Deep brain stimulation of the subthalamic nucleus enhances emotional processing in Parkinson disease

BACKGROUND: High-frequency electrical stimulation of the subthalamic nucleus is a new and highly effective therapy for complications of long-term levodopa therapy and motor symptoms in advanced Parkinson disease (PD). Clinical observations indicate additional influence on emotional behavior. METHODS: Electrical stimulation of deep brain nuclei with pulse rates above 100 Hz provokes a reversible, lesioning-like effect. Here, the effect of deep brain stimulation of the subthalamic nucleus on emotional, cognitive, and motor performance in patients with PD (n = 12) was examined. The results were compared with the effects of a suprathreshold dose of levodopa intended to transiently restore striatal dopamine deficiency. Patients were tested during medication off/stimulation off (STIM OFF), medication off/stimulation on (STIM ON), and during the best motor state after taking levodopa without deep brain stimulation (MED). RESULTS: More positive self-reported mood and an enhanced mood induction effect as well as improvement in emotional memory during STIM ON were observed, while during STIM OFF, patients revealed reduced emotional performance. Comparable effects were revealed by STIM ON and MED. Cognitive performance was not affected by the different conditions and treatments. CONCLUSIONS: Deep brain stimulation of the subthalamic nucleus selectively enhanced affective processing and subjective well-being and seemed to be antidepressive. Levodopa and deep brain stimulation had similar effects on emotion. This finding may provide new clues about the neurobiologic bases of emotion and mood disorders, and it illustrates the important role of the basal ganglia and the dopaminergic system in emotional processing in addition to the well-known motor and cognitive functions.     

Dissociation between time reproduction of actions and of intervals in patients with Parkinson’s disease

Alterations in temporal estimation have been observed in patients with Parkinson’s disease (PD) and have been associated to dopaminergic dysfunction. Nevertheless, levodopa treatment and deep brain stimulation of the subthalamic nucleus (DBS-STN) have been shown to improve motor deficits and temporal estimation skills in such patients. So far, temporal estimation tasks in PD patients have evaluated the ability to reproduce intervals of time, but never the duration of an action. Here we investigated: (1) the ability of PD patients to reproduce the duration of their previous actions as compared to their ability to reproduce intervals of time and (2) the effect that DBS-STN has on both skills. Nineteen PD patients with DBS-STN and 19 controls were requested to reproduce the duration of an action and that of an interval of time. The patients were tested in the following treatment conditions: on stimulation/off medication, off stimulation/off medication and off stimulation/on medication. The results demonstrated that patients in the off stimulation/off medication condition under-reproduced the duration of their actions while accurately reproducing the duration of time intervals. The accuracy of the performance improved significantly in both treatment regimens. Our results indicate that in PD patients the ability to reproduce motor acts can be dissociated from that of reproducing time intervals and that it can be improved by the administration of medical or surgical treatment.     

Contrast sensitivity in Parkinson's disease patients with subthalamic nucleus deep brain stimulation

This study examined whether deep brain stimulation (DBS) would affect the contrast sensitivity (CS) curve in patients with PD. CS was tested in 12 nondemented PD patients treated with bilateral subthalamic nucleus DBS on and off stimulation and medications. Neither stimulation condition (on vs. off) nor medications altered CS performance in this group of patients. However, collapsed across conditions, patients with bipolar stimulation in this study had significantly poorer CS at higher spatial frequencies (12 and 18 cycles per degree) than patients with monopolar stimulation. This suggests that CS deficits in PD may possibly be influenced by DBS polarity and merits further study. © 2009 Movement Disorder Society     

Effects of bilateral subthalamic nucleus deep brain stimulation on motor symptoms in Parkinson's disease:a retrospective cohort study

