Assessing reliable change using the repeatable battery for the assessment of neuropsychological status (RBANS) for patients with Parkinson's Disease undergoing deep brain stimulation (DBS) surgery

Parkinson's disease (PD) is progressive neurological disease characterized by resting tremor, rigidity, akinesia, postural instability and cognitive changes. The symptoms of PD are debilitating and often become unsatisfactorily treated by medication. Deep brain stimulation (DBS) is an effective treatment to significantly reduce the cardinal motor symptoms of PD. However, the neuropsychological effects of this treatment are less clear. This study examined pre- to post-DBS scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) using Reliable Change Indices (RCIs) derived from 20 patients with PD who were medically managed, and then compared to 20 patients with PD treated with DBS and medication. When using group statistical analyses and false discovery rate correction, no significant differences between or within groups were evident at baseline or at follow-up. However, when using the RCIs more patients in the DBS group exhibited reliable change in RBANS scores than did the Med Tx group. Although preliminary, these RCIs provide clinicians and researchers a foundational tool for assessing the effects of interventions (e.g., DBS) independent of the effects of PD and measurement error when using the RBANS.     

Deep brain stimulation in movement disorders

Deep brain stimulation (DBS) is used for advanced and medically intractable patients with Parkinson's disease (PD), essential tremor (ET), and dystonia who meet strict criteria after a detailed motor, cognitive, and psychiatric evaluation. The potential targets are the ventral intermediate nucleus (VIM) of the thalamus for tremor, the globus pallidus interna (GPI) and the subthalamic nucleus (STN) for PD, and GPI for dystonia. The optimal target for PD has not been determined yet, although STN DBS has been performed more frequently in recent years. The mechanism of DBS effect is believed to be associated with disruption of pathological network activity in the cortico-basal ganglia-thalamic circuits by affecting the firing rates and bursting patterns of neurons and synchronized oscillatory activity of neuronal networks. Good candidates should be free of dementia, major psychiatric disorders, structural brain lesions, and important general medical problems. Although the risk for complications with DBS is less than with lesioning techniques, there is still a small risk for major complications associated with surgery. Bilateral procedures are more likely to cause problems with speech, cognition, and gait.     

脑深部电刺激治疗帕金森病作用机制的探讨

目的从蛋白组学的角度探索脑深部电刺激(DBS)与毁损术治疗帕金森病的机制是否类同。方法采用荧光差异凝胶电泳(DIGE)技术,测定3例行双侧丘脑底核DBS治疗的帕金森病病人脑脊液中蛋白,在手术前(未干预组)、手术7 d后但未刺激前(微毁损组)和刺激1周后(DBS组)的表达变化。另留取3例非中枢系统疾病病人的脑脊液蛋白作为正常对照组。结果未干预组和微毁损组、未干预组和DBS组、微毁损组和DBS组的组间比较分别发现14、18和13个明显差异蛋白点。除3个蛋白点外,未干预组和微毁损组与未干预组和DBS组的组间蛋白差异点完全不同;且在这3个相同的蛋白点中,两个蛋白点呈相反方向表达。结论结果初步提示DBS与毁损术治疗帕金森病的机制不相同。     

Surgical Treatment of Parkinson’s Disease: Devices and Lesion Approaches

Surgical treatments have transformed the management of Parkinson’s disease (PD). Therapeutic options available for the management of PD motor complications include deep brain stimulation (DBS), ablative or lesioning procedures (pallidotomy, thalamotomy, subthalamotomy), and dopaminergic medication infusion devices. The decision to pursue these advanced treatment options is typically done by a multidisciplinary team by considering factors such as the patient’s clinical characteristics, efficacy, ease of use, and risks of therapy with a goal to improve PD symptoms and quality of life. DBS has become the most widely used surgical therapy, although there is a re-emergence of interest in ablative procedures with the introduction of MR-guided focused ultrasound. In this article, we review DBS and lesioning procedures for PD, including indications, selection process, and management strategies.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00939-x) contains supplementary material, which is available to authorized users.Key Words: Deep brain stimulation, ablation, RF ablation, stereotactic radiosurgery, focused ultrasound     

