Stimulation of the subthalamic nucleus compared with the globus pallidus internus in patients with Parkinson disease

OBJECT: The authors compared the effects of deep brain stimulation (DBS) in the globus pallidus internus (GPi) with those in the subthalamic nucleus (STN) in patients with Parkinson disease (PD) in whom electrodes had been bilaterally implanted in both targets. METHODS: Eight of 14 patients with advanced PD in whom electrodes had been implanted bilaterally in both the GPi and STN for DBS were selected on the basis of optimal DBS effects and were studied 2 months postsurgery in off- and on-stimulus conditions and after at least 1 month of pharmacological withdrawal. Subcutaneous administration of an apomorphine test dose (0.04 mg/kg) was also performed in both conditions. Compared with the off status, the results showed less reduction in the Unified PD Rating Scale Section III scores during DBS in the GPi (43.1%) than during DBS of the STN (54.5%) or DBS of both the STN and GPi (57.1%). The difference between the effects of DBS in the GPi compared with that in the STN or simultaneous DBS was statistically significant (p < 0.01). In contrast, no statistical difference was found between DBS in the STN and simultaneous DBS in the STN and GPi (p < 0.9). The improvement induced by adding apomorphine administration to DBS was similar in all three stimulus modalities. The abnormal involuntary movements (AIMs) induced by apomorphine were almost abolished by DBS of the GPi, but were not affected by stimulation of the STN. The simultaneous stimulation of STN and GPi produced both antiparkinsonian and anti-AIM effects. CONCLUSIONS: The improvement of parkinsonian symptoms during stimulation of the GPi, STN, and both nuclei simultaneously may indicate a similar DBS mechanism for both nuclei in inducing antiparkinsonian effects, although STN is more effective. The antidyskinetic effects produced only by DBS of the GPi, with or without STN, may indicate different mechanisms for the antidyskinetic and antiparkinsonian activity related to DBS of the GPi or an additional mechanism in the GPi. These findings indicate that implantation of double electrodes for DBS should not be proposed as a routine procedure, but could be considered as a possible subsequent choice if electrode implantation for DBS of the STN does not control AIMs.     

Combined pallidal and subthalamic nucleus stimulation in sporadic dystonia-parkinsonism

Multifocal deep brain stimulation (DBS) is a new technique that has been introduced recently. A 39-year-old man with dystonia-parkinsonism underwent the simultaneous implantation of subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS electrodes. While bilateral STN DBS controlled the parkinsonian symptoms well and allowed for a reduction in levodopa, the improvement of dystonia was only temporary. Additional GPi DBS also alleviated dystonic symptoms. Formal assessment at the 1-year follow-up showed that both the parkinsonian symptoms and the dystonia were markedly improved via continuous bilateral combined STN and GPi stimulation. Sustained benefit was achieved at 3 years postoperatively.     

Deep brain stimulation in Parkinson's disease: bilateral implantation of globus pallidus and subthalamic nucleus

AIM: Deep brain stimulation (DBS) of subthalamic nucleus (STN) and of the pars interna of globus pallidus (GPi) is used to improve Parkinsonian symptoms and attenuate levodopa-induced motor complications in Parkinson's disease (PD). What are the physiological effect of DBS and the best anatomical structure to stimulate are still not completely clear. In this way we could evaluate the clinical effects of simultaneous stimulation of STN and GPi as well as the isolated stimulation of each target. METHODS: The stereotactic methods used to localise STN and GPi were based on non-telemetric ventriculography, with 3P Maranello or Leksell Stereotactic System. The effects of DBS have been assessed in 13 cases of PD, immediately after (30 minutes) the stimulation has turned on and during chronic stimulation (weeks or months). RESULTS: Most of the studies have been conducted on patients with STN implantation, and these studies reported relevant improvement in motor function and relatively low rate of complication. CONCLUSION: The large experience of ablative surgery associate with the DBS experience of some group worldwide indicate that GPi is a possible and very promising target for the management of Parkinsonian symptoms. Our patients demonstrate in acute and chronic evaluation, the best clinical results with contemporary activation of DBS in both targets.     

