Advances in Deep Brain Stimulation: From Mechanisms to Applications.

Deep brain stimulation (DBS) is an effective therapy for various neurologic and neuropsychiatric disorders, involving chronic implantation of electrodes into target brain regions for electrical stimulation delivery. Despite its safety and efficacy, DBS remains an underutilized therapy. Advances in the field of DBS, including in technology, mechanistic understanding, and applications have the potential to expand access and use of DBS, while also improving clinical outcomes. Developments in DBS technology, such as MRI compatibility and bidirectional DBS systems capable of sensing neural activity while providing therapeutic stimulation, have enabled advances in our understanding of DBS mechanisms and its application. In this review, we summarize recent work exploring DBS modulation of target networks. We also cover current work focusing on improved programming and the development of novel stimulation paradigms that go beyond current standards of DBS, many of which are enabled by sensing-enabled DBS systems and have the potential to expand access to DBS.

Long-term neuropsychological outcomes of deep brain stimulation in early-stage Parkinson's disease.

INTRODUCTION: The pilot trial of deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) randomized 30 patients (medication duration 0.5-4 years; without dyskinesia or motor fluctuations) to receive optimal drug therapy alone (early ODT) or subthalamic nucleus (STN) DBS plus ODT (early DBS + ODT). This study reports long-term neuropsychological outcomes from the early DBS pilot trial. METHODS: This is an extension of an earlier study that examined two-year neuropsychological outcomes in the pilot trial. The primary analysis was conducted on the five-year cohort (n = 28), and a secondary analysis was conducted on the 11-year cohort (n = 12). Linear mixed effects models for each analysis compared overall trend in outcomes for randomization groups. All subjects who completed the 11-year assessment were also pooled to evaluate long-term change from baseline. RESULTS: There were no significant differences between groups in either the five- or 11-year analyses. Across all PD patients who completed the 11-year visit, there was significant decline in Stroop Color and Color-Word and Purdue Pegboard from baseline to 11 years. CONCLUSIONS: Previous significant differences between the groups in phonemic verbal fluency and cognitive processing speed showing more decline for early DBS + ODT subjects one year after baseline diminished as PD progressed. No cognitive domains were worse for early DBS + ODT subjects compared to standard of care subjects. There were shared declines across all subjects on cognitive processing speed and motor control, likely reflecting disease progression. More study is needed to understand the long-term neuropsychological outcomes associated with early DBS in PD.

Connectivity Profile for Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson Disease.

OBJECTIVE: This study was undertaken to describe relationships between electrode localization and motor outcomes from the subthalamic nucleus (STN) deep brain stimulation (DBS) in early stage Parkinson disease (PD) pilot clinical trial. METHODS: To determine anatomical and network correlates associated with motor outcomes for subjects randomized to early DBS (n = 14), voxelwise sweet spot mapping and structural connectivity analyses were carried out using outcomes of motor progression (Unified Parkinson Disease Rating Scale Part III [UPDRS-III] 7-day OFF scores [∆baseline➔24 months, MedOFF/StimOFF]) and symptomatic motor improvement (UPDRS-III ON scores [%∆baseline➔24 months, MedON/StimON]). RESULTS: Sweet spot mapping revealed a location associated with slower motor progression in the dorsolateral STN (anterior/posterior commissure coordinates: 11.07 ± 0.82mm lateral, 1.83 ± 0.61mm posterior, 3.53 ± 0.38mm inferior to the midcommissural point; Montreal Neurological Institute coordinates: +11.25, -13.56, -7.44mm). Modulating fiber tracts from supplementary motor area (SMA) and primary motor cortex (M1) to the STN correlated with slower motor progression across STN DBS subjects, whereas fiber tracts originating from pre-SMA and cerebellum were negatively associated with motor progression. Robustness of the fiber tract model was demonstrated in leave-one-patient-out (R = 0.56, p = 0.02), 5-fold (R = 0.50, p = 0.03), and 10-fold (R = 0.53, p = 0.03) cross-validation paradigms. The sweet spot and fiber tracts associated with motor progression revealed strong similarities to symptomatic motor improvement sweet spot and connectivity in this early stage PD cohort. INTERPRETATION: These results suggest that stimulating the dorsolateral region of the STN receiving input from M1 and SMA (but not pre-SMA) is associated with slower motor progression across subjects receiving STN DBS in early stage PD. This finding is hypothesis-generating and must be prospectively tested in a larger study. ANN NEUROL 2023;94:271-284.