High-frequency stimulation of the subthalamic nucleus reverses limb-use asymmetry in rats with unilateral 6-hydroxydopamine lesions

Deep brain stimulation (DBS) is a widely used clinical treatment for Parkinson's disease (PD). A rodent model of DBS is a necessary tool for understanding the neural mechanisms of this method. Our previous study showed that high-frequency stimulation (HFS) of the subthalamic nucleus (STN) improved treadmill locomotion in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of nigrostriatal dopamine (DA) neurons. The present study tested DBS effects on limb-use asymmetry (LUA) during vertical/lateral exploration in a cylindrical chamber in rats with similar unilateral nigrostriatal DA lesions. Limb-use asymmetry assessment has been used to detect functional capacity over a wide range of dopamine depletion. Before lesioning, rats exhibited regular rearing activity and used both forelimbs equally often to support weight during exploration of the walls of the cylinder. After unilateral nigrostriatal DA lesioning, rats displayed reduced rearing activity and predominant use of the ipsilateral (good) forelimb to touch the wall. HFS of the STN, but not of other nearby regions surrounding the STN, in the lesioned rats restored normal rearing activity and reversed the limb-use asymmetry caused by the unilateral DA depletion. This study is consistent with the possibility that there can be beneficial effects of STN-DBS on behavioral impairments in unilateral DA-depleted rats and may suggest an appropriate rodent model for DBS study.     

Lesion therapy for Parkinson's disease and other movement disorders: update and controversies.

An analysis of the international literature on lesioning for movement disorders was undertaken to review lesion therapy for Parkinson's disease (PD) and other movement disorders and to highlight important controversies surrounding this surgical technique. Lesions have been placed throughout the neuraxis with varying approaches and success. Our understanding of the pathophysiological basis underlying the development of PD and other movement disorders has led to a better understanding of why lesioning certain portions of the nervous system should improve motor function. Advances in imaging technology and electrophysiological techniques used for localization of brain structures, such as microelectrode mapping, have improved the ability to accurately identify and lesion target structures deep in the brain. This improvement has led to an increase in the degree and consistency of clinical benefit. The major controversies in lesion therapy include: (1) which target for which disorder; (2) determination of the optimal lesion site and whether the external globus pallidus (GPe) should be included in the pallidotomy lesion for PD; (3) determination of the size of the lesion; (4) whether bilateral lesions can be placed without the high incidence of side effects reported by some investigators; (5) whether microelectrodes aid in the ability to improve clinical outcomes or increase the risk of side effects by making multiple microelectrode penetrations; (6) whether the subthalamic nucleus (STN) should be explored further as a lesioning target; and (7) whether lesioning should be abandoned entirely in favor of deep brain stimulation (DBS). Many important questions and controversies regarding lesion therapy remain unanswered. It is unlikely given the pro-DBS environment that these questions will be answered in the near future. We should, however, be careful not to abandon an effective therapy before fully exploring through randomized trials the relative effect of different surgical approaches for the treatment of patients with movement disorders.     

Deep brain stimulation of the Vim nucleus of the thalamus in the treatment of parkinsonian tremor

Deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus (Vim) has been recently introduced by Benabid and his colleagues as a new surgical procedure in the treatment of tremor-dominant Parkinson's disease (PD). The advantage of DBS Vim over lesioning (thalamotomy) is its reversibility and adjustability with the same clinical effect, but without the need to make a destructive thalamic lesion. In this procedure high-frequency stimulation is employed to simulate a thalamic lesion using an implanted electrode connected to a subcutaneously placed neuropacemaker. Four patients with tremor-dominant PD were included in the study. There were 3 men and one women. Three stimulators were implanted in the left and one in the right cerebral hemisphere. The patients were evaluated using clinical scales, before and up to 24 months after surgery. Adverse effects associated with chronic Vim stimulation were mild and reversible. Chronic thalamic stimulation is effective for drug-resistance parkinsonian tremor suppression, with few adverse side-effects. The method results in a significant improvement of function.     

