Pallidal Connectivity Profiling of Stimulation-Induced Dyskinesia in Parkinson's Disease.

OBJECTIVES: The aim of this study is to identify anatomical regions related to stimulation-induced dyskinesia (SID) after pallidal deep brain stimulation (DBS) in Parkinson's disease (PD) patients and to analyze connectivity associated with SID. METHODS: This retrospective study analyzed the clinical and imaging data of PD patients who experienced SID during the monopolar review after pallidal DBS. We analyzed structural and functional connectivity using normative connectivity data with the volume of tissue activated (VTA) modeling. Each contact was assigned to either that producing SID (SID VTA) or that without SID (non-SID VTA). Structural and functional connectivity was compared between SID and non-SID VTAs. "Optimized VTAs" were also estimated using the DBS settings at 6 months after implantation. RESULTS: Of the 68 consecutive PD patients who underwent pallidal implantation, 20 patients (29%) experienced SID. SID VTAs were located more dorsally and anteriorly compared with non-SID and optimized VTAs and were primarily in the dorsal globus pallidus internus (GPi) and dorsal globus pallidus externus (GPe). SID VTAs showed significantly higher structural connectivity than non-SID VTAs to the associative cortex and supplementary motor area/premotor cortex (P < 0.0001). Simultaneously, non-SID VTAs showed greater connectivity to the primary sensory cortex, cerebellum, subthalamic nucleus, and motor thalamus (all P < 0.0004). Functional connectivity analysis showed significant differences between SID and non-SID VTAs in multiple regions, including the primary motor, premotor, and prefrontal cortices and cerebellum. CONCLUSION: SID VTAs were primarily in the dorsal GPi/GPe. The connectivity difference between the motor-related cortices and subcortical regions may explain the presence and absence of SID. © 2020 International Parkinson and Movement Disorder Society.

Globus Pallidus Internus (GPi) Deep Brain Stimulation for Parkinson's Disease: Expert Review and Commentary.

INTRODUCTION: The globus pallidus internus (GPi) region has evolved as a potential target for deep brain stimulation (DBS) in Parkinson's disease (PD). DBS of the GPi (GPi DBS) is an established, safe and effective method for addressing many of the motor symptoms associated with advanced PD. It is important that clinicians fully understand this target when considering GPi DBS for individual patients. METHODS: The literature on GPi DBS in PD has been comprehensively reviewed, including the anatomy, physiology and potential pitfalls that may be encountered during surgical targeting and post-operative management. Here, we review and address the implications of lead location on GPi DBS outcomes. Additionally, we provide a summary of randomized controlled clinical trials conducted on DBS in PD, together with expert commentary on potential applications of the GPi as target. Finally, we highlight future technologies that will likely impact GPi DBS, including closed-loop adaptive approaches (e.g. sensing-stimulating capabilities), advanced methods for image-based targeting and advances in DBS programming, including directional leads and pulse shaping. RESULTS: There are important disease characteristics and factors to consider prior to selecting the GPi as the DBS target of PD surgery. Prior to and during implantation of the leads it is critical to consider the neuroanatomy, which can be defined through the combination of image-based targeting and intraoperative microelectrode recording strategies. There is an increasing body of literature on GPi DBS in patients with PD suggesting both short- and long-term benefits. Understanding the GPi target can be useful in choosing between the subthalamic (STN), GPi and ventralis intermedius nucleus as lead locations to address the motor symptoms and complications of PD. CONCLUSION: GPi DBS can be effectively used in select cases of PD. As the ongoing DBS target debate continues (GPi vs. STN as DBS target), clinicians should keep in mind that GPi DBS has been shown to be an effective treatment strategy for a variety of symptoms, including bradykinesia, rigidity and tremor control. GPi DBS also has an important, direct anti-dyskinetic effect. GPi DBS is easier to program in the outpatient setting and will allow for more flexibility in medication adjustments (e.g. levodopa). Emerging technologies, including GPi closed-loop systems, advanced tractography-based targeting and enhanced programming strategies, will likely be future areas of GPi DBS expansion. We conclude that although the GPi as DBS target may not be appropriate for all PD patients, it has specific clinical advantages.

