Tremor reduction by subthalamic nucleus stimulation and medication in advanced Parkinson’s disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has proved to be effective for tremor in Parkinson’s disease (PD). Most of the recent studies used only clinical data to analyse tremor reduction. The objective of our study was to quantify tremor reduction by STN DBS and antiparkinsonian medication in elderly PD patients using an objective measuring system. Amplitude and frequency of resting tremor and re-emergent resting tremor during postural tasks were analysed using an ultrasound-based measuring system and surface electromyography. In a prospective study design nine patients with advanced PD were examined preoperatively off and on medication, and twice postoperatively during four treatment conditions: off treatment, on STN DBS, on medication, and on STN DBS plus medication. While both STN DBS and medication reduced tremor amplitude, STN DBS alone and the combination of medication and STN DBS were significantly superior to pre- and postoperative medication. STN DBS but not medication increased tremor frequency, and off treatment tremor frequency was significantly reduced postoperatively compared to baseline. These findings demonstrate that STN DBS is highly effective in elderly patients with advanced PD and moderate preoperative tremor reduction by medication. Thus, with regard to the advanced impact on the other parkinsonian symptoms, STN DBS can replace thalamic stimulation in this cohort of patients. Nevertheless, medication was still effective postoperatively and may act synergistically. The significantly superior efficacy of STN DBS on tremor amplitude and its impact on tremor frequency in contrast to medication might be explained by the influence of STN DBS on additional neural circuits independent from dopaminergic neurotransmission. Received in revised form: 27 April 2006     

Effects of deep brain stimulation and medication on strength, bradykinesia, and electromyographic patterns of the ankle joint in Parkinson's disease.

We investigated the control of movement in 12 patients with Parkinson's disease (PD) after they received surgically implanted high-frequency stimulating electrodes in the subthalamic nucleus (STN). The experiment studied ankle strength, movement velocity, and the associated electromyographic patterns in PD patients, six of whom had tremor at the ankle. The patients were studied off treatment, ON STN deep brain stimulation (DBS), on medication, and on medication plus STN DBS. Twelve matched control subjects were also examined. Medication alone and STN DBS alone increased patients' ankle strength, ankle velocity, agonist muscle burst amplitude, and agonist burst duration, while reducing the number of agonist bursts during movement. These findings were similar for PD patients with and without tremor. The combination of medication plus STN DBS normalized maximal strength at the ankle joint, but ankle movement velocity and electromyographic patterns were not normalized. The findings are the first to demonstrate that STN DBS and medication increase strength and movement velocity at the ankle joint.     

Comparative effects of unilateral and bilateral subthalamic nucleus deep brain stimulation.

OBJECTIVE: To compare the effects of unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) with bilateral STN DBS in advanced PD. METHODS: Our initial 10 consecutive patients with medication-refractory motor fluctuations and levodopa-induced dyskinesias undergoing chronic bilateral STN DBS underwent a standardized evaluation of unilateral and bilateral STN DBS in the medication-off state 6 to 18 months after electrode implantation. RESULTS: Bilateral STN DBS improved the mean total Unified Parkinson's Disease Rating Scale motor score by 54%, whereas unilateral stimulation improved motor scores only 23%. Unilateral STN DBS improved postural stability and gait 14%, other axial motor features 19%, and overall parkinsonism in limbs contralateral to stimulation by 46%, including an 86% improvement in contralateral tremor. However, bilateral STN DBS resulted in greater improvement in each of these domains, including limb function, i.e., the reduction in scores from the limbs on one side was greater with bilateral than with unilateral stimulation of the contralateral STN. CONCLUSIONS: Bilateral STN DBS improves parkinsonism considerably more than unilateral STN DBS; bilateral simultaneous electrode implantation may be the most appropriate surgical option for patients with significant bilateral disability. Unilateral STN DBS results in moderate improvement in all aspects of off-period parkinsonism and improves tremor as much as is typically reported with DBS of the ventral intermedius nucleus of the thalamus (Vim). For this reason, STN DBS may be a more appropriate choice than Vim DBS or thalamotomy for parkinsonian tremor. Some patients with highly asymmetric tremor-dominant PD might be appropriately treated with unilateral instead of bilateral STN DBS.     

