GPi Stimulation Research Articles

Deep Brain Stimulation of the Subthalamic Nucleus vs. Globus Pallidus Internus in the Treatment of Parkinson’s Disease: A Systematic Review

Abstract Background Parkinson’s disease (PD) is a very common debilitating disease especially in the elderly population. Bilateral stimulation of the subthalamic nucleus or the globus pallidus internus provides significant motor benefits for patients with advanced Parkinson’s disease, while reducing dyskinesia and motor fluctuation. High frequency stimulation of the STN and the GPi is relatively safe. The effects are stable even after 1 year of stimulation. Aim of the Work The primary goal of the current review is to compare the efficacy of using the Subthalamic Nucleus (STN) vs. the Globus Pallidus Internus (GPi) as the primary target for Deep Brain Stimulation (DBS) in the treatment of Parkinson disease (PD); in terms of improved motor function measured using the Unified Parkinson's Disease Rating Scale (UPDRS), psychiatric symptoms, rate of reduction of medication, and complications. This will be done through a systematic review of literature addressing this research question. Patients and Methods In this Review, the authors are aiming at the analysis of the collective outcomes from studies comparing bilateral deep brain stimulation of the Subthalamic Nucleus and the Globus Pallidus Internus in the management of idiopathic Parkinson’s disease. The following electronic databases were searched for included articles: PubMed, Google Scholar, EMBASE, Science Direct, Cochrane database of systematic reviews, using the keywords “Parkinson’s disease – treatment – management – deep brain stimulation – subthalamic – globus pallidus internus” in different combinations. Also, manual search were conducted for reference lists of included articles. Limiting the search in English. The information sources previously mentioned were searched from 2000 to 2021. Results A total of 594 patients underwent STN-DBS, with a mean change in total UPDRSIII score of 3.26 on medication and 25.04 off medication. A total of 446 patients underwent GPi-DBS, with a mean change in total UPDRSIII score of 4.75 on medication and 19.31 off medication. There was a higher change for GPi on medication that was statistically significant with a p value (˂0.001), while off medication STN caused a higher change that was also statistically significant with a p value (˂0.001). We observed a statistically significant higher average improvement in ADLs after STN-DBS than GPi, however, non- motor function improvements were greater after GPi DBS than STN DBS. Conclusion Based on our systematic review and other available data in the literature, the STN may be the preferred target for DBS in consideration of motor function improvement, medication reduction, and economic efficiency, although GPI stimulation has some advantages in terms of mood and cognition. Treatment decisions should be individualized and based on patients’ specific symptoms and expectations. Additional well-designed multicenter clinical trials that can minimize bias are needed, especially for evaluation of the long-term outcomes of the two stimulation targets.

Randomized double-blind sham-controlled trial of thalamic versus GPi stimulation in patients with severe medically refractory Gilles de la Tourette syndrome

BackgroundThere are still no sufficient data regarding the use of deep brain stimulation (DBS) in Gilles de la Tourette syndrome (GTS) and no agreement on optimal target. ObjectiveTo compare efficacy and safety of bilateral DBS of thalamus (centromedian-ventro-oral internus, CM-Voi) versus posteroventral lateral globus pallidus internus (pvl GPi)) versus sham stimulation, and baseline in severe medically refractory GTS. MethodsIn this randomized double-blind sham stimulation-controlled trial (RCT), 10 patients (3 women, mean age = 29.4 ± 10.2 SD, range 18–47) underwent three blinded periods each lasting three months including (i) sham, (ii) pvl GPi (on-GPi), and (iii) thalamic stimulation (on-thal) followed by an open uncontrolled long-term follow-up (up to 9 years) with individually determined target and stimulation settings. ResultsNine patients completed the RCT. At group level, on-GPi – but not on-thal – resulted in a significant tic reduction compared to baseline, but had no effect on premonitory urges and psychiatric comorbidities. Direct comparisons of targets resulted in inconsistent or negative (compared to sham) findings. During follow-up, we found no improvement of tics, comorbidities, and quality of life at group level, however, single patients benefitted continuously from thalamic DBS. At last follow-up 89.9 months (mean) after surgery, 50% of patients had discontinued DBS. Hardware infections occurred in 3/10 patients. ConclusionOur data suggest that the initial effect of pvl GPi DBS is superior to thalamic (CM-Voi) DBS. While half of the patients discontinued treatment, single patients benefitted from thalamic DBS even after years. It is likely that outcome is influenced by various factors beyond the mere change in tic severity.