Impaired performance on the Wisconsin Card Sorting Test under left- when compared to right-sided deep brain stimulation of the subthalamic nucleus in patients with Parkinson’s disease

Over the past decade, deep brain stimulation (DBS) has become an effective treatment option for managing severe Parkinson’s disease (PD). However, evidence is accumulating that DBS of target sites like the subthalamic nucleus (STN) can result in unintended cognitive effects that lie beyond motor control. The aim of the present study was to evaluate whether changes in executive task performance after chronic DBS might be predominantly associated with the stimulation of only one hemisphere. Eight patients with PD who had undergone DBS treatment of the STN were selected to participate in the study. Using a repeated measurements design, they underwent a neuropsychological examination under unilateral left- and right-sided stimulation in order to investigate laterality effects in their performance on the Wisconsin Card Sorting Test. All patients showed a significant improvement in motor symptoms postoperatively. Selected aspects of executive task performance were compromised under left- when compared to right-sided stimulation. Performance measures were unrelated to demographic, neurological, and behavioral characteristics of the patients. Findings are consistent with the emerging evidence that the STN is not only involved in motor control, but also participates in functions of the cognitive domain. Moreover, results raise the possibility that the left and right hemisphere might differ in their vulnerability to tolerate side effects on executive functions of DBS treatment. Potential consequences for future research questions and the management of cognitive side effects are discussed.     

Seventy years of pallidotomy for movement disorders

The year 2017 marks the 70th anniversary of the birth of human stereotactic neurosurgery. The first procedure was a pallidotomy for Huntington's disease. However, it was for Parkinson's disease that pallidotomy was soon adopted worldwide. Pallidotomy was abandoned in the late 1950s in favor of thalamotomy because of the latter's more striking effect on tremor. The advent of levodopa put a halt to all surgery for PD. In the mid‐1980s, Laitinen reintroduced the posteroventral pallidotomy of Leksell, and this procedure spread worldwide thanks to its efficacy on most parkinsonian symptoms including levodopa‐induced dyskinesias and thanks to basic scientific work confirming the role of the globus pallidus internus in the pathophysiology of PD. With the advent of deep brain stimulation of the subthalamic nucleus, pallidotomy was again abandoned, and even DBS of the GPi has been overshadowed by STN DBS. The GPi reemerged in the late 1990s as a major stereotactic target for DBS in dystonia and, recently, in Tourette syndrome. Lately, lesioning of the GPI is being proposed to treat refractory status dystonicus or to treat DBS withdrawal syndrome in PD patients. Hence, the pallidum as a stereotactic target for either lesioning or DBS has been the phoenix of functional stereotactic neurosurgery, constantly abandoned and then rising again from its ashes. This review is a tribute to the pallidum on its 70th anniversary as a surgical target for movement disorders, analyzing its ebbs and flows and highlighting its merits, its versatility, and its resilience. © 2017 International Parkinson and Movement Disorder Society     

Unilateral subthalamic nucleus lesioning: a safe and effective treatment for Parkinson's disease

The present study, the largest in the literature, was performed to assess the effectiveness and safety of unilateral subthalamic nucleus (STN) lesioning for Parkinson's disease (PD). From August 1999 to September 2000, 21 consecutive patients evaluated pre- and postoperatively by a single examiner were operated. Levodopa intake and dyskinesia, Hoehn & Yahr, Schwab & England and UPDRS motor scores were recorded. Stereotactic CT and MRI and the effects of macrostimulation were used to determine STN coordinates. A single radiofrequency lesion was made (60-75 degrees C/60"). Concomitant ipsilateral Vim/VOp lesions were made in 8 patients. Using a new technique, we were able to determine the territory of STN involved by the surgical lesion. The Wilcoxon and Mann-Whitney statistical tests were applied to evaluate the surgical results. All recorded parameters showed stable improvement after a mean follow up of 13.5 months. Recurrence occurred in two patients. Contralateral tremor arrest and decrease of rigidity and bradykinesia should be regarded as STN hallmarks to stimulation. Hyperintense lesions in the early-phase MRI seem to be a poor prognostic factor. Lateral territory lesioning correlates with better results. There was no significant difference between the cohorts with and without a Vim/VOp lesion. Dyskinesias happened in two patients (promptly abolished by a Vim/VOp lesion). Other complications were transient and/or rare. In conclusion, STN lesioning is a safe and very effective procedure to treat PD and probably an underutilized operation for those who can not afford the costs of DBS.     