Deep brain stimulation of the bilateral subthalamic nucleus(STN) is a therapeutic option for patients with Parkinson's disease(PD) in whom medical therapies have been ineffective. This retrospective cohort study analyzed the motor function of 27 patients with advanced PD, from the First Affiliated Hospital of Guangzhou Medical University, China, who received deep brain stimulation of the bilateral subthalamic nucleus and evaluated its therapeutic effects. The 10-year follow-up data of patients was analyzed in Qingyuan People's Hospital, Sixth Affiliated Hospital of Guangzhou Medical University, China. The follow-up data were divided into two categories based on patients during levodopa treatment(on-medication) and without levodopa treatment(off-medication). Compared with baseline, the motor function of onmedication PD patients improved after deep brain stimulation of the bilateral subthalamic nucleus. Even 2 years later, the motor function of off-medication PD patients had improved. On-medication PD patients exhibited better therapeutic effects over the 5 years than offmedication PD patients. On-medication patients' akinesia, speech, postural stability, gait, and cognitive function worsened only after 5 years. These results suggest that the motor function of patients with advanced PD benefitted from treatment with deep brain stimulation of the bilateral subthalamic nucleus over a period up to 5 years. The overall therapeutic effects were more pronounced when levodopa treatment was combined with deep brain stimulation of the bilateral subthalamic nucleus. This study was approved by Institutional Review Board of Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, China(approval No. QPH-IRB-A0140) on January 11, 2018.     

Effects of bilateral subthalamic nucleus deep brain stimulation on motor symptoms in Parkinson’s disease: a retrospective cohort study

Deep brain stimulation of the bilateral subthalamic nucleus (STN) is a therapeutic option for patients with Parkinson’s disease (PD) in whom medical therapies have been ineffective. This retrospective cohort study analyzed the motor function of 27 patients with advanced PD, from the First Affiliated Hospital of Guangzhou Medical University, China, who received deep brain stimulation of the bilateral subthalamic nucleus and evaluated its therapeutic effects. The 10-year follow-up data of patients was analyzed in Qingyuan People’s Hospital, Sixth Affiliated Hospital of Guangzhou Medical University, China. The follow-up data were divided into two categories based on patients during levodopa treatment (on-medication) and without levodopa treatment (off-medication). Compared with baseline, the motor function of on-medication PD patients improved after deep brain stimulation of the bilateral subthalamic nucleus. Even 2 years later, the motor function of off-medication PD patients had improved. On-medication PD patients exhibited better therapeutic effects over the 5 years than off-medication PD patients. On-medication patients’ akinesia, speech, postural stability, gait, and cognitive function worsened only after 5 years. These results suggest that the motor function of patients with advanced PD benefitted from treatment with deep brain stimulation of the bilateral subthalamic nucleus over a period up to 5 years. The overall therapeutic effects were more pronounced when levodopa treatment was combined with deep brain stimulation of the bilateral subthalamic nucleus. This study was approved by Institutional Review Board of Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, China (approval No. QPH-IRB-A0140) on January 11, 2018.

Chinese Library Classification No. R454.1; R741; R338.2+4     

Evolution of Parkinson's disease during 4 years of bilateral deep brain stimulation of the subthalamic nucleus.

Patients with advanced Parkinson's disease (PD) and motor complications can obtain significant symptom improvement by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Very little is published, however, about long-term effect and disease evolution during DBS. We performed a 4-year prospective study of the first 22 consecutive patients treated with STN DBS. The patients were evaluated with Unified Parkinson's Disease Rating Scale Part II to VI and a patient diary concerning on-off periods and dyskinesia. Patients were scored before surgery on medication and off medication for 10 to 12 hours and in four conditions 1 and 4 years after surgery: off medication+/-stimulation and on medication+/-stimulation. In advanced PD, a significant reduction of dyskinesia and off periods was present 4 years (90%/67%) after the operation. Total motor function on stimulation alone improved 55% at 4 years, compared with baseline and activities of daily living (42%). On stimulation, significant worsening of axial symptoms and speech was present from 1 to 4 years. To evaluate disease evolution, motor symptoms were assessed off stimulation and medication for 12 hours and were found not to worsen compared with baseline, which is remarkable in an otherwise progressive disorder. Five patients developed dementia. Severe adverse events were not observed.     

