Subthalamic nucleus deep brain stimulation suppresses neuroinflammation by Fractalkine pathway in Parkinson’s disease rat model

Subthalamic nucleus deep brain stimulation (STN-DBS) is widely used to treat patients with Parkinson’s disease (PD), and recent studies have shown that it is more beneficial for early stages, suggesting a potential neuroprotective effect. And the neuroinflammation plays an indispensable role in progress of PD. However, the underlying mechanisms are not well understood. The aim of this study was to investigate the effect of STN-DBS on neuroinflammation and the potential pathway. To address this question, we established a rat PD model by unilateral 6-hydroxydopamine injection into the left striatum and implanted stimulation leads into the ipsilateral STN to deliver electrical stimulation for a week. The neuroprotective effects of STN-DBS were examined by molecular biology techniques, including western blotting, immunohistochemistry and so on. We found that motor deficits were alleviated by STN-DBS, with increased survival of dopaminergic neurons in the substantia nigra (SN). Furthermore, STN-DBS decreased Fractalkine (CX3CL1) and its receptor (CX3CR1) expression. Meanwhile, the suppressed microglia activation and nuclear factor-κB expression, decrease in the levels of pro-inflammatory cytokine interleukin (IL)-1β and IL-6 and increase in anti-inflammatory cytokine IL-4, downregulated IL-1 receptor, extracellular signal-regulated kinase (ERK) and cleaved-caspase3 were also observed in SN of PD models received STN-DBS. In conclusion, we observed a significant association between the suppressed neuroinflammation and STN-DBS, which may be attributed to CX3CL1/CX3CR1 signaling. These results provide novel insight into the mechanistic basis of STN-DBS therapy for PD.     

The neurocircuitry involved in oxytocin modulation of methamphetamine addiction

The role of oxytocin in attenuating the abuse of licit and illicit drugs, including the psychostimulant methamphetamine, has been examined with increased ferocity in recent years. This is largely driven by the potential application of oxytocin as a pharmacotherapy. However, the neural mechanisms by which oxytocin modulates methamphetamine abuse are not well understood. Recent research identified an important role for the accumbens core and subthalamic nucleus in this process, which likely involves an interaction with dopamine, glutamate, GABA, and vasopressin. In addition to providing an overview of methamphetamine, the endogenous oxytocin system, and the effects of exogenous oxytocin on drug abuse, we propose a neural circuit through which exogenous oxytocin modulates methamphetamine abuse, focusing on its interaction with neurochemicals within the accumbens core and subthalamic nucleus. A growing understanding of exogenous oxytocin effects at a neurochemical and neurobiological level will assist in its evaluation as a pharmacotherapy for drug addiction.     

The latest evidence on target selection in deep brain stimulation for Parkinson’s disease

Deep brain stimulation (DBS) is one of the most promising neuromodulatory techniques to gain momentum over the last 20 years, with significant evidence showing the benefit of DBS for Parkinson’s disease (PD). However, many questions still exist pertaining to the optimal placement of stimulation contacts. This paper aims to review the latest and most relevant studies evaluating subthalamic nucleus (STN) and globus pallidus interna (GPi) stimulation. Additionally, it aims to shine a light on several of the lesser-known targets with mounting evidence of efficacy. Referenced literature for the main body of the article was gathered from Medline and PubMed databases. Results were limited to “full text”, “English language” and publications from 1999 onwards. Case reports were excluded. The current evidence irrefutably demonstrates the benefits of both STN and GPi DBS on Unified Parkinson’s Disease Rating Scale (UPDRS) III motor scores, with very similar outcomes seen after 1–2 years. Currently, it appears the greatest differences lie in the associated adverse effects. STN DBS was associated with a greater reduction in dopamine replacement therapy, but also appeared to have more negative effects on speech and mood. Meanwhile, in regards to alternative targets, the pedunculopontine nucleus has shown promising improvement in axial symptoms, while the ventral intermediate nucleus has demonstrated significant efficacy at suppressing tremor, and the caudal zona incerta may be superior to the STN and GPi in improving UPDRS-III scores. Due to the complexity of Parkinson’s disease, an individual disease profile must be determined in a patient-by-patient fashion such that appropriate targets can be selected accordingly.     

脑深部电刺激术治疗毁损术后帕金森病的疗效

目的 探讨脑深部电刺激术（DBS）治疗苍白球或丘脑毁损术后帕金森病的疗效与安全性。方法 回顾性分析2013年1月至2021年3月毁损术后复发或出现新症状而行DBS治疗的33例帕金森病的临床资料。DBS后6个月,采用统一帕金森病量表（UPDRS）运动功能（UPDRS Ⅲ）评分和生活能力（UPDRS Ⅱ）评分、H-Y分期、简明精神量表评分（MMSE）以及左旋多巴等效日剂量（LEDD）评估疗效以及用药情况;记录刺激频率、脉宽、电压、阻抗,并计算刺激能量。结果 术后随访6个月~8.25年,未出现言语障碍、眼球活动障碍、偏瘫、颅内出血或梗死、癫痫发作、颅内感染病例,无硬件故障;5例因电池耗竭行脉冲发生器置换术。DBS后6个月,UPDRS Ⅲ评分、UPDRS Ⅱ评分、H-Y分期、LEDD均较术前明显降低（P<0.05）,而MMSE评分较术前无明显变化（P>0.05）;和非毁损侧相比,毁损侧肢体震颤评分改善率明显增高（P<0.05）,但僵硬评分改善率、运动迟缓评分改善率均无明显变化（P>0.05）;和非毁损侧相比,毁损侧刺激电压和刺激能量明显降低（P<0.05）,但刺激频率、脉宽和阻抗无明显变化（P>0.05）。结论 PD病人神经核团毁损术后复发或出现新症状,DBS是安全、有效的,毁损侧DBS后电刺激所需能量及电压更低。     