Deep brain stimulation for Parkinson's disease. A critical re-evaluation of STN versus GPi DBS

Deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) is increasingly being used for the treatment of advanced Parkinson's disease (PD). Although both targets have demonstrated clinical efficacy in the treatment of the cardinal motor signs of PD, the STN has gained greater popularity and is now considered the site of choice by most centers performing these procedures. This preference stems predominately from the belief that STN DBS provides greater improvement in reducing the motor manifestations of PD and allows a reduction in dopaminergic medication not permitted with GPi DBS. There are, however, a number of issues that must be considered before abandoning GPi in favor of STN as the surgical target of choice for DBS. The maximal benefit reported for GPi stimulation is not significantly different than that reported for the STN, 67 versus 71%, and while reductions in medication are required with STN stimulation to avoid inducing dyskinesia, GPi stimulation may directly suppress dyskinesia obviating any need to reduce medication. As such, many centers may not attempt to reduce antiparkinsonian medication with GPi DBS. In addition, there are significantly more reports of changes in mood, behavior and a higher incidence of adverse events reported for STN stimulation. Most studies of DBS are nonrandomized, assessment protocols are not standardized, and lead locations are not reported. Thus, before drawing conclusions regarding the optimal site for DBS for advanced PD we must take a critical eye to the present data and address the outstanding questions that remain with well-designed clinical trials that evaluate motor, nonmotor and adverse events and address the above clinical variables by randomizing patients, using standardized methods of assessment and defining the lead location.     

Weight Change after Globus Pallidus Internus or Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease and Dystonia

Background: Weight gain has been described in Parkinson's disease (PD) patients after subthalamic nucleus (STN) deep brain stimulation (DBS). Objectives: We examined change in weight following DBS in both PD and dystonia patients to further investigate the role of disease and brain target (STN or globus pallidus internus, GPi) specificity. Methods: Data was retrospectively collected on 61 PD DBS patients (STN n = 31 or GPi n = 30) and on 36 dystonia DBS patients (STN n = 9 and GPi n = 27) before and after surgery. Annual change in body mass index (BMI) was evaluated with nonparametric tests between groups and multiple quantile regression. Results: PD patients treated with STN DBS had a small increase in median BMI while those with GPi had a small decrease in BMI. Dystonia patients treated with STN DBS had a greater increase in BMI per year compared to those treated with GPi DBS. Multivariable regression analyses for each disease showed little difference between targets in weight gain in those with PD, but STN target was strongly associated with weight gain in dystonia patients (STN vs. GPi, +7.99 kg, p = 0.012). Conclusions: Our results support previous reports of weight gain after DBS in PD. This is the first report to suggest a target-specific increase in weight following STN DBS in dystonia patients.     

Parkinson’s disease: Surgical options

Opinion statement Surgical therapy for Parkinson’s disease (PD) has been a treatment option for over 100 years. Advances in the knowledge of basal ganglia physiology and in techniques of stereotactic neurosurgery and neuroimaging have allowed more accurate placement of lesions or “brain pacemakers” in the sensorimotor regions of target nuclei. This, in turn, has led to improved efficacy with fewer complications than in the past. Currently, bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) is the preferred option (and is approved by the US Food and Drug Administration) for the surgical treatment of PD. The most important predictors for outcome for DBS for PD are patient selection and electrode location. Patients should have a documented preoperative improvement from dopaminergic medication of at least 30% in the patient’s Unified Parkinson’s Disease Rating Scale motor disability scores. A levodopa challenge may be needed to document the best “on” state. Dementia or active cognitive decline must be excluded. Active psychiatric disease should be treated preoperatively. Patients should be motivated, with good support systems, and committed to the postoperative management of DBS therapy. Deep brain stimulation should be considered when the patient begins to experience dyskinesia and on-off fluctuations despite optimal medical therapy. Deep brain stimulation is not a good option at the final stages of the disease because of the increased incidence of dementia and severe comorbidity. The DBS electrode should be placed in the sensorimotor region of the GPi or STN. Subthalamic nucleus and GPi DBS can improve all motor aspects of PD, as well as predictable “on” time, without dyskinesia or fluctuations. On average, STN DBS results in a greater reduction of dopaminergic medication compared with GPi DBS. Because of the smaller size of the target region, the pulse generator battery life is longer with STN then with GPi DBS. Deep brain stimulation programming is a skill that is readily learned and may be required of all neurologists in the future. Emerging surgical therapies are restorative, and they aim to replace or regenerate degenerating dopaminergic neurons. These include embryonic mesencephalic tissue transplantation, human embryonic stem cell transplantation, and gene-derived methods of intracerebral implantation of growth factors and dopamineproducing cell lines. It will be important to determine whether DBS, if performed before the onset of motor response complications to medical therapy, may prevent this stage of disease altogether or delay it for a significant period of time. The same question applies to the future with restorative therapy.     