Eleven-Year Outcomes of Deep Brain Stimulation in Early-Stage Parkinson Disease.

OBJECTIVE: The deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) pilot clinical trial randomized 30 patients (Hoehn & Yahr II off; medication duration 0.5-4 years; without dyskinesia/motor fluctuations) to optimal drug therapy (ODT) (early ODT) or bilateral subthalamic nucleus (STN) DBS plus ODT (early DBS+ODT). This study aims to report the 11-year outcomes of patients who completed the DBS in early-stage PD pilot clinical trial. MATERIALS AND METHODS: Attempts were made to contact all 29 subjects who completed the two-year trial to participate in an 11-year follow-up study. Mixed-effects models compared overall trend in outcomes for randomization groups (fixed-effects: assigned treatment, year, their interaction; random-effect: subject) to account for repeated measures. RESULTS: Twelve subjects participated in this 11-year follow-up study (n = 8 early ODT, n = 4 early DBS+ODT). Participating subjects were 70.0 ± 4.8 years old with a PD medication duration of 13.7 ± 1.7 years (early DBS duration 11.5 ± 1.3 years, n = 4). Three early ODT subjects received STN-DBS as standard of care (DBS duration 6.5 ± 2.0 years). Early ODT subjects had worse motor complications (Unified Parkinson's Disease Rating Scale [UPDRS]-IV) than early DBS+ODT subjects over the 11-year follow-up period (between-group difference = 3.5 points; pinteraction = 0.03). Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to early ODT for other UPDRS domains, Parkinson Disease Questionnaire-39 (PDQ-39), and levodopa equivalent daily dose (LEDD). CONCLUSIONS: Eleven years after randomization, early DBS+ODT subjects had fewer motor complications than early ODT subjects. These results should be interpreted with caution because only 40% of pilot trial subjects participated in this 11-year follow-up study. The Food and Drug Administration has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016). CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00282152.

BDNF rs6265 Genotype Influences Outcomes of Pharmacotherapy and Subthalamic Nucleus Deep Brain Stimulation in Early-Stage Parkinson's Disease.

INTRODUCTION: The efficacy of pharmacotherapy and deep brain stimulation of the subthalamic nucleus in treating Parkinson's disease motor symptoms is highly variable and may be influenced by patient genotype. The relatively common (prevalence about one in three) and protein-altering rs6265 single nucleotide polymorphism (C > T) in the gene BDNF has been associated with different clinical outcomes with levodopa. OBJECTIVE: We sought to replicate this reported association in early-stage Parkinson's disease subjects and to examine whether a difference in clinical outcomes was present with subthalamic nucleus deep brain stimulation. MATERIALS AND METHODS: Fifteen deep brain stimulation and 13 medical therapy subjects were followed for 24 months as part of the Vanderbilt DBS in Early Stage PD clinical trial (NCT00282152, FDA IDE #G050016). Primary outcome measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Questionnaire-39. RESULTS: Outcomes with drug therapy in subjects carrying the rs6265 T allele were significantly worse following 12 months of treatment compared to C/C subjects (UPDRS: +20 points, p = 0.019; PDQ-39: +16 points, p = 0.018). In contrast, rs6265 genotype had no effect on overall motor response to subthalamic nucleus deep brain stimulation at any time point; further, rs6265 C/C subjects treated with stimulation were associated with worse UPDRS part II scores at 24 months compared to medical therapy. CONCLUSIONS: Genotyping for the rs6265 polymorphism may be useful for predicting long-term response to drug therapy and counseling Parkinson's disease patients regarding whether to consider earlier subthalamic nucleus deep brain stimulation. Validation in a larger cohort of early-stage Parkinson's disease subjects is warranted.

Exploring the presence of multiple abnormal non-motor features in patients with cervical dystonia.

