Globus Pallidus Internus Deep Brain Stimulation Research Articles

Basal Ganglia Pathways Associated With Therapeutic Pallidal Deep Brain Stimulation for Tourette Syndrome

BackgroundDeep brain stimulation (DBS) targeting the globus pallidus internus (GPi) can improve tics and comorbid obsessive-compulsive behavior (OCB) in patients with treatment-refractory Tourette syndrome (TS). However, some patients’ symptoms remain unresponsive, the stimulation applied across patients is variable, and the mechanisms underlying improvement are unclear. Identifying the fiber pathways surrounding the GPi that are associated with improvement could provide mechanistic insight and refine targeting strategies to improve outcomes. MethodsRetrospective data were collected for 35 patients who underwent bilateral GPi DBS for TS. Computational models of fiber tract activation were constructed using patient-specific lead locations and stimulation settings to evaluate the effects of DBS on basal ganglia pathways and the internal capsule. We first evaluated the relationship between activation of individual pathways and symptom improvement. Next, linear mixed-effects models with combinations of pathways and clinical variables were compared in order to identify the best-fit predictive models of tic and OCB improvement. ResultsThe best-fit model of tic improvement included baseline severity and the associative pallido-subthalamic pathway. The best-fit model of OCB improvement included baseline severity and the sensorimotor pallido-subthalamic pathway, with substantial evidence also supporting the involvement of the prefrontal, motor, and premotor internal capsule pathways. The best-fit models of tic and OCB improvement predicted outcomes across the cohort and in cross-validation. ConclusionsDifferences in fiber pathway activation likely contribute to variable outcomes of DBS for TS. Computational models of pathway activation could be used to develop novel approaches for preoperative targeting and selecting stimulation parameters to improve patient outcomes.

DBS in restless legs syndrome: a new therapeutic approach?

ObjectiveRestless legs syndrome (RLS) is a sleep disorder characterized by an urge to move legs or arms, with a typical circadian rhythm. RLS can be treated with pharmacological and non-pharmacological therapies. Nevertheless, in some patients RLS can be refractory to all medical and non-medical treatments.Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been reported to improve RLS symptoms in Parkinson's disease (PD) patients with RLS. We describe the case of a patient suffering from refractory idiopathic RLS implanted with bilateral GPi DBS. MethodThe patient underwent DBS targeting the bilateral GPi. Follow up for three years involved clinical evaluation and polysomnography (PSG). ResultsThe patient reported subjective improvement, with reduction in the IRLS score. Furthermore, the polysomnography (PSG) showed an objective improvement of polysomnographic parameters, which remained stable during the follow-up. ConclusionDBS for RLS can be a new therapeutic approach for severe RLS, but further studies are needed.

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

IntroductionThe 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.MethodsThe 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.ResultsThere 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.ConclusionGPi 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.Electronic supplementary materialThe online version of this article (10.1007/s40120-020-00220-5) contains supplementary material, which is available to authorized users.

STN Versus GPi Deep Brain Stimulation for Action and Rest Tremor in Parkinson's Disease.