Subthalamic nucleus stimulation for advanced Parkinson's disease: how to find a far medial STN.

In a patient with advanced Parkinson's disease, an anatomically deviant far medial subthalamic nucleus (STN) posed problems in the placement of DBS electrodes for chronic high frequency (HF) stimulation despite the use of multimodal targeting with 1) statistical atlas data, 2) T (2)-weighted (T (2)W) magnetic resonance imaging (MRI), 3) microelectrode recording, and 4) clinical testing with macro stimulation. Diagnostic T (2)W MRI suggested that the patient's STN was in a typical location and seemed to confirm the statistical atlas-based planning. Intraoperatively, cell activity recording (MER) with five parallel electrodes could not reveal any STN typical activity profile and electrical stimulation was not able to disclose a medial or lateral displacement of the electrodes. The operation was discontinued and postoperative stereotactic CT confirmed that the correct target area had been approached during the operation. Postoperative T (2)W MRI now disclosed a left STN which was 2 mm medial of the initial target and lead to a further medial target definition and finally to a successful DBS placement. In conclusion, finding a deep seated DBS target like the STN can be difficult in cases with an extremely deviant anatomy even if reiterative sophisticated multimodal planning is used. In the presented case we applied the integrated information from intraoperative MER, macrostimulation and postoperative imaging work-up and were able to complete DBS implantation successfully.     

Does deep brain stimulation improve lower urinary tract symptoms in Parkinson's disease?

Aims

To investigate whether deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) or the subthalamic nucleus (STN) improve lower urinary tract symptoms (LUTS) in advanced Parkinson's disease (PD).

Methods

An exploratory post‐hoc analysis was performed of specific LUTS items of questionnaires used in a randomized clinical trial with 128 patients (NSTAPS study). First, we compared scores on LUTS items at baseline and 12 months for the GPi DBS and STN DBS group separately. Second, we divided the group by sex, instead of DBS location; to assess a possible gender associated influence of anatomical and pathophysiological differences, again comparing scores at baseline and 12 months. Third, we reported on Foley‐catheter use at baseline and after 12 months.

Results

Urinary incontinence and frequency improved after both GPi DBS and STN DBS at 12 months, postoperatively, but this was only statistically significant for the STN DBS group (P = 0.004). The improvements after DBS were present in both men (P = 0.01) and women (P = 0.05). Nocturia and urinary incontinence did not improve significantly after any type of DBS, irrespective of sex. At 12 months, none of the patients had a Foley‐catheter.

Conclusions

Urinary incontinence and frequency significantly improved after STN DBS treatment in male and female patients with PD. Nocturia and nighttime incontinence due to parkinsonism did not improve after DBS, irrespective of gender.     

Hemorrhagic complications of microelectrode-guided deep brain stimulation

BACKGROUND: The incidence of intracranial hemorrhage occurring during microelectrode-guided implantation of deep brain stimulators (DBS) for movement disorders has not been well defined. We report the incidence of hemorrhage in a large series of DBS implants into the subthalamic nucleus (STN), thalamus (VIM) and internal globus pallidus (GPi). METHODS: All DBS procedures performed by a single surgeon (P.A.S.) between June 1998 and April 2003 were included in this study. Patients had postoperative imaging (MRI or CT) 4-24 h following surgery, and all hematomas >0.2 cm(3) in volume were noted and scored as symptomatic (associated with any new neurologic deficit lasting >24 h) or asymptomatic. RESULTS: The total number of lead implants was 357. There were 5 symptomatic hematomas and 6 asymptomatic hematomas. The relative risk of hematoma (any type) per lead implant was 3.1%. The incidence of hematoma by target site was 2.5% per lead for STN-DBS, 6.7% for GPi-DBS and 0% for VIM-DBS. CONCLUSION: The overall risk of intraoperative or early postoperative symptomatic hemorrhage with microelectrode-guided DBS, over all targets, was 1.4% per lead implant. The brain target had a significant effect on the risk of hemorrhage.     