Stimulation of the subthalamic nucleus in a patient with Parkinson disease and essential tremor

BACKGROUND: The preferred surgical target for the treatment of Parkinson disease (PD) is either the internal globus pallidus or the subthalamic nucleus (STN); the target for treatment of essential tremor (ET) is the thalamic subnucleus ventralis intermedius (Vim). Some patients with PD have coexistent ET, and the identification of a single surgical target to treat both parkinsonian motor symptoms and ET would be of practical importance. OBJECTIVE: To describe the use of the STN target in deep brain stimulator (DBS) surgery to treat PD motor symptoms and the action-postural tremor of ET. DESIGN: Case report. PATIENT: A 62-year-old man had a greater than 30-year history of action-postural tremor in both hands, well controlled with beta-blockers for more than 20 years. He developed resting tremor, bradykinesia, and rigidity on his right side that progressed to his left side during the past 10 years. Dopaminergic medication improved his rigidity and bradykinesia, with only mild improvement of his resting tremor and no effect on his action-postural tremor. INTERVENTIONS: Left pallidotomy followed by placement of a left DBS in the Vim and subsequent placement of a right STN DBS. MAIN OUTCOME MEASURES: Control of symptoms of PD and ET. RESULTS: The left pallidotomy controlled the patient's parkinsonian motor symptoms on the right side of his body, but did not affect the action-postural component of his tremor. The symptoms on the left side of the body, including both an action-postural and a resting tremor (as well as the rigidity and bradykinesia), improved after placement of a single right STN DBS. CONCLUSION: Placement of an STN DBS should be considered as the procedure of choice for surgical treatment of patients with a combination of PD and ET.     

Unilateral subthalamic nucleus deep brain stimulation contralateral to thalamic stimulation in Parkinson disease

The effects of unilateral subthalamic nucleus (STN) stimulation contralateral to thalamic stimulation in Parkinson disease (PD) have not been previously reported. We are reporting a patient who developed left arm tremor in 1994, at age 62, as her first PD symptom. She underwent right thalamic DBS surgery in 1999 that resulted in complete resolution of left arm tremor. Her PD symptoms progressed and she developed severe motor fluctuations and disabling dyskinesias. In 2003, she underwent left STN electrode implantation. Left STN stimulation improved contralateral motor scores in the medication OFF state, and allowed for reduced medication doses and less dyskinesia. However, there was no significant improvement in activities of daily living (ADL), motor scores in the medication ON state, gait, or postural stability.     

Subthalamic nucleus deep brain stimulation changes speech respiratory and laryngeal control in Parkinson’s disease

Adequate respiratory and laryngeal motor control are essential for speech, but may be impaired in Parkinson’s disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on respiratory and laryngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of respiratory and laryngeal control, and whether these changes were correlated with limb function and stimulation parameters. Eighteen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12 h since their most recent dose of anti-PD medication. Testing occurred when DBS was on, and again 1 h after DBS was turned off, and included aerodynamic measures during syllable production, and standard clinical ratings of limb function. We found that PD participants exhibited changes with DBS, consistent with increased respiratory driving pressure (n = 9) and increased vocal fold closure (n = 9). However, most participants exceeded a typical operating range for these respiratory and laryngeal control variables with DBS. Changes were uncorrelated with limb function, but showed some correlation with stimulation frequency and pulse width, suggesting that speech may benefit more from low-frequency stimulation and shorter pulse width. Therefore, high-frequency STN DBS may be less beneficial for speech-related respiratory and laryngeal control than for limb motor control. It is important to consider these distinctions and their underlying mechanisms when assessing the impact of STN DBS on PD.     

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: comparison of pre- and postoperative neuropsychological evaluation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for the motor symptoms of advanced Parkinson's disease (PD). The aim of this study was to assess the effect of the bilateral surgical procedure and STN DBS on the neuropsychological functions. Twenty Parkinson's disease patients underwent a neuropsychological assessment before and 6 months after surgery in four different conditions: medication on (with levodopa) and medication off (without levodopa) during the preoperative period, medication on/stimulation on (levodopa plus stimulators switched on) and medication off/stimulation on (stimulators switched on without levodopa) during the postoperative period. We did not find any significant difference in the four conditions for all the neuropsychological tests, confirming the lack of an overall cognitive decline after surgery. From a neuropsychological point of view, these results seem to indicate that bilateral STN DBS is a safe treatment for advanced PD.     