ObjectiveTo investigate the effects of subthalamic nucleus (STN) and globus pallidus internus (GPi), deep brain stimulation (DBS) on individual action tremor/postural tremor (AT) and rest tremor (RT) in Parkinson’s disease (PD). Randomized DBS studies have reported marked benefit in tremor with both GPi and STN and DBS, however, there is a paucity of information available on AT vs RT when separated by the surgical target.MethodsWe retrospectively reviewed the 1-year clinical outcome of PD patients treated with STN and GPi DBS at the University of Florida. We specifically selected patients with moderate to severe AT. Eighty-eight patients (57 STN and 31 GPi) were evaluated at 6 and 12 months for changes in AT and RT in the OFF-medication/ON stimulation state. A comparison of “response” was performed and defined as greater than or equal to a 2-point decrease in tremor score.ResultsSTN and GPi DBS both improved AT at 6- and 12-months post-implantation (p < 0.001 and p < 0.001). The STN DBS group experienced a greater improvement in AT at 6 months compared to the GPi group (p = 0.005) but not at the 12 months follow-up (p = 0.301). Both STN and GPi DBS also improved RT at 6- and 12-months post-implantation (p < 0.001 and p < 0.001). There was no difference in RT scores between the two groups at 6 months (p = 0.23) or 12 months (p = 0.74). The STN group had a larger proportion of patients who achieved a “response” in AT at 6 months (p < 0.01), however, this finding was not present at 12 months (p = 0.23). A sub-analysis revealed that in RT, the STN group had a larger percentage of “responders” when followed through 12 months (p < 0.01).ConclusionBoth STN and GPi DBS reduced PD associated AT and RT at 12 months follow-up. There was no advantage of either brain target in the management of RT or AT. One nuance of the study was that STN DBS was more effective in suppressing AT in the early postoperative period, however, this effect diminished over time. Clinicians should be aware that it may take longer to achieve a similar tremor outcome when utilizing the GPi target.

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

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. 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. 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). 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.

An individual patient analysis of the efficacy of using GPi-DBS to treat Huntington’s disease

ObjectiveThe efficacy of globus pallidus internus-deep brain stimulation (GPi-DBS) for the treatment of Huntington’s disease (HD) has not been validated in large-scale studies. We conducted an individual patient analysis to pool outcomes of all of the published HD-GPi-DBS studies. MethodsPubMed, Embase and the Cochrane Library were searched for relevant articles. The Unified Huntington’s Disease Rating Scale (UHDRS)-motor and UHDRS-chorea improvements were analyzed during different follow-up periods. Secondary outcomes, including UHDRS-motor subitem scores and functional assessment results, were also analyzed. Correlation and regression analyses were conducted to find improvement predictors. This study was registered in PROSPERO (CRD42018105995). ResultsEighteen studies including 39 patients with 124 visits were analyzed. GPi-DBS significantly improved the UHDRS-motor score in <3 months (p = 0.001), 3–9 months (p < 0.001), and 9–12 months (p < 0.001), but did not continue in later follow-ups. UHDRS-chorea was significantly improved even in the >30-month follow-up (p = 0.003). Functional assessment was not improved 12 months postoperatively (p = 0.196). The Westphal variant of HD (W-HD) gained no motor benefits 6 months postoperatively (p = 0.178). The Westphal variant was the only risk factor for DBS efficacy (p = 0.044). The rate of stimulation-related adverse events was 87.2%. ConclusionsGPi-DBS has a stable effect on chorea symptoms in HD patients. Chorea-dominant patients may be the best candidates for surgery, while attention should be paid to postoperative stimulation-related complications. Given that GPi-DBS has limited effects on other motor symptoms, W-HD patients are not surgical candidates.

Pallidal deep brain stimulation in primary Meige syndrome: clinical outcomes and psychiatric features

ObjectivesTo study the efficacy and safety of bilateral globus pallidus internus deep brain stimulation (GPi-DBS) in refractory Meige syndrome (MS) and evaluate the psychiatric disorders before and after surgery.MethodsTwenty-two patients...

A severe case of status dystonicus caused by a de novo KMT2B missense mutation

Here, we present the case of a 15-year-old Japanese girl with Dystonia 28, childhood-onset; DYT28 (MIM#606834) showing early-onset generalized progressive dystonia and status dystonicus. The patient was genetically undiagnosed and had not responded to various medications. By trio-based whole exome sequencing and in silico analyses, we identified a de novo heterozygous variant of KMT2B: NM_014727.2: c.7828C > T, p(Arg2610Cys). Globus pallidus internus deep brain stimulation (GPi-DBS) therapy was considered; however, the therapy could not be performed due to the patient's poor nutritional status and repeated infections. GPi-DBS is considered to be an effective treatment for patients with KMT2B mutations, and genetic diagnosis is important before progression to status dystonicus.