Model-Based Closed-Loop Suppression of Parkinsonian Beta Band Oscillations Through Origin Analysis.

Excessive beta band (13-30 Hz) oscillations have been observed in the basal ganglia (BG) of patients with Parkinson's disease (PD). Understanding the origin and transmission of beta band oscillations are important to improve treatments of PD, such as closed-loop deep brain stimulation (DBS). This paper proposed a model-based closed-loop GPi stimulation system to suppress pathological beta band oscillations of BG. The feedback nucleus was selected through the analysis of GPi oscillations variation when different synaptic currents were blocked, mainly projections from globus pallidus external (GPe), the subthalamic nucleus (STN) and striatum. Since simulation results proved the important role of synaptic current from GPe in shaping the excessive GPi beta band oscillations, the local field potential (LFP) of GPe was chosen as the feedback signal. That is to say, the feedback nucleus was selected based on the origin analysis of the pathological GPi beta band oscillation. The closed-loop algorithm was the multiplication of linear delayed feedback of the filtered GPe-LFP and modeled synaptic dynamics from GPe to GPi. Thus, the formed stimulation waveform was synaptic current like shape, which was proved to be more energy efficient than open-loop continuous DBS in suppressing GPi beta band oscillation. With the development of DBS devices, the efficiency of this closed-loop stimulation could be testified in animal model and clinical.

Randomized double-blind controlled trial of thalamic versus GPi stimulation in patients with Gilles de la Tourette Syndrome

Randomized double-blind controlled trial of thalamic versus GPi stimulation in patients with Gilles de la Tourette Syndrome

Refractory Gait Freezing Following GPi Stimulation for Parkinson’s Disease (P1.8-036)

Refractory Gait Freezing Following GPi Stimulation for Parkinson’s Disease (P1.8-036)

Simultaneous Stimulation of the Globus Pallidus Interna and the Nucleus Basalis of Meynert in the Parkinson-Dementia Syndrome

Background/Aim: The prevalence of cognitive symptoms in recently diagnosed Parkinson’s disease (PD) patients may be as high as 60%. We report a novel deep brain stimulation (DBS) strategy targeting both motor and cognitive symptoms. Methods: A PD patient diagnosed with mild cognitive impairment underwent DBS surgery targeting the globus pallidus interna (GPi; to treat motor symptoms) and the nucleus basalis of Meynert (NBM; to treat cognitive symptoms) using a single electrode per hemisphere. Results: Compared to baseline, 2-month follow-up after GPi stimulation was associated with motor improvements, whereas partial improvements in cognitive functions were observed 3 months after the addition of NBM stimulation to GPi stimulation. Conclusion: This case explores an available alternative for complete DBS treatment in PD, stimulating 2 targets at different frequencies with a single electrode lead.

Before and after the veterans affairs cooperative program 468 study: Deep brain stimulator target selection for treatment of Parkinson's disease

IntroductionThe Veterans Affairs Cooperative Study Program 468 study (CSP 468) produced significant findings regarding deep brain stimulation (DBS) target selection for Parkinson's Disease (PD) treatment, yet its impact on clinical practices has not been described. Here we assess how CSP 468 influenced target selection at a high-volume movement disorders treatment center. MethodsWe compared DBS target site selection between 4-year periods that immediately preceded and followed CSP 468 publication. Additionally, we examined how baseline clinical features influenced target selection following CSP 468. ResultsThe STN was the predominant site of DBS implantation before and after CSP 468 publication (93.2% of cases, and 60.4%, respectively), but GPi targeting increased significantly following CSP 468 publication (from 5.3% to 37.4%; p < .001). Patients who underwent GPi stimulation following CSP 468 exhibited worse indices of depression (p < .001), less responsiveness to medications (p < .05), and a trend towards worse pre-operative cognitive performance (p = .06). In multi-variate analysis, advanced patient age and depression were independent predictors of GPi targeting (p < .01). ConclusionsKey findings of CSP 468 were reflected in our target selection of DBS for Parkinson's Disease. Following CSP 468, GPi targeting increased, and it was selected for patients with poorer cognitive and mood indices.