This study's aim was to investigate prevalence of four non-motor symptoms in patients with cervical dystonia and healthy controls to explore whether the presence of multiple non-motor features is associated with cervical dystonia diagnosis. Fifteen patients with cervical dystonia and 15 healthy controls underwent non-invasive testing of spatial discrimination threshold, temporal discrimination threshold, vibration-induced illusion of movement, and kinesthesia. All spatial discrimination threshold, temporal discrimination threshold, and vibration-induced illusion of movement measures were converted to standardized Z scores with scores >2.0 considered abnormal. Any incorrect kinesthesia response was considered abnormal. Prevalence of each abnormal non-motor feature was compared between groups using a chi-squared test. A higher proportion of patients with cervical dystonia had abnormal spatial discrimination threshold (p = 0.01) and abnormal kinesthesia (p = 0.03) scores compared to healthy control subjects. There were no significant differences between the proportion of patients with cervical dystonia versus healthy controls for abnormal temporal discrimination threshold (p = 0.07) or abnormal vibration-induced illusion of movement (p = 0.14). Forty-seven percent of patients with cervical dystonia (7/15) demonstrated one abnormal non-motor feature, 20% (3/15) displayed two abnormal features, and 13% (2/15) displayed three abnormal features. Kinesthesia was the only non-motor feature identified as abnormal in the control group (20%, 3/15). All four tests demonstrated high specificity (80-100%) and low-moderate sensitivity (13-60%). These findings suggest that non-motor feature testing, specifically for spatial discrimination threshold and kinesthesia, could be a highly specific diagnostic tool to inform cervical dystonia diagnosis. Further investigation is needed to confirm these findings.

Long-Term Care Resident Awareness and Interest in Spasticity Treatments.

Spasticity is common in long-term care settings (affecting up to one in three residents), yet it remains under-treated despite safe and effective, Food and Drug Administration (FDA)-approved therapies. One barrier to treatment may be lack of awareness of available therapies for long-term care residents living with spasticity. A standardized spasticity treatment awareness and interest interview was conducted with 18 nursing home residents and 11 veterans' home residents in this cross-sectional study. Veterans' home residents were also asked about potential barriers to receiving spasticity treatment. Many residents across both long-term care facilities were unaware of most of the treatment options for spasticity. Participants were most aware of physical/occupational therapy (83%, 95% CI: 65-93%) and least aware of intrathecal baclofen (21%, 95% CI: 9-39%). After learning about treatments, only 7% of participants (95% CI: 0-23%) were not interested in receiving any form of spasticity treatment. Among residents previously unaware of spasticity treatments, at least one quarter became interested in receiving treatment and at least one-fifth indicated possibly being interested in the treatment after learning about it. Potential barriers to receiving treatment included traveling to see a doctor and limited knowledge of insurance coverage of spasticity treatments. These results suggest that patient-centered approaches, including education and discerning patient preferences, may improve spasticity treatment in long-term care settings.

The Minimum Data Set: An Opportunity to Improve Spasticity Screening.

Spasticity is a common movement disorder that arises from trauma or disease affecting the central nervous system. Untreated spasticity can result in limitations in completing activities of daily living, painful limb contractures, and other conditions associated with loss of mobility. In the long-term care setting, this treatable condition is prevalent, yet often unrecognized likely because of a lack of spasticity-trained practitioners. A recently published spasticity referral tool holds promise for addressing the underdiagnosis of spasticity in the long-term care population. The Minimum Data Set (MDS) would be an ideal mechanism for increasing the diagnosis and treatment of spasticity because it is a government-directed comprehensive screening tool that informs care plans for all residents residing in federally funded long-term care facilities. The MDS could easily integrate the published referral assessment to record the presence of spastic postures and muscle rigidity. We propose expanding the MDS to include 3 questions related to spasticity to improve the recognition and treatment of this prevalent and treatable condition.

A comparative evaluation of telehealth and direct assessment when screening for spasticity in residents of two long-term care facilities.

