at the highest possible speed). This latter training is characterized by a lower number of repetitions and a higher movement speed, guided by the therapists assisting. The progression of muscle power exercises will occur at 35%, 40%, 45%, 50%, 55%, and 60% of 1RM over the 12 weeks, distributed in 2 sets of 6 to 8 repetitions, with rest times of 60 to 120 seconds. Group 3 will undergo a protocol similar to traditional physiotherapy, without 1RM-based intensity control, periodization, or systematic load progression as applied in the other groups. Load and exercise progression will be adjusted subjectively based on the physiotherapist's clinical judgment and the participant's perceived exertion. Assessments will occur at the same time points (T0, T1, T2, and T3), and the same exercises will be performed, but intensity and exercise difficulty progression will be controlled subjectively.

Safinamide vs Placebo for Pain in Patients With Parkinson's Disease and Motor Fluctuations

This is a Phase III, single-center, randomized, double-blind, placebo-controlled clinical trial designed to investigate the superiority of safinamide compared to a placebo in reducing Parkinson's Disease (PD)-related pain. The trial plans to enroll 60 adult patients diagnosed with PD who experience motor fluctuations and chronic pain (lasting more than 3 months) despite receiving stable doses of levodopa. Participants will be randomized in a 1:1 ratio to receive either oral safinamide or a matching placebo as an add-on therapy. The treatment regimen consists of 50 mg/day for the first week, increasing to 100 mg/day for the remaining 11 weeks, for a total treatment duration of 12 weeks. The primary endpoint is to evaluate the mean change in pain severity from baseline to 12 weeks, measured using the 11-point Numeric Rating Scale (NRS) Secondary endpoints will assess additional qualitative and quantitative pain characteristics (KPPS, BPI, PD-PCS), motor symptoms and treatment complications (UPDRS Parts III and IV, Home Diary), quality of life (PDQ-39), and other non-motor symptoms (MDS-NMS). The total expected duration of the clinical trial is 24 months.

Daily Amino Acid Supplementation for People With Parkinson's Disease

The goal of this clinical trial is to learn if a tailored amino acid supplement works to help adults living with Parkinson's disease to improve nutrition, metabolic function, body composition, and physical and mental function. The main questions it aims to answer are: Does the tailored amino acid supplement increase essential amino acids (nutritional status)? Does the tailored amino acid supplement increase an antioxidant (complex amino acid) and decrease an amino acid associated with oxidative stress? Does the tailored amino acid supplement improve physical and mental health compared to a placebo supplement? Researchers will compare the tailored amino acid supplement to a placebo (a look-alike substance that contains no active ingredients) to see if the tailored amino acid supplements work to support health for people with Parkinson's disease. Participants will: Take the tailored amino acid supplement or a placebo every day for 6 months, visit the lab at baseline, after 3 months, and after 6 months for fasting blood draws, body composition assessment, and physical and mental health testing and keep a diary of their food intake and supplement intake.

NEO-REEDUC - Mixed Reality for Motor Rehabilitation: a Prospective, Multicenter, Controlled, Randomized, Open Study.

This study aims to assess the effectiveness of a motor rehabilitation protocol that includes mixed reality activities, compared to conventional rehabilitation, on postural stability in children and adult patients with neurological impairments.

Different Frequency Temporal Interference Stimulation on Bilateral Subthalamic Nucleus for Parkinson's Disease

This clinical trial will evaluate the efficacy of accelerated Temporal Interference Stimulation (TIS) as a therapeutic intervention for individuals diagnosed with Parkinson's disease. Different frequency TIS will be delivered targeting the bilateral subthalamic nuclei of the brain according to the patient's clinical symptoms. Specifically, the basal thalamic nuclei on the side opposite to the side where the patient's symptoms are most severe receive stimulation at 130 Hz, whilst those on the other side receive stimulation at 60 Hz. The primary objective is to assess whether accelerated TIS yields measurable improvements in motor performance and verbal speech function among enrolled subjects. Functional magnetic resonance imaging (fMRI) will be adopted as an auxiliary imaging modality to objectively characterize underlying cerebral functional alterations induced by accelerated TIS intervention. The core scientific research questions to be addressed in this trial are listed as follows: Will different frequency accelerated TIS administered to the bilateral subthalamic nuclei produce significant improvements in motor function and cognitive function among enrolled subjects with Parkinson-related disorders? What quantitative and qualitative modifications in cerebral functional activity will be detected via fMRI after standardized accelerated TIS intervention administration? Investigators will implement a two-arm parallel controlled comparative design for all enrolled eligible subjects. This design remains a parallel design, with two independent groups of subjects receiving different active interventions simultaneously rather than a sham control. All confirmed Parkinson's disease patients will undergo standardized random grouping and be allocated into two independent research arms. Subjects in the experimental arm will receive continuous, standardized TIS intervention targeting bilateral subthalamic nuclei, with the basal thalamic nuclei on the side opposite to the side where the patient's symptoms are most severe receiving stimulation at 130 Hz, and those on the other side receiving stimulation at 60 Hz. Subjects in the control arm will receive continuous, standardized TIS intervention targeting bilateral subthalamic nuclei with bilateral 130 Hz stimulation. The control intervention adopts identical operation procedures, equipment wearing mode and on-site operating environment as the formal TIS intervention, with the only difference being the stimulation frequency setting (bilateral 130 Hz in the control arm versus asymmetric frequency in the experimental arm). Rigorous controlled grouping design will ensure objective, verifiable data support for verifying the actual intervention efficacy of different frequency TIS modes on motor dysfunction and speech impairment in Parkinson-related patients, and will also help to clarify the potential advantages of asymmetric frequency TIS over bilateral same-frequency TIS. All enrolled subjects will complete the following standardized trial procedures in full compliance with the trial protocol: Receive continuous targeted intervention of either formal asymmetric frequency TIS (130 Hz on the contralateral side of severe symptoms, 60 Hz on the ipsilateral side) or bilateral 130 Hz TIS control intervention on bilateral subthalamic nuclei, with consecutive 5-day fixed-course administration in strict accordance with trial operating specifications. Complete unified fMRI brain scanning examinations and standardized motor function as well as speech function quantitative evaluation assessments at two fixed time nodes, including the baseline time point before intervention initiation and the follow-up time point after all intervention courses are completed. Truthfully record all adverse reactions and abnormal physical discomfort symptoms that occur throughout the whole intervention and follow-up observation cycle in standardized adverse event registration forms.