326 Characterization of Synchronization Between Globus Pallidus Neurons and Motor Cortex in Parkinson's Disease

Abstract INTRODUCTION Excessive oscillatory neuronal synchronization throughout the basal ganglia thalamocortical motor loop is a hallmark of the Parkinsonian state. This may manifest as spike-spike correlations, coherence between field potentials, or spike-field interactions within or between structures in the circuit. Globus pallidus occupies a central role in basal ganglia processing, but neither internal (GPi) nor external (GPe) globus pallidus is monosynaptically connected to motor cortex. Understanding patterns of M1-pallidal synchronization will provide insight into the possible different roles of GPi and GPe stimulation, compared to STN stimulation, in ameliorating the excessive neuronal synchronization in PD. METHODS Using subdural electrodes and high resolution electrocorticography (ECoG) contacts temporarily placed over motor cortex during DBS implantation and microelectrode recordings, we evaluate the strength and topography of synchronization between pallidal neurons and cortical ECoG potentials in 16 PD patients. RESULTS &gt;Recording from 59 GPe and 42 GPi cells with cortical ECoG field potentials demonstrated that 17% of GPe and 12% of GPi neurons showed significant interactions associated with cortical recording sites approximately 25 mm from midline. For those pairs with significant interactions, peak of the spike-triggered average potentials occurred within 100ms prior to spike time. GPe neurons showed maximum coherence with M1 in the beta (13-30 Hz) frequency range while GPi neurons had maximum coherence in the alpha (8-12 Hz) range. CONCLUSION Topography of significant M1-pallidal interactions is consistent with tractography findings showing more mesial areas of M1 to dominate cortical-basal ganglia anatomic connectivity. The observation that GPe stimulation is more “prokinetic” than GPi stimulation may be explained by the finding that GPe is more synchronized to the cortex in beta frequencies than GPi, as disruption of beta oscillation is important in ameliorating akinesia.

218 Target Selection for Deep Brain Stimulation in Children with Secondary Dystonia Utilizing Temporary Depth Electrodes for Stimulation and Chronic Recording

Abstract INTRODUCTION The optimal target for deep brain stimulation (DBS) treatment in children with secondary dystonia is not known, and the target may vary depending on the etiology and anatomic distribution of injury in each child. We present a new technique for determining optimal neuro-anatomical targets in these patients. METHODS Up to ten depth electrodes are implanted in each child in multiple brain regions, including bilateral STN, GPi, and the VLa (Vo), VLp (Vim) and VPL nuclei of the thalamus. Each electrode had both high-impedance micro contacts to identify single unit firing and macro contacts for identifying local field potentials and for performing test stimulation. Children were monitored for up to one week with continuous recording from all electrodes and intermittent test stimulation at bilateral contact pairs. RESULTS &gt;No single consistent pattern of abnormality was found. Most often, single-unit recording showed high firing rates in GPi, and dystonic movement correlated with activity VLa or VLp. The optimal stimulation target varied between children, with rapid improvement of dystonic postures during stimulation in either VLa, VLp or VPL. Stimulation of STN caused resolution of spasms during sleep in one child. Stimulation in GPi did not produce an immediate effect during the recording period, consistent with known latency of treatment effect. All of the children were implanted with up to 4 permanent stimulation leads connected to implanted pulse generators. Preliminary clinical observations show significant beneficial effect in all children. CONCLUSION This new method of DBS targeting identified targets that varied between children. Early response to therapy suggests a beneficial effect that exceeds what would be expected for GPi stimulation alone. This technique may increase the effectiveness of DBS in secondary dystonia and may allow application to a broader range of conditions in children not previously known to respond to stimulation.