The effects of subthalamic nucleus deep brain stimulation on parkinsonian tremor

Deep brain stimulation (DBS) of the ventral intermediate (Vim) nucleus of the thalamus has been the target of choice for patients with disabling essential tremor or medication refractory parkinsonian tremor. Recently there is evidence that the subthalamic nucleus (STN) should be the targets for patients with tremor associated with Parkinson's disease (PD). To assess the effects of STN DBS on parkinsonian tremor, eight consecutive patients with PD and disabling tremor were videotaped using a standardized tremor protocol. Evaluations were performed at least 12 h after last dose of medication with the DBS turned off followed by optimal DBS on state. A rater blinded to DBS status evaluated randomized video segments with the tremor components of the Unified Parkinson Disease Rating Scale (UPDRS) and Tremor Rating Scale (TRS). Compared with DBS off state there were significant improvements in mean UPDRS tremor score 79.4% (p = 0.008), total TRS score 69.9% (p = 0.008) and upper extremity 92.5% (p = 0.008) TRS subscore. Functional improvement was noted with pouring liquids. Our findings provide support that STN DBS is an effective treatment of tremor associated with PD.     

The persistent effects of unilateral pallidal and subthalamic deep brain stimulation on force control in advanced Parkinson's patients

The persistent effects of unilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi) or subthalamic nucleus (STN) on specific movement parameters produced by Parkinson's disease (PD) patients are poorly understood. The aim of this study was to determine the effects of unilateral GPi and STN DBS on the force-producing capabilities of PD patients during maximal efforts and functional bimanual dexterity. Clinical and biomechanical data were collected from 14 unilaterally implanted patients (GPi=7; STN=7), at least 13 months post-DBS surgery, during On and Off stimulation in the absence of medication. Unilateral DBS of either location produced a 33% improvement in UPDRS motor scores. Significant gains in maximum force production were present in both limbs during unimanual efforts. The greatest increase in maximum force, for both limbs, was under bimanual conditions. Force in the contralateral limb increased more than 30% during bimanual efforts while ipsilateral force increased by 25%. Unilateral DBS improved grasping force control and consistency of digit placement during the performance of a bimanual dexterity task. The clinical and biomechanical data indicate that unilateral DBS of GPi or STN results in persistent improvements in the control and coordination of grasping forces during maximal efforts and functional dexterous actions. Unilateral DBS implantation of either site should be considered an option for those patients in which bilateral procedures are contraindicated.     

Changes in cognitive‐emotional and physiological symptoms of depression following STN‐DBS for the treatment of Parkinson’s disease

Background and purpose: Subthalamic nucleus deep brain stimulation (STN‐DBS) has been shown to have beneficial effects on the motor features of Parkinson’s disease (PD), but its impact on non‐motor symptoms, most notably mood, has not been fully explored. Methods: In the first study to independently compare the emotional‐cognitive and somatic/physiological symptoms of depression, we examined mood differences in 17 bilateral STN‐DBS and 22 matched non‐surgical PD patients at baseline and 6 months. Results: The STN‐DBS group reported higher levels of depression at baseline with significant endorsement of physical symptomatology. Postoperatively, no significant between‐group differences in physical symptoms of depression were found. In contrast, a significant group by time interaction for cognitive‐emotional symptoms of depression was found, with the STN‐DBS group reporting an increase in psychological symptoms of distress. The STN‐DBS group also reported an increase in anxiety following surgery. The suicide rate of 5% found in our study is consistent with other postoperative studies in PD. The impact of changes in levodopa and psychotropic medication are also explored. Conclusions: Preliminary results suggest that the motor improvement often observed in patients with PD following bilateral STN‐DBS may be partially offset by an increase in affective‐cognitive symptoms of depression.     

3D left hyperschematia after right brain damage

ABSTRACT

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson’s disease (PD). The STN may represent an important relay station not only in the motor but also the associative cortico-striato-thalamocortical pathway. Therefore, STN stimulation may alter cognitive functions, such as working memory (WM). We examined cortical effects of STN-DBS on WM in early PD patients using functional near-infrared spectroscopy. The effects of dopaminergic medication on WM were also examined. Lateral frontal activity during WM maintenance was greater when patients were taking dopaminergic medication. STN-DBS led to a trend-level worsening of WM performance, accompanied by increased lateral frontal activity during WM maintenance. These findings suggest that STN-DBS in PD might lead to functional modifications of the basal ganglia-thalamocortical pathway during WM maintenance.     