Deep Brain Stimulation for Parkinson’s Disease: Recent Trends and Future Direction

To date, deep brain stimulation (DBS) has already been performed on more than 120,000 patients worldwide and in more than 7,000 patients in Japan. However, fundamental understanding of DBS effects on the pathological neural circuitry remains insufficient. Recent studies have specifically shown the importance of cortico-striato-thalamo-cortical (CSTC) loops, which were identified as functionally and anatomically discrete units. Three main circuits exist in the CSTC loops, namely, the motor, associative, and limbic circuits. From these theoretical backgrounds, it is determined that DBS sometimes influences not only motor functions but also the cognitive and affective functions of Parkinson’s disease (PD) patients. The main targets of DBS for PD are subthalamic nucleus (STN) and globus pallidus interna (GPi). Ventralis intermedius (Vim)-DBS was found to be effective in improving tremor. However, Vim-DBS cannot sufficiently improve akinesia and rigidity. Therefore, Vim-DBS is seldom carried out for the treatment of PD. In this article, we review the present state of DBS, mainly STN-DBS and GPi-DBS, for PD. In the first part of the article, appropriate indications and practical effects established in previous studies are discussed. The findings of previous investigations on the complications caused by the surgical procedure and on the adverse events induced by DBS itself are reviewed. In the second part, we discuss target selection (GPi vs. STN) and the effect of DBS on nonmotor symptoms. In the final part, as issues that should be resolved, the suitable timing of surgery, symptoms unresponsive to DBS such as on-period axial symptoms, and the related postoperative programing of stimulation parameters, are discussed.     

Eye Movement Network Originating from Frontal Eye Field: Electric Cortical Stimulation and Diffusion Tensor Imaging

This study investigated the networks originating from frontal eye fields (FEFs) using electric cortical stimulation and diffusion tensor imaging (DTI). Seven patients with intractable focal epilepsy, in which FEFs were identified by electrical cortical stimulation, were enrolled in this study. Electric stimulation at 50 Hz was applied to the electrodes for functional mapping. DTI was used to identify the subcortical fibers originating from the FEFs with two regions of interests (ROIs) in the FEF and contralateral paramedian pontine reticular formation (PPRF). FEFs were found in the superior precentral sulcus (pre-CS) in six patients and superior frontal gyrus (SFG) in three patients. DTI detected fibers connecting FEFs and contralateral PPRFs, passing within the internal capsule. The fibers were located close to the lateral antero-superior border of the subthalamic nucleus (STN) and medial posterior border of the globus pallidus internus (GPi). This study found the characteristic subcortical networks of the FEF. These tracts should be noted to prevent complications of deep brain stimulation (DBS) of the STN or GPi.     

Placement of deep brain stimulators into the subthalamic nucleus

We present our technique for deep brain stimulation (DBS) of the subthalamic nucleus (STN) and include information which may be helpful in general DBS. With the patient in a stereotactic head frame, the anterior and posterior commissures are identified on SPGR-sequence magnetic resonance imaging (MRI). STN coordinates are based on a stereotactic brain atlas at 12 mm lateral, 2 mm posterior and 5 mm caudal to the midcommissural point. Surgical navigation software allows for planning of the trajectory. Electromyography is used to quantitatively measure tremor responses to macrostimulation. Permanent lead placement is confirmed with intraoperative fluoroscopy and postoperative MRI.     