S84 Subthalamic and GPI stimulation and cortical plasticity

Objectives Review the effects of subthalamic (STN) and internal globus pallidus (GPi) stimulation on cortical plasticity. Methods Several relevant studies are reviewed. Results Using paired associative stimulation, most studies found decreased plasticity in Parkinson’s disease (PD). Dopaminergic medications restored plasticity in patients without levodopa-induced dyskinesia but not in patients with dyskinesia. Early, drug naive PD patients had decreased plasticity on the more affected side but had exaggerated plasticity on the less affected side. This asymmetry in plastsicity decreased over 12 months, which may reflect reduced compensation. In dyskinetic PD patients treated with STN deep brain stimulation (DBS), cortical plasticity was deficient in the off medication state but was restored in the medication on state with the stimulator turned on. STN DBS increases motor cortical excitability at about 3 ms likely through antidromic activation of the hyperdirect pathway, and at 23 ms likely through the indirect pathway. Repeated pairing STN DBS and cortical magnetic stimulation at these specific intervals induced motor cortical plasticity in PD patients. Similarly, repeated pairing of GPi stimulation and cortical magnetic stimulation at specific intervals induced cortical plasticity in dystonia patients. Discussion Cortical plasticity appears to be decreased in PD patients and is partially restored in some patients on medications while increased plasticity may be a compensatory mechanism in early PD. Cortical plasticity is strongly influenced by the basal ganglia. Conclusion DBS can modulate and induce cortical plasticity in PD and dystonia. Significance Modulation of cortical plasticity may be involved in mediating the effects of DBS.

Adverse events in deep brain stimulation: A retrospective long-term analysis of neurological, psychiatric and other occurrences.

Background and objectiveThe extent to which deep brain stimulation (DBS) can improve quality of life may be perceived as a permanent trade-off between neurological improvements and complications of therapy, comorbidities, and disease progression.Patients and methodsWe retrospectively investigated 123 consecutive and non-preselected patients. Indications for DBS surgery were Parkinson's disease (82), dystonia (18), tremor of different etiology (21), Huntington's disease (1) and Gilles de la Tourette syndrome (1). AEs were defined as any untoward clinical occurrence, sign or patient complaint or unintended disease if related or unrelated to the surgical procedures, implanted devices or ongoing DBS therapy.ResultsOver a mean/median follow-up period of 4.7 years (578 patient-years) 433 AEs were recorded in 106 of 123 patients (86.2%). There was no mortality or persistent morbidity from the surgical procedure. All serious adverse events (SAEs) that occurred within 4 weeks of surgery were reversible. Neurological AEs (193 in 85 patients) and psychiatric AEs (78 in 48 patients) were documented most frequently. AEs in 4 patients (suicide under GPI stimulation, weight gain >20 kg, impairment of gait and speech, cognitive decline >2 years following surgery) were severe or worse, at least possibly related to DBS and non reversible. In PD 23.1% of the STN-stimulated patients experienced non-reversible (or unknown reversibility) AEs that were at least possibly related to DBS in the form of impaired speech or gait, depression, weight gain, cognitive disturbances or urinary incontinence (severity was mild or moderate in 15 of 18 patients). Age and Hoehn&Yahr stage of STN-simulated PD patients, but not preoperative motor impairment or response to levodopa, showed a weak correlation (r = 0.24 and 0.22, respectively) with the number of AEs.ConclusionsDBS-related AEs that were severe or worse and non-reversible were only observed in PD (4 of 82 patients; 4.9%), but not in other diseases. PD patients exhibited a significant risk for non-severe AEs most of which also represented preexisting and progressive axial and non-motor symptoms of PD. Mild gait and/or speech disturbances were rather frequent complaints under VIM stimulation. GPI stimulation for dystonia could be applied with negligible DBS-related side effects.

Effect GPi Stimulation on Human Thalamic Neuronal Activity: A Decade Later

Effect GPi Stimulation on Human Thalamic Neuronal Activity: A Decade Later

Deep brain stimulation of the globus pallidus internus or ventralis intermedius nucleus of thalamus for Holmes tremor.