OBJECTIVE: To evaluate the performance of telehealth as a screening tool for spasticity compared to direct patient assessment in the long-term care setting. DESIGN: Cross-sectional, observational study. SETTING: Two long-term care facilities: a 140-bed veterans' home and a 44-bed state home for individuals with intellectual and developmental disabilities. SUBJECTS: Sixty-one adult residents of two long-term care facilities (aged 70.1 ± 16.2 years) were included in this analysis. Spasticity was identified in 43% of subjects (Modified Ashworth Scale rating mode = 2). Contributing diagnoses included traumatic brain injury, spinal cord injury, birth trauma, stroke, cerebral palsy, and multiple sclerosis. MAIN MEASURES: Movement disorders neurologists conducted in-person examinations to determine whether spasticity was present (reference standard) and also evaluated subjects with spasticity using the Modified Ashworth Scale. Telehealth screening examinations, facilitated by a bedside nurse, were conducted remotely by two teleneurologists using a three-question screening tool. Telehealth screening determinations of spasticity were compared to the reference standard determination to calculate sensitivity, specificity, and the area under the curve (AUC) in receiver operating characteristics. Teleneurologist agreement was evaluated using Cohen's kappa. RESULTS: Teleneurologist 1 had a specificity of 89% and sensitivity of 65% to identify the likely presence of spasticity (n = 61; AUC = 0.770). Teleneurologist 2 showed 100% specificity and 82% sensitivity (n = 16; AUC = 0.909). There was almost perfect agreement between the two examiners at 94% (kappa = 0.875, 95% CI: 0.640-1.000). CONCLUSION: Telehealth may provide a useful, efficient method of identifying residents of long-term care facilities that likely need referral for spasticity evaluation.

BDNF rs6265 Variant Alters Outcomes with Levodopa in Early-Stage Parkinson's Disease.

Disease outcomes are heterogeneous in Parkinson's disease and may be predicted by gene variants. This study investigated if the BDNF rs6265 single nucleotide polymorphism (SNP) is associated with differential outcomes with specific pharmacotherapy treatment strategies in the "NIH Exploratory Trials in PD Long-term Study 1" (NET-PD LS-1, n = 540). DNA samples were genotyped for the rs6265 SNP and others (rs11030094, rs10501087, rs1491850, rs908867, and rs1157659). The primary measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and its motor component (UPDRS-III). Groups were divided by genotype and treatment regimen (levodopa monotherapy vs levodopa with other medications vs no levodopa). T allele carriers were associated with worse UPDRS outcomes compared to C/C subjects when treated with levodopa monotherapy (+ 6 points, p = 0.02) and to T allele carriers treated with no levodopa treatment strategies (UPDRS: + 8 points, p = 0.01; UPDRS-III: + 6 points, p = 0.01). Similar effects of worse outcomes associated with levodopa monotherapy were observed in the BDNF rs11030094, rs10501087, and rs1491850 SNPs. This study suggests the levodopa monotherapy strategy is associated with worse disease outcomes in BDNF rs6265 T carriers. Pending prospective validation, BDNF variants may be precision medicine factors to consider for symptomatic treatment decisions for early-stage PD patients.

Prevalence of Comorbid Spasticity and Urinary Incontinence in Residents of a Long-Term Care Facility.

The current study evaluated the prevalence of comorbid spasticity and urinary incontinence (UI) in a long-term care facility. Medical history, presence of UI, and activities of daily living (ADL) dependency were obtained from medical records and Minimum Data Set 3.0. Quality of life was assessed with the EuroQoL-5D-5L (EQ-5D). Comorbid spasticity and UI presented in 29% of participants (14 of 49). Participants with spasticity and UI had higher ADL dependency and lower EQ-5D than participants without both conditions (4.9, 95% confidence interval [CI] [1.6, 80.], p = 0.003; -0.17, 95% CI [-0.33, 0.00], p = 0.044; respectively). More than one half of participants with lower limb spasticity had severe UI, compared to only 10% without lower limb spasticity (relative risk = 5.5; 95% CI [1.9, 15.9]; p = 0.006). Comorbid spasticity and UI may be common in the long-term care setting and negatively associated with ADL and quality of life. Further investigation is needed to confirm these findings. [Journal of Gerontological Nursing, 46(10), 35-42.].

Deep brain stimulation in early-stage Parkinson disease: Five-year outcomes.