Variability in position of the subthalamic nucleus targeted by magnetic resonance imaging and microelectrode recordings as compared to atlas co-ordinates

BACKGROUND: Traditional methods for localisation of target nuclei for deep brain stimulation (DBS) have used brain atlas co-ordinates for initial targeting. It is now possible to visualise the subthalamic nucleus (STN) on magnetic resonance imaging (MRI) and determine the individual variability of its position. METHODS: The present study was performed in patients undergoing STN DBS for Parkinson's disease. The STN was directly targeted from axially obtained MRI and verified with microelectrode recordings. Postoperatively, the most effective contact was identified for each patient, and its position was calculated. RESULTS: Fifty electrodes were inserted in 25 patients. The target position varied considerably in relation to the mid-commissural point. The mean effective contact position lies just dorsal to the location of the STN in a standard brain atlas. CONCLUSION: The STN varies in position, and can be accurately targeted from MRI alone.     

Postmortem analysis following 71 months of deep brain stimulation of the subthalamic nucleus for Parkinson disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a clinically effective neurosurgical treatment for Parkinson disease. Tissue reaction to chronic DBS therapy and the definitive location of active stimulation contacts are best studied on a postmortem basis in patients who have undergone DBS. The authors report the postmortem analysis of STN DBS following 5 years and 11 months of effective chronic stimulation including the histologically verified location of the active contacts associated with bilateral implants. They also describe tissue response to intraoperative test passes with recording microelectrodes and stimulating semimacroelectrodes. The results indicated that 1) the neural tissue surrounding active and nonactive contacts responds similarly, with a thin glial capsule and foreign-body giant cell reaction surrounding the leads as well as piloid gliosis, hemosiderin-laden macrophages, scattered lymphocytes, and Rosenthal fibers; 2) there was evidence of separate tracts in the adjacent tissue for intraoperative microelectrode and semimacroelectrode passes together with reactive gliosis, microcystic degeneration, and scattered hemosiderin deposition; and 3) the active contacts used for approximately 6 years of effective bilateral DBS therapy lie in the zona incerta, just dorsal to the rostral STN. To the authors' knowledge, the period of STN DBS therapy herein described for Parkinson disease and subjected to postmortem analysis is the longest to date.     

Suppression of secondary generalization of limbic seizures by stimulation of subthalamic nucleus in rats

OBJECT: Deep brain stimulation (DBS) of subcortical nuclei such as the subthalamic nucleus (STN) or the substantia nigra pars reticulata (SNR) may provide an alternative therapy for intractable epilepsy. The authors attempted to evaluate the antiepileptic effects of DBS to these structures in an experimental seizure model. METHODS: Three groups of rats were prepared. In the first two groups, the rats underwent unilateral implantation of stimulation electrodes in the STN (six rats) or the SNR (six rats). A control group received no electrodes (six rats). Kainic acid (KA) was systemically administered to induce limbic seizures, which started with focal seizures and became generalized secondarily. High-frequency electrical stimulation of the STN or SNR was begun immediately after KA administration, and changes on electroencephalography (EEG) and the magnitude of clinical seizures were evaluated. Results showed that STN stimulation significantly reduced the duration of generalized seizures on EEG, although the total duration of seizures (generalized plus focal seizures) was unchanged. The duration of focal seizures on EEG was prolonged by STN DBS, a result possibly due to the suppression of secondary generalization. In addition, STN DBS reduced the severity of clinical seizures. On the other hand, stimulation of the SNR demonstrated no effect. CONCLUSIONS: Unilateral STN DBS showed significant suppression of the secondary generalization of limbic seizures. Note, however, that SNR DBS was less effective, which implies that in addition to the nigral control of the epilepsy system, another antiepileptic mechanism such as antidromic stimulation of the corticosubthalamic pathway should be considered.     

Deep brain stimulation for Parkinson’s disease: how to select candidates for pallidal or subthalamic stimulation