The impact of subthalamic deep brain stimulation on belief revision and social validation

We investigated whether Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) influences social validation as measured by a Judge-Advisor task. In contrast to healthy controls and patients with their DBS OFF, patients with their stimulation switched on do not experience a gain of confidence after receiving competent advice.     

Long-term Efficacy of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A 5-year Follow-up Study in China

Background:

Subthalamic nucleus deep brain stimulation (STN DBS) is effective against advanced Parkinson''s disease (PD), allowing dramatic improvement of Parkinsonism, in addition to a significant reduction in medication. Here we aimed to investigate the long-term effect of STN DBS in Chinese PD patients, which has not been thoroughly studied in China.

Methods:

Ten PD patients were assessed before DBS and followed up 1, 3, and 5 years later using Unified Parkinson''s Disease Rating Scale Part III (UPDRS III), Parkinson''s Disease Questionnatire-39, Parkinson''s Disease Sleep Scale-Chinese Version, Mini-mental State Examination, Montreal Cognitive Assessment, Hamilton Anxiety Scale and Hamilton Depression Scale. Stimulation parameters and drug dosages were recorded at each follow-up. Data were analyzed using the ANOVA for repeated measures.

Results:

In the “off” state (off medication), DBS improved UPDRS III scores by 35.87% in 5 years, compared with preoperative baseline (P < 0.001). In the “on” state (on medication), motor scores at 5 years were similar to the results of preoperative levodopa challenge test. The quality of life is improved by 58.18% (P < 0.001) from baseline to 3 years and gradually declined afterward. Sleep, cognition, and emotion were mostly unchanged. Levodopa equivalent daily dose was reduced from 660.4 ± 210.1 mg at baseline to 310.6 ± 158.4 mg at 5 years (by 52.96%, P < 0.001). The average pulse width, frequency and amplitude at 5 years were 75.0 ± 18.21 μs, 138.5 ± 19.34 Hz, and 2.68 ± 0.43 V, respectively.

Conclusions:

STN DBS is an effective intervention for PD, although associated with a slightly diminished efficacy after 5 years. Compared with other studies, patients in our study required lower voltage and medication for satisfactory symptom control.     

Cognitive change on the repeatable battery of neuropsychological status (RBANS) in parkinson's disease with and without bilateral subthalamic nucleus deep brain stimulation surgery

Cognitive change following bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery in those with Parkinson's disease (PD) has led to equivocal results. The current study applied a standardized regression-based (SRB) method based on 20 medically managed PD patients and 20 STN DBS PD surgical patients who were administered the Repeatable Battery of Neuropsychological Status (RBANS). Of the medically managed PD participants, 94% remained stable compared to 73% of the DBS group. In the DBS group cognitive change was noted on the Total scale and the Immediate Memory Index. A secondary analysis also revealed reliable change on several subtest scores. Although preliminary, the current study provides change parameters for post DBS surgery on this brief battery.     

Lack of differential motor outcome with subthalamic nucleus region stimulation in Parkinson’s disease

Deep brain stimulation (DBS) has emerged as a viable therapy for Parkinson’s disease (PD). The impact of subthalamic nucleus (STN) lead placement (lateral versus medial) on motor outcome, however, has not been systematically evaluated. Forty-eight patients with PD underwent STN-DBS surgery and were evaluated postoperatively for 48 weeks for motor improvement as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part III (standardized motor examination) and levodopa equivalent daily dose (LEDD). Postoperative MRI was used to identify the location of the active stimulating contact and motor outcome was analyzed. STN-DBS was associated with significant improvement in motor outcome as determined by a reduction in the UPDRS part III subscore from 34.44 ± 1.29 at baseline to 18.76 ± 1.06 at end visit (p < 0.0001) and a reduction in LEDD from 1721 ± 152 mg/day at baseline to 1134 ± 119 mg/day at end visit (p = 0.0024). Patients with stimulating contacts in the medial STN compared to the lateral STN did not demonstrate any significant differences in motor outcome (UPDRS, p = 0.5811; LEDD, p = 0.7341). No significant differences were found in motor outcome between patients with STN stimulation compared to stimulation of surrounding fiber tracts (p = 0.80). No significant difference in stimulation voltage was noted with respect to lead location. Our study did not find a significant effect for the location of active contact and motor outcome neither within the subregions of the STN nor between the STN and surrounding fibers. Further research is needed to better understand the neurophysiological basis for these results.