OBJECTIVE: To report 5-year outcomes from the subthalamic nucleus (STN) deep brain stimulation (DBS) in early-stage Parkinson disease (PD) pilot clinical trial. METHODS: The pilot was a prospective, single-blind clinical trial that randomized patients with early-stage PD (Hoehn & Yahr II off medications) to receive bilateral STN DBS plus optimal drug therapy (ODT) vs ODT alone (IDEG050016, NCT0282152, IRB040797). Participants who completed the 2-year trial participated in this observational follow-up study, which included annual outpatient visits through 5 years. This analysis includes 28 patients who were taking PD medications for 6 months to 4 years at enrollment. Outcomes were analyzed using both proportional odds logistic regression and linear mixed effects models. RESULTS: Early STN DBS + ODT participants required lower levodopa equivalent daily doses (p = 0.04, ß = -240 mg, 95% confidence interval [CI] -471 to -8) and had 0.06 times the odds of requiring polypharmacy at 5 years compared to early ODT participants (p = 0.01, odds ratio [OR] 0.06, 95% CI 0.00 to 0.65). The odds of having worse rest tremor for early STN DBS + ODT participants were 0.21 times those of early ODT participants (p < 0.001, OR 0.21, 95% CI 0.09 to 0.45). The safety profile was similar between groups. CONCLUSIONS: These results suggest that early DBS reduces the need for and complexity of PD medications while providing long-term motor benefit over standard medical therapy. Further investigation is warranted, and the Food and Drug Administration has approved the conduct of a prospective, multicenter, pivotal clinical trial of DBS in early-stage PD (IDEG050016). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DBS implanted in early-stage PD decreases the risk of disease progression and polypharmacy compared to optimal medical therapy alone.

A Simple Bedside Screening Tool for Spasticity Referral.

BACKGROUND AND OBJECTIVES: Spasticity is common in long-term care facilities; however, this often-disabling condition is largely underdiagnosed in this setting and therefore left untreated. This study aimed to test the ability of a three-question flowchart used at the bedside by primary care providers in the long-term care setting to identify residents in need of referral to a specialist for spasticity consultation. METHODS: All residents of a single long-term care facility were approached for participation in this cross-sectional, observational study. Spasticity diagnostic evaluations by a movement disorders specialist neurologist (reference standard) were compared with referral determinations made by two primary care providers [a primary care physician (PCP) and a nurse practitioner (NP)] using the simple flowchart. RESULTS: The analysis included 49 residents (80% male, age 78.2±9.0 years) who were evaluated by the reference standard neurologist and at least one primary care provider. The bedside referral tool demonstrated high sensitivity and moderate specificity when used by the PCP (92% and 78%, respectively; AUC=0.84) and NP (80% and 53%, respectively; AUC=0.67). CONCLUSION: This simple tool may be useful for primary care providers to identify residents to be referred to a specialist for evaluation and treatment of spasticity. These results warrant further investigation of the potential utility of this screening tool across multiple long-term care facilities and various types of care providers.

Prevalence of Spasticity in Nursing Home Residents.

OBJECTIVES: To determine the prevalence, rate of underdiagnosis and undertreatment, and association with activities of daily living dependency of spasticity in a nursing home setting. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: This study is an analysis of a deidentified data set generated by a prior quality improvement project at a 240-bed nursing home for residents receiving long-term care or skilled nursing care services. METHODS: Each resident was examined by a movement disorders specialist neurologist to determine whether spasticity was present and, if so, the total number of spastic postures present in upper and lower limbs was recorded. Medical records, including the Minimum Data Set, were reviewed for neurologic diagnoses associated with spasticity, activities of daily living (ADL) dependency, and prior documentation of diagnosis and past or current treatments. Ordinary least squares linear regression models were used to evaluate the association between spasticity and ADL dependency. RESULTS: Two hundred nine residents (154 women, 81.9 ± 10.9 years) were included in this analysis. Spasticity was present in 22% (45/209) of residents examined by the neurologist. Only 11% of residents (5/45) had a prior diagnosis of spasticity and were receiving treatment. Presence of spasticity was associated with greater ADL dependency (χ2 = 51.72, P < .001), which was driven by lower limb spasticity (χ2 = 14.56, P = .006). CONCLUSIONS AND IMPLICATIONS: These results suggest that spasticity (1) is common in nursing homes (1 of 5 residents), (2) is often not diagnosed or adequately treated, and (3) is associated with worse ADL dependency. Further research is needed to enhance the rates of diagnosis and treatment of spasticity in long-term care facilities.