Deep brain stimulation of the subthalamic nucleus improves sense of well-being in Parkinson's disease

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of Parkinson's disease. Although a range of psychiatric and behavioral problems have been documented following deep brain stimulation, the short-term effects of subthalamic nucleus stimulation on patients' mood have only been investigated in a few studies. Our aim was to compare self-reported mood in Parkinson's patients with deep brain stimulation of the subthalamic nucleus ON versus OFF. Twenty-three Parkinson's patients with bilateral deep brain stimulation of the subthalamic nucleus and 11 unoperated Parkinson's patients completed a mood visual analogue scale twice. Operated patients were tested with deep brain stimulation of the subthalamic nucleus both ON and OFF. All were assessed on medication. The operated Parkinson's group reported feeling significantly better coordinated, stronger, and more contented with deep brain stimulation ON compared to OFF. Fourteen of the 16 mood scales changed in a positive direction when deep brain stimulation of the subthalamic nucleus was ON. When changes in motor scores were taken into account, the operated patients still reported feeling better-coordinated, but also less gregarious with stimulation ON. Unoperated Parkinson's patients showed no differences on any of these measures between their 2 ratings. Short-term changes in deep brain stimulation of the subthalamic nucleus have a small and mostly positive effect on mood, which may be partly related to improvements in motor symptoms. The implications for day-to-day management of patients with deep brain stimulation of the subthalamic nucleus are discussed.     

Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson's disease

We describe two patients with Parkinson's disease (PD) who developed clinical criteria of pathological gambling addiction in the setting of increased dopamine replacement therapy (levodopa and dopamine agonist medications). The second patient showed also signs of dopamine dysregulation syndrome, with an addiction to dopaminergic medication. Neither patients responded to the standard therapy for gambling behavior, but dramatically improved after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) and early postoperative withdrawal of dopaminergic therapy. The possible therapeutic role of subthalamic nucleus deep brain stimulation (STN-DBS) on such a disabling behavior needs to be investigated prospectively.     

丘脑底核脑深部刺激术治疗帕金森病的手术方法和疗效分析

目的 总结帕金森病(PD)脑深部刺激术(DBS)治疗的手术方法和效果。方法 对25例帕金森病患者进行了丘脑底核DBS治疗,其中单侧17例,双侧8例。采用磁共振扫描结合微电极记录技术进行靶点定位。术后用UPDRS运动评分评价刺激效果。结果 25例PD患者术后随访5～34个月,平均8.3个月。脉冲发生器开启时,在“关”状态下,UPDRS运动评分改善率50.2％;在“开”状态下,UPDRS运动评分改善率20.7％,未发现任何并发症。结论 丘脑底核DBS是改善PD患者运动功能较为理想的治疗方法。     

Long-term outcome of 50 consecutive Parkinson's disease patients treated with subthalamic deep brain stimulation

OBJECTIVE: To describe the long-term outcome in 50 consecutive advanced Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). METHOD: Assessments were carried out at baseline, 6 months, 2 years, and 5 years postoperatively. RESULTS: Compared to baseline scores without medication, we found a highly significant improvement of UPDRS III with stimulation, maintained at 5 years (p<0.001). This improvement, however, tended to diminish over time. Dyskinesia and off periods were also improved (p<0.0001 for both). Seventeen patients died during follow-up, who tended to be older at surgery (p<0.01). CONCLUSIONS: STN-DBS is an effective treatment for advanced PD patients, and the beneficial effect is maintained at 5 years. However, worsening occurs over time due to disease progression.     