Long-term clinical outcomes of bilateral GPi deep brain stimulation in advanced Parkinson's disease: 5 years and beyond.

OBJECTIVE: Few studies have reported long-term outcomes of globus pallidus internus (GPi) deep brain stimulation (DBS) in Parkinson's disease (PD). The authors aimed to investigate long-term outcomes of bilateral GPi DBS for 5 years and beyond for PD patients. METHODS: The authors retrospectively analyzed the clinical outcomes in 65 PD patients treated with bilateral GPi DBS at a single center. The outcome measures of motor symptoms and health-related quality of life (HRQoL) included the Unified Parkinson's Disease Rating Scale (UPDRS) and the Parkinson's Disease Questionnaire (PDQ-39). Scores at baseline were compared with those at 1, 3, 5, and 6-8 years after implantation using Wilcoxon signed-rank tests with α correction. RESULTS: GPi DBS significantly improved the off-medication UPDRS III total scores, UPDRS IV, and dyskinesia score at 1 year when compared with baseline (all p < 0.001). The off- and on-medication tremor scores, UPDRS IV, and dyskinesia scores showed moderate and sustained improvement (the ranges of the mean percentage improvement at each time point were 61%-75%, 30%-80%, 29%-40%, and 40%-65%, respectively) despite lacking statistical significance at long-term follow-up with diminishing sample sizes. The off-medication UPDRS III total scores did not show significant improvement at 5 years or later, primarily because of worsening in rigidity, akinesia, speech, gait, and postural stability scores. The on-medication UPDRS III total scores also worsened over time, with a significant worsening at 6-8 years when compared with baseline (p = 0.008). The HRQoL analyses based on the PDQ-39 revealed significant improvement in the activities of daily living and discomfort domains at 1 year (p = 0.003 and 0.006, respectively); however, all the domains showed gradual worsening at the later time points without reaching statistical significance. At 3 years, the communication domain showed significant worsening compared with baseline scores (p = 0.002). CONCLUSIONS: GPi DBS in PD patients in this single-center cohort was associated with sustained long-term benefits in the off- and on-medication tremor score and motor complications. HRQoL and the cardinal motor symptoms other than tremor may worsen gradually in the long term. When counseling patients, it is important to recognize that benefits in tremor and dyskinesia are expected to be most persistent following bilateral GPi DBS implantation.

Parkinson's disease motor subtypes and bilateral GPi deep brain stimulation: One-year outcomes.

OBJECTIVE: We aimed to explore the differences in motor symptoms and quality of life (QOL) outcomes following bilateral globus pallidus internus deep brain stimulation (GPi DBS), across well-defined motor subtypes of Parkinson's disease (PD), to improve clinical decision making. METHODS: This single-center retrospective study investigated bilateral GPi DBS outcomes in 65 PD patients. Outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Questionnaire (PDQ-39) before and one year after surgery. Outcomes were compared between the tremor-dominant (TD) and postural instability and gait difficulty (PIGD) subtypes and between the TD and akinetic-rigid (AR) subtypes. RESULTS: For the entire cohort, motor function (UPDRS III) in the Off-medication state, motor complications (UPDRS IV), activities of daily living (ADL, UPDRS II), and the ADL and discomfort domains of PDQ-39 significantly improved one year following GPi implantation compared to baseline (effect size = 1.32, 1.15, 0.25, 0.45, and 0.34, respectively). GPi DBS improved the Off-medication UPDRS III scores regardless of the motor subtypes. However, compared to the PIGD and AR patients, the TD patients showed greater improvement in overall UPDRS III postoperatively primarily due to greater tremor improvement in the Off-medication state. The outcomes in akinesia, rigidity, axial symptoms and QOL were similar among all subtypes. CONCLUSION: Bilateral GPi DBS was effective for advanced PD patients regardless of motor subtypes. Greater tremor improvement in the TD patients accounted for greater Off-medication motor improvement. Longer-term GPi DBS outcomes across different motor subtypes and brain targets should be further studied.