Effect of deep brain stimulation on autonomic dysfunction in patients with Parkinson’s disease

Increasing attention is being paid to the non-motor symptoms of Parkinson’s disease (PD). While deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to clearly improve motor symptoms of PD, the effects of STN DBS on autonomic symptoms have not been well studied. We examined 11 patients undergoing STN DBS for PD. Patients were administered a questionnaire by phone to evaluate pre-operative and post-operative function. Three out of the 11 patients reported marked improvement post-DBS in one or more symptoms of autonomic dysfunction (sweating, bladder, or bowel function). All three patients had early-onset PD (EOPD), whereas the eight patients reporting no significant improvement were those with late-onset PD. Thus, we found that some patients experienced marked improvement in sweating and/or bowel and bladder function after STN DBS, with a trend towards a response in patients with EOPD. Our results suggest the utility of a larger prospective study.     

Deep brain stimulation for movement disorders before DBS for movement disorders

Deep brain stimulation (DBS) is an established surgical treatment for Parkinson’s disease (PD), essential tremor and dystonia. It is generally acknowledged that the development of DBS as we know it today started with the publication of Benabid, Pollak et al in 1987 on thalamic DBS for tremor. This technique gained momentum in the mid-Nineties after that Pollak and Benabid introduced the subthalamic nucleus as a target in advanced PD.This paper reviews the gestational pre-natal era of deep brain stimulation, before 1987. The origin of DBS can be traced back to the practice of intra-operative electrical stimulation, used for target exploration prior to lesioning, during the early years of stereotactic functional neurosurgery. During the 60s, Sem-Jacobsen and others implanted externalised electrodes which were used for intermittent stimulation and evaluation during weeks or months, prior to subsequent ablation of thalamic and other basal ganglia targets. In the early 70s Bechtereva treated PD patients using “therapeutic electrical stimulation” through electrodes implanted for up to 1.5 years. In the late 70s and early 80s the term Deep Brain Stimulation was coined and few groups attempted treatment of Parkinson’s disease, non-Parkinsonian tremor and dystonia with high-frequency stimulation using chronically implanted DBS systems. Cumbersome, un-sophisticated DBS hardware, together with the general decline of all surgery for PD following the introduction of levodopa, may have contributed to the lack of popularity of old-times DBS. It is to the credit of the Grenoble Group to have reinvented, modernised and expanded modern DBS in surgical treatment of movement disorders.     

Pallidal deep brain stimulation and L-dopa do not improve qualitative aspects of skilled reaching in Parkinson's disease

OBJECTIVE: To determine effects of dopaminergic medication and pallidal deep brain stimulation (DBS) on skilled reach in Parkinson's disease (PD). BACKGROUND: PD is a neurodegenerative disorder affecting motor control. While speed and execution of movements are improved by L-dopa, not all motor symptoms are alleviated. Little is known about the effects of DBS or medication on reaching. DESIGN METHOD: Eight PD patients with unilateral pallidal DBS reached with the contra-lateral hand for a piece of food, placing it in the mouth, and returning to starting position. Testing was performed on no treatment, medication only, DBS only, and combined treatment. Reaches were digitally recorded and analyzed on a 21 point scale adapted from Eshkol-Wachman Notation. Analysis was blinded, with patients compared to age-matched controls. RESULTS: Patients were tested 6-13 months after surgery. All showed significant improvement clinically and in UPDRS (III) scores. The following data were obtained on the reaching scale: normal controls 16.5-21.0 (mean 18.3), no treatment 3.0-12.5 (mean 7.4), medication only 7.0-14.0 (mean 10.3), DBS only 4.5-16.0 (mean 9.2), combined treatment 4.0-15.0 (mean 9.5). The difference between controls and all treatment groups was statistically significant (P<0.005). All aspects of reach were compromised. No significant differences were found among the four conditions. CONCLUSIONS: This study is consistent with accumulating evidence that some aspects of motor performance in PD patients, such as reaching, are resistant to L-dopa. Also, pallidal DBS does not improve those parameters that are resistant to L-dopa, either alone or in combination with medication.     