Bilateral deep brain stimulation of subthalamic nucleus STN in the surgical treatment of Parkinson's disease

Dopamine deficiency in the nigrostriatal system leads to a series of changes in the basal ganglia, resulting in an increased neuronal activity of the subthalamic nucleus (STN). Reduction of the STN glutaminergic excitatory effect on the main output structures of the basal ganglia (globus pallidum pars interna GPi and substantia nigra pars reticulata SNr) is accompanied by a marked alleviation of parkinsonian motor sings in the MPTP monkey model of parkinsonism. Also a high-frequency stimulation of STN in the MPTP monkey model of parkinsonism produced the same clinical effect as did lesioning. Due to these observations bilateral deep subthalamic stimulation was introduced in the treatment of PD patients with severe akinetic-rigid form of this disease. Four patients with akinetic-rigid PD form of PD were included in the study. The electrodes for deep brain stimulation were implanted in two separate surgical interventions in every case. The second implantation was performed not earlier than at least 3 months after the first procedure. Evaluations using the UPDRS were conducted before surgery in "on" and "off" conditions and at 3, 6 and 12 months after the bilateral implantation. Bilateral DBS STN seems to be the best stereotactic target in controlling motor symptoms in the "off" condition in the treatment of PD patients with severe symptoms. The technique enables a dramatic reduction in the daily dose of L-dopa.     

脑深部电刺激治疗帕金森病的长期随访研究

目的长期随访一组采用双侧脑深部电刺激(DBS)丘脑底核(STN)的帕金森(PD)病人,为临床研究提供参考。方法 195例PD病人在我院接受了双侧STN-DBS手术。术中采用微电极记录STN的外放电信号,刺激电极测试病人症状改善情况及副反应阈值。分别在术前术后1年、3年和5年采用UPDRS评分评估PD病人"开/关"两种状态下的症状改善程度。结果术前对照,PD病人术后5年"关"状态运动评分改善率为60.3%;日常生活评分的改善率为54.2%。语言是运动评分中唯一没有改善的症状。异动症除外,术后1年"开"状态下运动评分没有显著改善。第1年和第5年"开"状态下运动迟缓、姿势障碍和步僵症状较术前均有加重。术后第5年异动症较术前明显改善。结论 PD病人双侧STN-DBS术后长期随访结果表明,"关"状态下运动评分和"开"状态下异动症均明显改善。术后第1年和第5年比较,行动迟缓、语言、姿势异常、步僵和认知功能的障碍均有加重。     

End of day dyskinesia in advanced Parkinson's disease can be eliminated by bilateral subthalamic nucleus or globus pallidus deep brain stimulation.

We report the therapeutic effects of deep brain stimulation (DBS) in 2 patients with Parkinson's disease (PD) with severe end of dose dyskinesia that was resistant to medical therapy. In both patients, severe, end of day ballistic dyskinesias occurred when the last levodopa dose of the day was wearing off. Globus pallidus (GPi) DBS in 1 case and subthalamic (STN) DBS in the second case produced full resolution of end of day dyskinesia.     

Local field potential beta activity in the subthalamic nucleus of patients with Parkinson's disease is associated with improvements in bradykinesia after dopamine and deep brain stimulation

Parkinson's disease is treated pharmacologically with dopamine replacement medication and, more recently, by stimulating basal-ganglia nuclei such as the subthalamic nucleus (STN). Depth recordings after this procedure have revealed excessive activity at frequencies between 8 and 35 Hz ([Brown et al., 2001], [Kuhn et al., 2004] and [Priori et al., 2004]) that are reduced by dopamine therapy in tandem with improvements in bradykinesia/rigidity, but not tremor (Kuhn et al., 2006). It has also been shown that improvements in motor symptoms after dopamine correlate with single unit activity in the beta range (Weinberger et al., 2006). We recorded local field potentials (LFPs) from the subthalamic nucleus of patients with Parkinson's disease (PD) after surgery to implant deep brain stimulating electrodes while they were on and off dopaminergic medication. As well as replicating Kuhn et al., using the same patients we were able to extend Weinberger et al. to show that LFP beta oscillatory activity correlated with the degree of improvement in bradykinesia/rigidity, but not tremor, after dopamine medication. We also found that the power of beta oscillatory activity uniquely predicted improvements in bradykinesia/rigidity, but again not tremor, after stimulation of the STN in a regression analysis. However improvements after STN stimulation related inversely to beta power, possibly reflecting the accuracy of the electrode placement and/or the limits of STN stimulation in patients with the greatest levels of beta oscillatory activity.     