Letter: Evaluation and Surgical Treatment of Functional Neurosurgery Patients With Implanted Deep Brain Stimulation and Vagus Nerve Stimulation Pulse Generators During the COVID-19 Pandemic.

Author(s): Gross, Robert E; Buetefisch, Cathrin M; Miocinovic, Svjetlana; Bullinger, Katie L; Okun, Michael S; Ostrem, Jill L; Foote, Kelly D; Starr, Phillip A

Quality of life outcomes after globus pallidus internus deep brain stimulation in idiopathic or inherited isolated dystonia: a meta-analysis

BackgroundSeveral studies reported the beneficial effects of globus pallidus internus deep brain stimulation (GPi DBS) on health-related quality of life (HRQoL) in patients with inherited or idiopathic isolated dystonia. However,...

Pulse Width and Implantable Pulse Generator Longevity in Pallidal Deep Brain Stimulation for Dystonia: A Population-Based Comparative Effectiveness Study

Introduction: A wide range of pulse widths (PWs) has been used in globus pallidus internus (GPi) deep brain stimulation (DBS) for dystonia. However, no specific PW has demonstrated clinical superiority, and the paradigm may differ among DBS centers. Objective: To investigate how different paradigms of PWs in GPi DBS for dystonia affect implantable pulse generator (IPG) longevities and energy consumption. Methods: Thirty-nine patients with dystonia treated with bilateral GPi DBS at 2 Swedish DBS centers from 2005 to 2015 were included. Different PW paradigms were used at the 2 centers, 60–90 µs (short PWs) and 450 µs (long PW), respectively. The frequency of IPG replacements, pulse effective voltage (PEV), IPG model, pre-/postoperative imaging, and clinical outcome based on the clinical global impression (CGI) scale were collected from the medical charts and compared between the 2 groups. Results: The average IPG longevity was extended for the short PWs (1,129 ± 50 days) compared to the long PW (925 ± 32 days; χ² = 12.31, p = 0.0005, log-rank test). IPG longevity correlated inversely with PEV (Pearson’s r = –0.667, p < 0.0001). IPG longevities did not differ between Kinetra® and Activa® PC in the short (p = 0.319) or long PW group (p = 0.858). Electrode distances to the central sensorimotor region of the GPi did not differ between the short or long PW groups (p = 0.595). Pre- and postoperative CGI did not differ between groups. Conclusions: Short PWs were associated with decreased energy consumption and increased IPG longevity. These effects were not dependent on the IPG model or the anatomic location of the electrodes. PWs did not correlate with symptom severities or clinical outcomes. The results suggest that the use of short PWs might be more energy efficient and could therefore be preferred initially when programming patients with GPi DBS for dystonia.

Non-staged bilateral Globus Pallidus Internus deep brain stimulation lead revision using intraoperative MRI: a case report and literature review

Background Deep brain stimulation (DBS) lead revision due to suboptimal therapy is common but there is no standardised protocol. We describe a novel technique using iMRI to perform concurrent new Globus Pallidus Internus (GPi) DBS lead implantation and old lead removal in a dystonia patient. Case-description: A 60-year-old woman with medication and neurotoxin-refractory isolated cervical dystonia underwent awake bilateral GPi DBS surgery with MER-guided lead implantation. She initially had a favourable response but later reported suboptimal benefit despite reprogramming. MRI demonstrated suboptimal lead placement and MRI-guided revision surgery under general anesthesia was planned. The goal was to place new leads superior and medial to the existing leads. Using a 1.5 T iMRI and the ClearPoint® NeuroNavigation system, new leads were placed through the existing burr holes, into the new targets with radial errors < 0.08mm bilaterally without crossing the old leads. The old leads were then removed and the new leads connected to the existing pulse generator. The patient tolerated the procedure well and had improved side-effect profile at all contacts at 1-month follow-up. Conclusions Non-staged iMRI-guided DBS revision surgery under general anesthesia is technically feasible and is an alternative strategy to a staged iMRI-guided revision surgery or an awake MER-guided revision surgery in select patients.