Psychiatric and Cognitive Effects of Deep Brain Stimulation for Parkinson’s Disease

Deep brain stimulation (DBS) is effective for Parkinson’s disease (PD), dystonia, and essential tremor (ET). While motor benefits are well documented, cognitive and psychiatric side effects from the subthalamic nucleus (STN) and globus pallidus interna (GPi) DBS for PD are increasingly recognized. Underlying disease, medications, microlesions, and post-surgical stimulation likely all contribute to non-motor symptoms (NMS).     

Stimulation of the subthalamic region facilitates the selection and inhibition of motor responses in Parkinson's disease

The aim of the present study was to specify the involvement of the basal ganglia in motor response selection and response inhibition. Two samples were studied. The first sample consisted of patients diagnosed with Parkinson's disease (PD) who received deep-brain stimulation (DBS) of the subthalamic nucleus (STN). The second sample consisted of patients who received DBS for the treatment of PD or essential tremor (ET) in the ventral intermediate nucleus of the thalamus (Vim). Stop-signal task and go/no-go task performances were studied in both groups. Both groups performed these tasks with (on stimulation) and without (off stimulation) DBS to address the question of whether stimulation is effective in improving choice reaction time (RT) and stop-signal RT. The results show that DBS of the STN was associated with significantly enhanced inhibitory control, as indicated by shorter stop-signal RTs. An additional finding is that DBS of the STN led to significantly shorter choice RT. The effects of DBS on responding and response inhibition were functionally independent. Although DBS of the Vim did not systematically affect task performance in patients with ET, a subgroup of Vim-stimulated PD patients showed enhanced stop-signal RTs in on stimulation versus off stimulation. This result suggests that the change in performance to stop signals may not be directly related to STN function, but rather results from a change in PD function due to DBS in general. The findings are discussed in terms of current functional and neurobiological models that relate basal ganglia function to the selection and inhibition of motor responses.     

Subdural motor cortex stimulation in Parkinson's disease does not modify movement-related rCBF pattern.

There has been some evidence that electrical stimulation of the primary motor cortex (MCS) may relieve motor symptoms of Parkinson's disease (PD). This surgical technique is being studied as alternative for PD patients who are considered poor candidates for deep brain stimulation (DBS) of subthalamic nucleus (STN). In 4 PD patients with unilateral MCS, we used [(15)O] H(2)O positron emission tomography to measure changes in regional cerebral blood flow (rCBF) while testing motor performance with a joystick motor task during different stimulation frequencies, OFF-condition, 50 and 130 Hz. We found that different stimulation settings did neither improve performance on joystick task nor modify the pattern of movement-related rCBF. Similarly, no changes were observed in UPDRS motor score between Off and On stimulation while off medication. We conclude that while MCS may be a simpler and safer surgical procedure than DBS of STN, it failed to provide evidence of clear effect on motor performance and movement-related activation pattern in patients with advanced PD.     

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。     

Directional communication during movement execution interferes with tremor in Parkinson's disease

Background : Both the cerebello‐thalamo‐cortical circuit and the basal ganglia/cortical motor loop have been postulated to be generators of tremor in PD. The recent suggestion that the basal ganglia trigger tremor episodes and the cerebello‐thalamo‐cortical circuitry modulates tremor amplitude combines both competing hypotheses. However, the role of the STN in tremor generation and the impact of proprioceptive feedback on tremor suppression during voluntary movements have not been considered in this model yet. Objectives : The objective of this study was to evaluate the role of the STN and proprioceptive feedback in PD tremor generation during movement execution. Methods: Local‐field potentials of the STN as well as electromyographical and electroencephalographical rhythms were recorded in tremor‐dominant and nontremor PD patients while performing voluntary movements of the contralateral hand during DBS surgery. Effective connectivity between these electrophysiological signals were analyzed and compared to electromyographical tremor activity. Results: There was an intensified information flow between the STN and the muscle in the tremor frequencies (5‐8 Hz) for tremor‐dominant, in comparison to nontremor, patients. In both subtypes, active movement was associated with an increase of afferent interaction between the muscle and the cortex in the β‐ and γ‐frequencies. The γ‐frequency (30‐40 Hz) of this communication between muscle and cortex correlated inversely with electromyographical tremor activity. Conclusions : Our results indicate an involvement of the STN in propagation of tremor‐related activity to the muscle. Furthermore, we provide evidence that increased proprioceptive information flow during voluntary movement interferes with central tremor generation. © 2018 International Parkinson and Movement Disorder Society     