Holmes tremor (HT) is a difficult-to-treat, very disabling symptomatic condition which characteristically appears weeks to years after a brain lesion. It features a unique combination of rest, action, and postural tremors. Pharmacotherapy is mostly not effective. Chronic deep brain stimulation (DBS) of ventralis intermedius nucleus (Vim) of thalamus has been described as being the best surgical approach in singular case series; various authors observe, however, cases with partial responses only; therefore, alternatives are still needed. We report ten patients with HT unresponsive to best medical therapy who underwent DBS in our center from March 2002 to June 2012. Based in our previous experience dealing with cases of unsatisfactory Vim intraoperative tremor control and in order to optimize surgical results, presurgical target planning included two Nuclei: Vim and posteroventral Globus pallidus internus (GPi) (Espinoza et al. 2010; Espinoza et al. Stereotact Funct Neurosurg 90(suppl 1):1-202, p 61, 2012). Definitive chosen target was decided after single-cell microelectrode recording, intraoperative test stimulation, thresholds for stimulation-induced adverse effects and best clinical response compared to baseline status. Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) was used to evaluate outcome. The electrode was implanted in the nucleus with the best tremor suppression achievement; on the other hand, GPi DBS was initially decided if one of the following conditions was present: (a) If Vim nucleus anatomy was grossly altered; (b) when intraoperative tremor control was unsatisfactory despite Vim high-intensity stimulation; or (c) if unaffordable side effects or even tremor worsening occurred during intraoperative macrostimulation. Seven patients received definitive Gpi DBS implantation, while three patients received Vim DBS. In all observed cases, we observed an improvement on the TRS. In two cases where Vim thalamic anatomy was altered by the pathological insult GPI was planned from the beginning, and same was true in two additional cases where the Gpi nucleus showed major alterations allowing only Vim planning. Over all cases, the average improvement in tremor was of 2.55 points on the TRS or a 64% increase in measured results; with a minimum of 1 point (25%) improvement in one case and a maximum of 4 points (100% improvement) also in one case. All the results were sustained at 2years follow-up. One case with predominant resting component, implanted in the GPi, achieved the maximum possible tremor reduction (from 4 to 0 points, meaning 100% tremor reduction); in the nine resting cases, the average reduction was of 3 points (or 75%). DBS demonstrated in this case series adequate tremor control in 10 patients unresponsive to medical therapy. Presurgical planning of two targets allowed choosing best optimal response. Gpi stimulation could be considered as an alternative target for cases in which thalamic anatomy is considerably altered or Vim intraoperative stimulation does not produce satisfactory results.

Interactive effects of GPI stimulation and levodopa on postural control in Parkinson's disease

IntroductionPostural instability is a major source of disability in idiopathic Parkinson's disease (IPD). Deep brain stimulation of the globus pallidus internus (GPI-DBS) improves clinician-rated balance control but there have been few quantitative studies of its interactive effects with levodopa (L-DOPA). The purpose of this study was to compare the short-term and interactive effects of GPI-DBS and L-DOPA on objective measures of postural stability in patients with longstanding IPD. MethodsStatic and dynamic posturography during a whole-body leaning task were performed in 10 IPD patients with bilateral GPI stimulators under the following conditions: untreated (OFF); L-DOPA alone; DBS alone; DBS+L-DOPA, and in 9 healthy Control subjects. Clinical status was assessed using the UPDRS and AIMS Dyskinesia Scale. ResultsStatic sway was greater in IPD patients in the OFF state compared to the Control subjects and was further increased by L-DOPA and reduced by GPI-DBS. In the dynamic task, L-DOPA had a greater effect than GPI-DBS on improving Start Time, but reduced the spatial accuracy and directional control of the task. When the two therapies were combined, GPI-DBS prevented the L-DOPA induced increase in static sway and improved the accuracy of the dynamic task. ConclusionThe findings demonstrate GPI-DBS and L-DOPA have differential effects on temporal and spatial aspects of postural control in IPD and that GPI-DBS counteracts some of the adverse effects of L-DOPA. Further studies on larger numbers of patients with GPI stimulators are required to confirm these findings and to clarify the contribution of dyskinesias to impaired dynamic postural control.

Unilateral Thalamic Vim and GPi Stimulation for the Treatment of Holmes' Tremor Caused by Midbrain Cavernoma: Case Report and Review of the Literature

A 30-year-old man with brainstem cavernoma experienced hemorrhage and was operated in 2008. Six months after the operation, the patient presented with new complaints of left arm tremor namely Holmes' tremor. Neurological examination also revealed left-sided internuclear ophthalmoplegia, left-sided mild paresis, and increased deep tendon reflexes of the left upper extremity, truncal ataxia, and dysarthria. Brain magnetic resonance imaging showed a postoperative cavity and gliosis at the level of the superior and inferior colliculus in the right tegmentum and right red nucleus with extension to the substantia nigra. Fahn-Tolosa-Marin tremor rating scale (TRS) for his left upper extremity (Part A, score 6) was 11 for the proximal and the distal arm. After the failure of medical treatment, the patient underwent right globus pallidum internus and ventral intermediate thalamic nucleus deep brain stimulation. There were no side effects related to the stimulation. Final TRS months after operation was 3 for the proximal and 4 for the distal arm.