Impact of Tremor on Patients With Early Stage Parkinson's Disease.

Tremor is one of the most visible features of Parkinson's disease (PD), and the majority of PD patients experience tremor during the course of the disease. However, the distress caused by this cardinal motor feature for patients early in the course of their PD is commonly underappreciated. People living with early stage PD often experience intense embarrassment and difficulties due to their tremor that limit social interactions, and tremor frequently interferes with the ability to perform activities of daily living and simple tasks at home and work. Although tremor is primarily managed with medications, both tremor response and satisfaction with medical therapy are highly variable. This review offers an overview of reports of the patient experience of tremor in early stage PD and current management options for this cardinal motor feature.

Recruitment and Retention in Clinical Trials of Deep Brain Stimulation in Early-Stage Parkinson's Disease: Past Experiences and Future Considerations.

BACKGROUND: Clinical trials are often hindered by inadequate patient recruitment. Overly optimistic investigator predictions of participation can lead to unmet recruitment goals and costly trial extensions. A patient-focused approach estimating recruitment in clinical trials may provide higher accuracy. OBJECTIVE: To assess the feasibility of recruitment in a future deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) multicenter trial by understanding motivations and concerns to participation of past and potential future DBS in early-stage PD clinical trial subjects. METHODS: To identify motivating factors and barriers influencing trial participation, an end-of-trial survey was administered to subjects enrolled in a DBS in early-stage PD pilot trial with subjects randomized to receive DBS plus optimal drug therapy (DBS+ODT) or ODT alone (NCT#00282152, IDE#G050016). Pilot trial survey results were analyzed in conjunction with results of a previously-reported survey querying PD patients about potential participation in a trial for DBS in early-stage PD with similar inclusion/exclusion criteria. RESULTS: Pilot trial subjects reported high levels of satisfaction with their participation in the study. Similar motivations and barriers to participation were expressed in comparable proportions by subjects who successfully completed the pilot trial and patients with early-stage PD considering enrollment in a comparable DBS study. CONCLUSIONS: The FDA has approved a prospective, randomized, double-blind, phase III, multicenter, pivotal clinical trial evaluating DBS in early-stage PD (IDE#G050016). These results suggest that the successful recruitment and retention of early-stage PD subjects, as observed in the pilot trial, is attainable in a future pivotal trial.

Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease.

OBJECTIVE: To evaluate whether the progression of individual motor features was influenced by early deep brain stimulation (DBS), a post hoc analysis of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) score (after a 7-day washout) was conducted from the 2-year DBS in early Parkinson disease (PD) pilot trial dataset. METHODS: The prospective pilot trial enrolled patients with PD aged 50-75 years, treated with PD medications for 6 months-4 years, and no history of dyskinesia or other motor fluctuations, who were randomized to receive optimal drug therapy (ODT) or DBS plus ODT (DBS + ODT). At baseline and 6, 12, 18, and 24 months, all patients stopped all PD therapy for 1 week (medication and stimulation, if applicable). UPDRS-III "off" item scores were compared between the ODT and DBS + ODT groups (n = 28); items with significant between-group differences were analyzed further. RESULTS: UPDRS-III "off" rest tremor score change from baseline to 24 months was worse in patients receiving ODT vs DBS + ODT (p = 0.002). Rest tremor slopes from baseline to 24 months favored DBS + ODT both "off" and "on" therapy (p < 0.001, p = 0.003, respectively). More ODT patients developed new rest tremor in previously unaffected limbs than those receiving DBS + ODT (p = 0.001). CONCLUSIONS: These results suggest the possibility that DBS in early PD may slow rest tremor progression. Future investigation in a larger cohort is needed, and these findings will be tested in the Food and Drug Administration-approved, phase III, pivotal, multicenter clinical trial evaluating DBS in early PD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with early PD, DBS may slow the progression of rest tremor.