Genotype and phenotype in Parkinson's disease: Lessons in heterogeneity from deep brain stimulation

Variation in the genetic risk(s) of developing Parkinson's disease (PD) undoubtedly contributes to the subsequent phenotypic heterogeneity. Although patients with PD who undergo deep brain stimulation (DBS) are a skewed population, they represent a valuable resource for exploring the relationships between heterogeneous phenotypes and PD genetics. In this series, 94 patients who underwent DBS were screened for mutations in the most common genes associated with PD. The consequent genetic subgroups of patients were compared with respect to phenotype, levodopa (l ‐dopa), and DBS responsiveness. An unprecedented number (29%) of patients tested positive for at least 1 of the currently known PD genes. Patients with Parkin mutations presented at the youngest age but had many years of disease before needing DBS, whereas glucocerebrosidase (GBA) mutation carriers reached the threshold of needing DBS earlier, and developed earlier cognitive impairment after DBS. DBS cohorts include large numbers of gene positive PD patients and can be clinically instructive in the exploration of genotype‐phenotype relationships.     

Deep brain stimulation for Parkinson's disease and camptocormia? A case report

Camptocormia is recognised as a severe postural movement disorder complicating neurodegenerative diseases like Parkinson's disease (PD) and multisystem atrophy. Pathophysiologically two main hypotheses are discussed: (i) a disorder of the basal ganglia resulting in axial dystonia and rigidity on the one hand and (ii) an extensor truncal myopathy on the other hand. Therapeutic efforts often result in limited success. Therefore, reports on improvements by deep brain stimulation (DBS) are of great interest. However, the role of DBS in the treatment of camptocormia remains unclear. Here, we report a female PD patient who responded well to DBS of the subthalamic nucleus for severe dyskinesias and fluctuations. However, after 6 months she started to develop a rapidly progressing camptocormia which did not respond to DBS. The clinical and electrophysiological examination suggested a truncal erector myopathy. The inconsistent reports on the effects of DBS on camptocormia in PD patients suggest heterogeneous pathogenetic pathways. A pathophysiological subtype with predominant basal ganglia dysfunction and responsivity to DBS, however, seems to be rather rare. A myopathy, in contrast, seems to be more frequent and DBS is not effective in this condition. Therefore, camptocormia in PD patients is not an established indication for DBS.     

Deep brain stimulation for dystonia.

Within the past few years, there has been a renaissance of functional neurosurgery for the treatment of dystonic movement disorders. In particular, deep brain stimulation (DBS) has widened the spectrum of therapeutical options for patients with otherwise intractable dystonia. It has been introduced only with a delay after DBS became an accepted treatment for advanced Parkinson' disease (PD). In this overview, the authors summarize the current status of its clinical application in dystonia. Deep brain stimulation for dystonia has been developed from radiofrequency lesioning, but it has replaced the latter largely in most centers. The main target used for primary dystonia is the posteroventral globus pallidus internus (GPi), and its efficacy has been shown in generalized dystonia, segmental dystonia, and complex cervical dystonia. The optimal target for secondary dystonias is still unclear, but some patients appear to benefit more from thalamic stimulation. The improvement of dystonia with chronic DBS frequently is delayed, in particular concerning tonic dystonic postures. Because more energy is needed for stimulation than in other movement disorders such as PD, more frequent battery replacements are necessary, which results in relatively higher costs for chronic DBS. The study of intraoperative microelectrode recordings and of local field potentials by the implanted DBS electrodes has yielded new insights in the pathophysiology of dystonia. Larger studies are underway presently to validate the observations being made.     

Performing functional magnetic resonance imaging in patients with Parkinson's disease treated with deep brain stimulation.