パーキンソン病に対するDBS療法－当施設での取り組み－

It is controversial whether the STN or the GPi, the main targets of DBS therapy in patients with Parkinson's disease, is the appropriate target. We select GPi-DBS in patients judged by our cognitive function test battery to be at high-risk for cognitive decline after STN-DBS. While DBS surgery is usually performed under local anesthesia for the precise placement of DBS electrodes, general anesthesia might be useful in patients intolerant of long-lasting surgical stress. Our monkey experiments revealed that the most medial part of the STN receives direct input from the limbic cortex, suggesting that the spread of stimulation to these limbic territories may elicit adverse emotional effects. Other monkey experiments on the physiological mechanism of DBS suggest that high-frequency GPi stimulation disrupts information flow through the GPi.

Deep Brain Stimulation for Movement Disorders – A History of Success and Challenges to Conquer

Deep Brain Stimulation for Movement Disorders – A History of Success and Challenges to Conquer

Low-Voltage Bilateral Pallidal Stimulation for Severe Meige Syndrome in a Patient With Primary Segmental Dystonia

Meige syndrome (MS) is an adult-onset segmental dystonia characterized by the combination of upper and lower cranial involvement. Its treatment is challenging and the use of oral medication or of botulinum neurotoxin treatment is not decisive. Deep brain stimulation of the globus pallidus internum (GPi DBS) has been used occasionally in severe cases. We report the long-term efficacy of low-voltage chronic bilateral GPi DBS in a patient with segmental dystonia featuring severe MS and cervical brachial involvement. The patient received a bilateral ventroposterolateral GPi implant. Postoperative 3-dimensional reconstruction allowed checking of the definitive position of the electrode and contacts within the targeted nucleus. Following implant, the patient received bilateral low-voltage stimulation, consisting in amplitude of 1.3 V with a pulse width of 90 microseconds and a frequency of 130 Hz, yielding a current of 23 microA. Clinical follow-up for 38 months showed a progressive and sustained improvement of dystonia with unchanged electrical settings throughout the observation period. The patient again undertook normal life activities. Bilateral low-voltage GPi stimulation allowed efficient control of MS symptoms and the associated brachial cervical dystonia.

Stimulation-induced parkinsonism after posteroventral deep brain stimulation of the globus pallidus internus for craniocervical dystonia

The authors report on a patient with craniocervical dystonia who was treated with bilateral GPi stimulation, with excellent improvement in dystonia but at the cost of stimulation-induced, reversible parkinsonism. Stimulation through ventral contacts resulted in maximal relief of craniocervical dystonia but induced considerable hypophonia, bradykinesia, rigidity, freezing, and impaired postural reflexes. Stimulation through dorsal contacts alleviated parkinsonism, but resulted in the return of dystonia. No stimulation parameters could alleviate the dystonia without inducing parkinsonism over the course of his 4-year follow-up.

Contrasting Changes in Cortical Activation Induced by Acute High-Frequency Stimulation within the Globus Pallidus in Parkinson's Disease

Continuous stimulation of the globus pallidus (GP) has been shown to be an effective treatment for Parkinson's disease (PD). We used the fact that the implanted quadripolar leads contain electrodes within the GPi and GPe to investigate the clinical effects of acute high-frequency stimulation applied in these nuclei and changes in regional cerebral blood flow (rCBF) as an index of synaptic activity. In five patients treated by chronic GP stimulation, we compared the effects on PD symptoms and the changes in rCBF at rest and during paced right-hand movements, with and without left GPe or GPi stimulation. Although improving contralateral rigidity and akinesia, left GPe stimulation decreased rCBF in the left cerebellum and lateral premotor cortex at rest and significantly increased it in the left primary sensorimotor cortex (SM1) during movement. In contrast, left ventral GPi stimulation, which improved rigidity and worsened akinesia, decreased rCBF in the left SM1, premotor area, anterior cingulum, and supplementary motor area but did not modify the movement-related activation. GPe stimulation seems to result in a reduced activity of motor-related areas and the facilitation of motor cortex activation during movement, the latter component being absent during GPi stimulation, and this may explain the observed worsening of akinesia.