Neurophysiological Correlates of Gait in the Human Basal Ganglia and the PPN Region in Parkinson's Disease.

This study aimed to characterize the neurophysiological correlates of gait in the human pedunculopontine nucleus (PPN) region and the globus pallidus internus (GPi) in Parkinson’s disease (PD) cohort. Though much is known about the PPN region through animal studies, there are limited physiological recordings from ambulatory humans. The PPN has recently garnered interest as a potential deep brain stimulation (DBS) target for improving gait and freezing of gait (FoG) in PD. We used bidirectional neurostimulators to record from the human PPN region and GPi in a small cohort of severely affected PD subjects with FoG despite optimized dopaminergic medications. Five subjects, with confirmed on-dopaminergic medication FoG, were implanted with bilateral GPi and bilateral PPN region DBS electrodes. Electrophysiological recordings were obtained during various gait tasks for 5 months postoperatively in both the off- and on-medication conditions (obtained during the no stimulation condition). The results revealed suppression of low beta power in the GPi and a 1–8 Hz modulation in the PPN region which correlated with human gait. The PPN feature correlated with walking speed. GPi beta desynchronization and PPN low-frequency synchronization were observed as subjects progressed from rest to ambulatory tasks. Our findings add to our understanding of the neurophysiology underpinning gait and will likely contribute to the development of novel therapies for abnormal gait in PD.Clinical Trial Registration: Clinicaltrials.gov identifier; NCT02318927.

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

ObjectiveWe 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. MethodsThis 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. ResultsFor 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. ConclusionBilateral 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.

Characteristics of globus pallidus internus local field potentials in generalized dystonia patients with TWNK mutation

ObjectiveWe focused on a rare gene mutation causing dystonia in two siblings who received globus pallidus internus deep brain stimulation (GPi-DBS). The aim was to characterize the relationship between neuronal activity patterns and clinical syndromes. MethodsWhole exome sequencing was applied to identify the TWNK (previous symbol C10orf2) mutation; Two siblings with TWNK mutation presented as generalized dystonia with rigidity and bradykinesia; four other sporadic generalized dystonia patients underwent GPi-DBS and local field potentials (LFPs) were recorded. Oscillatory activities were illustrated with power spectra and temporal dynamics measured by the Lempel-Ziv complexity (LZC). ResultsNormalized power spectra of GPi LFPs differed between patients with TWNK mutation and dystonia over the low beta bands. Patients with TWNK mutation had higher low beta power (15–27 Hz, unpaired t-test, corrected P < 0.0022) and lower LZC (15–27 Hz, unpaired t-test, P < 0.01) than other patients with generalized dystonia. On the other hand, the TWNK mutation patients showed decreased low frequency and beta oscillation in the GPi after DBS, as well as improved movement performance. ConclusionThe LFPs were different in TWNK mutation dystonia siblings than other patients with generalized dystonia, which indicate the abnormal LFPs were related to symptoms rather than specific disease. In addition, the inhibited effect on oscillations also provided a potential evidence for DBS treatment on rare movement disorders. SignificanceThis study could potentially aid in the future development of adaptive DBS via rare disease LFPs comparison.

A Case Report of Myoclonus-Dystonia with Isolated Myoclonus Phenotype and Novel Mutation Successfully Treated with Deep Brain Stimulation.