Quantitative assessments of the effect of bilateral subthalamic stimulation on multiple aspects of sensorimotor function for patients with Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for the treatment of advanced Parkinson's disease. Most studies have evaluated the effectiveness of DBS of the STN using clinical motor scores or simple timed tests of motor function. There have been few studies that quantitatively assessed the outcome of STN DBS using multiple testing paradigms. In the current study, 11 patients who had bilateral STN DBS were quantitatively evaluated under four conditions using gait, postural control, and gait initiation. The four conditions included the medication on/stimulation on (M_on/S_on), medication on/stimulation off (M_on/S_off), medication off/stimulation on (M_off/S_on), and medication off/stimulation off (M_off/S_off) conditions. DBS of the STN significantly increased walking speed with and without levodopa, but had no influence on the cadence. The addition of levodopa had a minimal additional effect on walking speed. The effect of STN DBS on gait initiation approached the significant level. The mean values of lateral body sway during quiet standing increased moderately with medication and/or DBS, but the changes were not statistically significant. Future studies need to determine whether or not there is a potential negative effect of STN DBS on the postural control.     

脑深部刺激电极埋置术治疗帕金森病疗效研究

目的 探讨脑深部刺激电极埋置术治疗帕金森病的疗效及其作用机制。方法 对32例帕金森病患者应用微电极导向立体定向技术,于丘脑底核埋置体外可控性脑深部刺激电极,对其疗效和预后进行随访。结果患者术后僵硬、震颤和运动迟缓等症状明显缓解,术前、术后统一帕金森病评分量表(unified Parkinson's disease ratingscale,UPDRS)运动评分和日常生活能力(activities of daily living,ADL)评分有显著性差异(P<0.01),部分患者由药物引起的开-关现象也有明显缓解;协同服用的多巴胺类药物的用量也有不同程度的减少。所有患者术中及术后均无严重的并发症,术后随访疗效肯定。结论 丘脑底核放置深部脑刺激电极,能明显改善帕金森病患者的临床症状,提高手术的安全性,并发症少。     

Two‐year follow‐up on the effect of unilateral subthalamic deep brain stimulation in highly asymmetric Parkinson's disease

Although bilateral subthalamic deep brain stimulation (STN DBS) provides greater relief from the symptoms of Parkinson's disease (PD) than unilateral STN DBS, it has been suggested that unilateral STN DBS may be a reasonable treatment option in selected patients, especially those with highly asymmetric PD. In previous studies on the effect of unilateral STN DBS, the asymmetry of PD symptoms was not prominent and the mean follow‐up durations were only 3 to 12 months. In this study, we report our findings in a series of 8 patients with highly asymmetric PD who were treated with unilateral STN DBS and were followed for 24 months. Serial changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor score and subscores in the ipsilateral, contralateral, and axial body parts were analyzed. Unilateral STN DBS improved the UPDRS motor score and the contralateral subscore in the on‐medication state for 5 nonfluctuating patients and in the off‐medication state for 3 fluctuating patients. However, the ipsilateral subscore progressively worsened and reversed asymmetry became difficult to manage, which led to compromised medication and stimulator adjustment. At 24 months, all the patients were considering the second‐side surgery. Our results suggest that bilateral STN DBS should be considered even in highly asymmetric PD. © 2008 Movement Disorder Society     

Speed effects of deep brain stimulation for Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) accelerates reaction time (RT) in patients with Parkinson's disease (PD), particularly in tasks in which decisions on the response side have to be made. This might indicate that DBS speeds up both motor and nonmotor operations. Therefore, we studied the extent to which modifications of different processing streams could explain changes of RT under subthalamic DBS. Ten PD patients on‐DBS and off‐DBS and 10 healthy subjects performed a choice‐response task (CRT), requiring either right or left finger button presses. At the same time, EEG recordings were performed, so that RTs could be assessed together with lateralized readiness potentials (LRP), indicative of movement preparation. Additionally, an oddball task (OT) was run, in which right finger responses to target stimuli were recorded along with cognitive P300 responses. Generally, PD patients off‐DBS had longer RTs than controls. Subthalamic DBS accelerated RT only in CRT. This could largely be explained by analog shortenings of LRP. No DBS‐dependent changes were identified in OT, neither on the level of RT nor on the level of P300 latencies. It follows that RT accelerations under DBS of the STN are predominantly due to effects on the timing of motor instead of nonmotor processes. This starting point explains why DBS gains of response speed are low in tasks in which reactions are initiated from an advanced level of movement preparation (as in OT), and high whenever motor responses have to be raised from scratch (as in CRT). © 2010 Movement Disorder Society