Chronic deep brain stimulation therapy has the reversibility, selectivity and adjustability needed to achieve an adequate effect, so that it represents an ideal tool for functional neurosurgery designed to treat parkinsonian symptoms. Some kinds of chronic stimulation have become an alternative to lesion-making surgery, supported by the fact that high-frequency stimulation induces quite a small area of inactivity around the stimulating electrode compared with the lesions induced with a lesionmaker, and stimulation directed at a particular target exerts more specific effects on particular symptoms of Parkinson’s disease (PD). Thus, whenever stimulation therapy is to be applied to patients, an effective stimulation target must be selected depending on the nature of the symptom to be improved. For example, ventral intermediate nucleus (VIM) thalamic stimulation is able to stop tremor completely, but has no appreciable effects on other symptoms. Bilateral globus pallidum interna (GPi) stimulation and subthalamic nucleus (STN) stimulation have been applied to reduce the pathological inhibitory effects on the thalamocortical circuit from the GPi and/or the substantia nigra pars reticular nucleus (SNr), which produces the final output of the basal ganglia circuits. However, there is still controversy about both the indications for and the role of GPi versus STN stimulation. This article presents a review of recent reports that describe follow-up results and double-blind studies on the signs for relief of each type of parkinsonian symptom, following GPi or STN stimulation. It also includes a discussion of how further research should be organized in order to identify whether GPi or STN stimulation exerts the greatest effect on particular kinds of parkinsonian symptoms.     

Deep brain stimulation for Parkinson's disease: how to select candidates for pallidal or subthalamic stimulation

Chronic deep brain stimulation therapy has the reversibility, selectivity and adjustability needed to achieve an adequate effect, so that it represents an ideal tool for functional neurosurgery designed to treat parkinsonian symptoms. Some kinds of chronic stimulation have become an alternative to lesion-making surgery, supported by the fact that high-frequency stimulation induces quite a small area of inactivity around the stimulating electrode compared with the lesions induced with a lesion-maker, and stimulation directed at a particular target exerts more specific effects on particular symptoms of Parkinson's disease (PD). Thus, whenever stimulation therapy is to be applied to patients, an effective stimulation target must be selected depending on the nature of the symptom to be improved. For example, ventral intermediate nucleus (VIM) thalamic stimulation is able to stop tremor completely, but has no appreciable effects on other symptoms. Bilateral globus pallidum interna (GPi) stimulation and subthalamic nucleus (STN) stimulation have been applied to reduce the pathological inhibitory effects on the thalamocortical circuit from the GPi and/or the substantia nigra pars reticular nucleus (SNr), which produces the final output of the basal ganglia circuits. However, there is still controversy about both the indications for and the role of GPi versus STN stimulation. This article presents a review of recent reports that describe follow-up results and double-blind studies on the signs for relief of each type of parkinsonian symptom, following GPi or STN stimulation. It also includes a discussion of how further research should be organized in order to identify whether GPi or STN stimulation exerts the greatest effect on particular kinds of parkinsonian symptoms.     

Subthalamic deep brain stimulation for severe idiopathic Parkinson's disease. Location study of the effective contacts

The subthalamic nucleus (STN) is the main target of deep brain stimulation (DBS) treatment for severe idiopathic Parkinson's disease. But there is still no clear information on the location of the effective contacts (used during the chronic phase of stimulation). Our aim was to assess the anatomical structures of the subthalamic area (STA) involved during chronic DBS. Ten patients successfully treated were included. The surgical procedure was based on direct STN targeting (stereotactic MRI based) pondered by the acute effects of intraoperative stimulation. We used a formaldehyde-fixed human specimen to compare by matching MRI images obtained at 1.5 Tesla (performed in clinical stereotactic conditions) and at very high field at 4.7 Tesla. This allowed accurate analysis of the anatomy of the STA and retrospective precision of the location of the center of effective contacts which were located within the STN in 4 patients, at the interface between the STN and the ZI and/or FF in 13, at the interface between ZI and FF in 2 and between the STN and the substantia nigra in one. These results were consistent with the literature, revealing the implication of neighboring structures, especially the zona incerta and Forel's Field, in the clinical benefit.     

A quick and universal method for stereotactic visualization of the subthalamic nucleus before and after implantation of deep brain stimulation electrodes

For deep brain stimulation (DBS) of the subthalamic nucleus (STN), it would be an advantage if the STN could be visualized with fast acquisition of MR images, allowing direct and individual targeting. We present a protocol for T2-weighted, nonvolumetric fast-acquisition MRI, implemented at 8 centers in 6 countries. Acquisition time varied between 3 min 5 s and 7 min 48 s according to the center, and imaging often provided visualization of the STN on axial and coronal scans. Postoperatively, the same imaging protocol permitted visualization of the target area and DBS electrodes with minimum artifacts. This imaging technique may contribute to a decrease in the number of electrode passes at surgery.