IntroductionMyoclonus-dystonia is an inherited disorder characterized by a combination of myoclonic jerks and dystonia. Mutations in the epsilon-sarcoglycan gene (SGCE) represent the main known genetic cause. In the last few years, deep brain stimulation (DBS) has shown significant promise in treating these patients. There is only one report in the literature of a patient with positive SGCE mutation and isolated myoclonus phenotype who has been successfully treated with DBS.Case PresentationWe present a case of a 16-year-old young man with a history of quick jerks since childhood. They progressed gradually over the years involving the entire body and interfering with most of his daily activities. He had no dystonia. Genetic testing identified a single base deletion in exon 3 of the SGCE gene, considered very likely pathogenic. After unsuccessfully trying several oral medications, he underwent DBS of the globus pallidus internus (GPi). His Unified Myoclonus Rating Scale score during rest and with action improved by 92.8% and 82.6%, respectively.DiscussionThe striking effect of DBS on myoclonic jerks confirms the superior benefit of DBS over oral medications. Further study is needed to determine the role of mutation status in predicting DBS response, especially considering that myoclonus-dystonia is genetically heterogeneous.ConclusionOur case confirms the poor response to oral medications and supports the use of GPi DBS for patients with genetically confirmed myoclonus-dystonia and isolated-myoclonus phenotype. In addition, our case represents familial myoclonus-dystonia due to a novel SGCE mutation.Electronic supplementary materialThe online version of this article (10.1007/s40120-020-00186-4) contains supplementary material, which is available to authorized users.

The Impact of Deep Brain Stimulation on Sleep in Parkinson's Disease: An update.

Background:Parkinson’s disease (PD) can have a significant impact on sleep. Deep brain stimulation (DBS) is an effective treatment for motor features of PD, but less is understood about the impact DBS may have on sleep architecture and various sleep issues commonly seen in PD.Objective:To review the impact of DBS on various sleep issues in PD.Methods:We reviewed the literature regarding the impact of DBS on sleep patterns, nocturnal motor and non-motor symptoms, and sleep disorders in PD.Results:Objective sleep measures on polysomnography (PSG), including sleep latency and wake after sleep onset improve after subthalamic nucleus (STN) and globus pallidus interna (GPi) DBS. Subjective sleep measures, nocturnal motor symptoms, and some non-motor symptoms (nocturia) also may improve. Current evidence suggests STN DBS has no impact on Rapid Eye Movement Behavior Disorder (RBD), while STN DBS may improve symptoms of Restless Legs Syndrome (RLS). There are no studies that have evaluated the impact of GPi DBS on RBD, while it is unclear if GPi has an effect on RLS in PD.Conclusion:DBS therapy at either site appears to improve objective and subjective sleep parameters in patients with PD. Most likely, the improvement of motor and some non-motor nocturnal symptoms leads to an increase in total sleep time by up to an hour, as well as reduction of sleep fragmentation. DBS most likely has no impact on RBD, while there is evidence that STN DBS appears to help reduce RLS severity. Further studies are needed.

Functional and Structural Connectivity Patterns Associated with Clinical Outcomes in Deep Brain Stimulation of the Globus Pallidus Internus for Generalized Dystonia.

Deep brain stimulation is a well-established treatment for generalized dystonia, but outcomes remain variable. Establishment of an imaging marker to guide device targeting and programming could possibly impact the efficacy of deep brain stimulation in dystonia, particularly in the absence of acute clinical markers to indicate benefit. We hypothesize that the stimulation-based functional and structural connectivity using resting-state fMRI and DTI can predict therapeutic outcomes in patients with generalized dystonia and deep brain stimulation. We performed a retrospective analysis of 39 patients with inherited or idiopathic-isolated generalized dystonia who underwent bilateral globus pallidus internus deep brain stimulation. After electrode localization, the volumes of tissue activated were modeled and used as seed regions for functional and structural connectivity measures using a normative data base. Resulting connectivity maps were correlated with postoperative improvement in the Unified Dystonia Rating Scale score. Structural connectivity between the volumes of tissue activated and the primary sensorimotor cortex was correlated with Unified Dystonia Rating Scale improvement, while more anterior prefrontal connectivity was inversely correlated with Unified Dystonia Rating Scale improvement. Functional connectivity between the volumes of tissue activated and primary sensorimotor regions, motor thalamus, and cerebellum was most correlated with Unified Dystonia Rating Scale improvement; however, an inverse correlation with Unified Dystonia Rating Scale improvement was seen in the supplemental motor area and premotor cortex. Functional and structural connectivity with multiple nodes of the motor network is associated with motor improvement in patients with generalized dystonia undergoing deep brain stimulation. Results from this study may serve as a basis for future development of clinical markers to guide deep brain stimulation targeting and programming in dystonia.