Deep brain stimulation (DBS) is a relatively novel treatment in advanced Parkinson's disease (PD). Functional magnetic resonance imaging (fMRI) is a useful technique for examining the effects of DBS both within the basal ganglia and its cortical connectivity. There are technical difficulties in imaging patients with PD, and the DBS itself can generate image artifacts. We describe aspects related to optimizing the fMRI acquisition parameters in patients with DBS and the results of sensorimotor activation tasks performed by four PD patients during hand, foot, and tongue movements, both before and after DBS implant. Provided that all safety conditions are followed, it is possible to perform fMRI in patients with PD and DBS. The standard DBS surgical procedure has to be slightly modified in order to reduce image artifacts. The event-related design provided increased power to detect sensorimotor cortex and basal ganglia activation.     

脑深部电刺激治疗帕金森病和特发性震颤的近期和远期疗效

自1987年以后,脑深部电刺激(deep brain stimulation,DBS)成为治疗难治性帕金森病和特发性震颤的主要外科手段。刺激的靶点最先为丘脑腹侧中间核(nucleus ventero-intermedius,Vim)。由于Vim DBS只能缓解震颤,而对于帕金森病的其他核心症状以及多巴长期应用后的不良反应,如运动波动和异动症疗效不显著,1990年后治疗PD的靶点转移到丘脑底核(subthalamic nucleus,STN)和苍白球内侧部(interal globus pallidus,GPi),上述问题在这两个靶点得到显著改善。Vim DBS仍然为治疗特发性震颤的位点。本文就这3个靶点的持续电刺激在治疗帕金森病和特发性震颤的近期和远期疗效等进行评述。     

Deep brain stimulation in neurologic disorders

Deep brain stimulation (DBS) is an effective surgical therapy for well-selected patients with medically intractable Parkinson's disease (PD) and essential tremor (ET). The purpose of this review is to describe the success of DBS in these two disorders and its promising application in dystonia, Tourette Syndrome (TS) and epilepsy. In the last 10 years, numerous short- and intermediate-term outcome studies have demonstrated significant relief to patients with PD and ET. A few long-term follow-up studies have also reported sustained benefits. When successful, DBS greatly reduces most of parkinsonian motor symptoms and drug-induced dyskinesia, and it frequently improves patients' ability to perform activities of daily living with less encumbrance from motor fluctuations. Quality of life is enhanced and many patients are able to significantly reduce the amount of antiparkinsonian medications required to still get good pharmacological benefit. Overall, adverse effects associated with DBS tend to be transient, although device-related and other postoperative complications do occur. DBS should be considered the surgical procedure of choice for patients who meet strict criteria with medically intractable PD, ET and selected cases of dystonia.     

Influence of deep brain stimulation and levodopa on sensory signs in Parkinson's disease

To examine the effects of levodopa (L ‐dopa) and deep brain stimulation of the subthalamic nucleus (STN‐DBS) on sensory symptoms and signs in Parkinson's disease (PD). Seventeen patients with PD were included. (1) Presence of sensory symptoms and (2) effects of L ‐dopa and STN‐DBS on sensory symptoms and signs [assessed by quantitative sensory testing (QST)] were examined 6 months after starting STN‐DBS. In addition, in 12 of these patients, presence of sensory symptoms prior and post STN‐DBS was compared. Pain was most frequently nociceptive. In about 30–40%, pain and sensory symptoms were associated with PD motor symptoms. In most of these cases, pain responded to L ‐dopa. Intensity of pain was reduced post STN‐DBS compared to pre STN‐DBS. L ‐Dopa had no influence on detection thresholds, whereas STN‐DBS improved thermal detection thresholds. However, thermal and mechanical pain thresholds were uninfluenced by L ‐dopa or STN‐DBS. Although some patients reported an improvement of pain with STN‐DBS or L ‐dopa, objectively pain sensitivity as assessed by QST was not altered by STN‐DBS or L ‐dopa suggesting that there is no evidence for a direct modulation of central pain processing by L ‐dopa or STN‐DBS. © 2010 Movement Disorder Society