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.     

Effect and time course of deep brain stimulation of the globus pallidus and subthalamus on motor features of Parkinson's disease

We studied the effect and temporal profile of deep brain stimulation (DBS) of the globus pallidus and subthalamic nucleus on the motor signs of Parkinson's disease (PD). Four patients with bilateral deep brain stimulators of the globus pallidus and four patients with bilateral deep brain stimulators of the subthalamus were studied while taking no medication and at 15 and 30 minutes and 1, 2, 4, and 6 hours after turning stimulation on. An immediate (15 minutes) and sustained (6 hours) benefit was observed for all the motor manifestations of PD for both stimulation sites. Deep brain stimulation of the globus pallidus and subthalamus is highly effective in reducing all the cardinal motor features of PD.     

双侧丘脑底核脑深部电刺激术治疗帕金森病(附33例报道)

目的总结双侧脑深部电刺激术(DBS)治疗帕金森病(PD)的手术方法和效果。方法对具有严重双侧症状和轴性症状的33例PD病人进行同期双侧丘脑底核DBS治疗。采用磁共振扫描结合微电极记录技术进行靶点定位。术后采用统一帕金森病评定量表(UPDRS)运动评分评价刺激效果。结果术后随访3个月~4年,平均7.3个月。脉冲发生器开启时,UPDRS运动评分平均改善率在“关”状态下为62.3%,在“开”状态下为24.2%。记忆力下降2例,情绪改变7例,睁眼困难1例,肢体异动15例;无明显的致残性永久并发症和副作用。结论双侧丘脑底核DBS手术的安全性较高,可明显改善PD病人的运动功能。     

Deep brain stimulation of the subthalamic nucleus improves sense of well‐being in parkinson's disease

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of Parkinson's disease. Although a range of psychiatric and behavioral problems have been documented following deep brain stimulation, the short‐term effects of subthalamic nucleus stimulation on patients' mood have only been investigated in a few studies. Our aim was to compare self‐reported mood in Parkinson's patients with deep brain stimulation of the subthalamic nucleus ON versus OFF. Twenty‐three Parkinson's patients with bilateral deep brain stimulation of the subthalamic nucleus and 11 unoperated Parkinson's patients completed a mood visual analogue scale twice. Operated patients were tested with deep brain stimulation of the subthalamic nucleus both ON and OFF. All were assessed on medication. The operated Parkinson's group reported feeling significantly better coordinated, stronger, and more contented with deep brain stimulation ON compared to OFF. Fourteen of the 16 mood scales changed in a positive direction when deep brain stimulation of the subthalamic nucleus was ON. When changes in motor scores were taken into account, the operated patients still reported feeling better‐coordinated, but also less gregarious with stimulation ON. Unoperated Parkinson's patients showed no differences on any of these measures between their 2 ratings. Short‐term changes in deep brain stimulation of the subthalamic nucleus have a small and mostly positive effect on mood, which may be partly related to improvements in motor symptoms. The implications for day‐to‐day management of patients with deep brain stimulation of the subthalamic nucleus are discussed. © 2012 Movement Disorder Society     

Failure of long-term pallidal stimulation corrected by subthalamic stimulation in PD

Bilateral high-frequency continuous stimulation of the internal globus pallidus or subthalamic nucleus constitutes a new therapeutic approach for the treatment of patients with severe PD. The authors report two patients in whom stimulation of the globus pallidus failed to give long-term relief and was successfully replaced by bilateral subthalamic stimulation. The results emphasize the reversibility of deep brain stimulation therapy and suggest that the subthalamic target is preferable to the pallidal target.     

Electroconvulsive therapy for depression in a Parkinson's disease patient with bilateral subthalamic nucleus deep brain stimulators

We report a patient with advanced Parkinson's disease (PD) who developed a recurrence of major depression with psychotic features after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. Electroconvulsive therapy (ECT) dramatically improved the depression without shifting electrode position or damaging the DBS hardware. This case suggests that ECT can be a safe and effective option for severe depression in PD patients treated with STN DBS.