Three-Year Gait and Axial Outcomes of Bilateral STN and GPi Parkinson's Disease Deep Brain Stimulation.

Objective: To examine the short- and long-term clinical outcomes of the bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) on gait and axial symptoms in Parkinson’s disease (PD) patients. Available data have been inconsistent and mostly short-term regarding the effect of both brain targets on gait and axial symptoms. We aimed to identify potential target specific differences at 3-year follow-up from a large single-center experience.Methods: We retrospectively reviewed short-term (6-month follow-up) and long-term (36-month follow-up) changes in the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II and III total scores of 72 PD patients (53 with bilateral STN-DBS and 19 with bilateral GPi-DBS). An interdisciplinary team made target-specific decisions for each DBS patient. We analyzed changes in gait and axial subscores derived from UPDRS II and III.Results: In both the STN- and GPi-DBS cohorts, we observed no significant differences in gait and axial UPDRS derived subscores in the off-med/on stimulation state at long-term follow-up when compared to baseline. On-med axial scores remained similar in the short-term but worsened in both groups (STN, 2.23 ± 3.43, p < 0.001; GPi, 2.53 ± 2.37, p < 0.01) in the long-term possibly due to disease progression. At long-term follow-up, the UPDRS III off-med/on stimulation scores worsened but were persistently improved from baseline in both groups (−9.07 ± 13.9, p < 0.001).Conclusions: The study showed that long-term both STN- and GPi-DBS had a similar effect on gait and axial symptoms in UPDRS derived subscores at 36-month follow-up despite potential baseline differences in criteria for selection of each target. More sophisticated measures of gait and balance beyond the categorical UPDRS score will be needed for future studies.

Direct Activation of Primary Motor Cortex during Subthalamic But Not Pallidal Deep Brain Stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is an effective treatment for parkinsonian motor signs. Though its therapeutic mechanisms remain unclear, it has been suggested that antidromic activation of the primary motor cortex (M1) plays a significant role in mediating its therapeutic effects. This study tested the hypothesis that antidromic activation of M1 is a prominent feature underlying the therapeutic effect of STN and GPi DBS. Single-unit activity in M1 was recorded using high-density microelectrode arrays in two parkinsonian nonhuman primates each implanted with DBS leads targeting the STN and GPi. Stimulation in each DBS target had similar therapeutic effects, however, antidromic activation of M1 was only observed during STN DBS. Although both animals undergoing STN DBS had similar beneficial effects, the proportion of antidromic-classified cells in each differed, 30 versus 6%. Over 4 h of continuous STN DBS, antidromic activation became less robust, whereas therapeutic benefits were maintained. Although antidromic activation waned over time, synchronization of spontaneous spiking in M1 was significantly reduced throughout the 4 h. Although we cannot discount the potential therapeutic role of antidromic M1 activation at least in the acute phase of STN DBS, the difference in observed antidromic activation between animals, and target sites, raise questions about its hypothesized role as the primary mechanism underlying the therapeutic effect of DBS. These results lend further support that reductions in synchronization at the level of M1 are an important factor in the therapeutic effects of DBS.SIGNIFICANCE STATEMENT Recently there has been great interest and debate regarding the potential role of motor cortical activation in the therapeutic mechanisms of deep brain stimulation (DBS) for Parkinson's disease. In this study we used chronically implanted high density microelectrode arrays in primary motor cortex (M1) to record neuronal population responses in parkinsonian nonhuman primates during subthalamic nucleus (STN) DBS and globus pallidus internus (GPi) DBS. Our results suggest a contribution of antidromic activation of M1 during STN DBS in disrupting synchronization in cortical neuronal populations; however, diminishing antidromic activity over time, and differences in observed antidromic activation between animals and target sites with antidromic activation not observed during GPi DBS, raise questions about its role as the primary mechanism underlying the therapeutic effect of DBS.