Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo.

BACKGROUND: Deep brain stimulation (DBS) has been widely used to manage debilitating neurological symptoms in movement disorders such as Parkinson's disease (PD). Despite its well-established symptomatic benefits, our understanding of the mechanisms underlying DBS and its possible effect on the accumulation of pathological proteins in neurodegeneration remains limited. Accumulation and oligomerization of the protein alpha-synuclein (α-Syn) are implicated in the loss of dopaminergic neurons in the substantia nigra in PD, making α-Syn a potential therapeutic target for disease modification. OBJECTIVE: We examined the effects of high frequency electrical stimulation on α-Syn levels and oligomerization in cell and rodent models. METHODS: High frequency stimulation, mimicking DBS parameters used for PD, was combined with viral-mediated overexpression of α-Syn in cultured rat primary cortical neurons or in substantia nigra of rats. Bimolecular protein complementation with split fluorescent protein reporters was used to detect and quantify α-Syn oligomers. RESULTS: High frequency electrical stimulation reduced the expression of PD-associated mutant α-Syn and mitigated α-Syn oligomerization in cultured neurons. Furthermore, DBS in the substantia nigra, but not the subthalamic nucleus, decreased overall levels of α-Syn, including oligomer levels, in the substantia nigra. CONCLUSIONS: Taken together, our results demonstrate that direct high frequency stimulation can reduce accumulation and pathological forms of α-Syn in cultured neurons in vitro and in substantia nigra in vivo. Thus, DBS therapy could have a role beyond symptomatic treatment, with potential disease-modifying properties that can be exploited to target pathological proteins in neurodegenerative diseases.

Recharge PSYCH: A Study on Rechargeable Implantable Pulse Generators in Deep Brain Stimulation for Psychiatric Disorders.

BACKGROUND: Rechargeable implantable pulse generators (r-IPGs) for deep brain stimulation (DBS) promise longer battery life and fewer replacement surgeries versus non-rechargeable systems. Long-term data on the effects of recharging in patients who received DBS for psychiatric indications is limited. The Recharge PSYCH trial is the first study that included DBS patients with psychiatric disorders treated with different r-IPG models. METHODS: Standardized questionnaires were sent to all psychiatric DBS patients with an r-IPG implanted at the time of the study. The primary endpoint was convenience of recharging. Secondary endpoints were rate of user confidence and rate of usage-related complications, as well as charge burden (defined as minutes per week needed to recharge). RESULTS: Data sets of n = 21 patients were eligible for data analysis. At the time of the survey patients were implanted with the r-IPG for a mean 31.8 ± 22.4 months. Prior to being implanted with an r-IPG, patients had undergone a median of 3 IPG replacements. The overall convenience of the charging process was rated as "easy" with a median of 8.0 out of 10.0 points. 33.3% of patients experienced situations in which the device could not be successfully recharged. In 38.1% of patients, therapy with the r-IPG was interrupted unintentionally. The average charge burden was 286 ± 22.4 minutes per week. CONCLUSIONS: Patients with psychiatric disorders rated the recharging process as "easy", but with a significantly higher charge burden and usage-related complication rates compared to published data on movement disorder DBS patients.

Complete resolution of postherpetic neuralgia following pallidotomy: case report.

The authors report on a female patient with left-dominant Parkinson's disease with motor fluctuations and levodopa-induced dyskinesias and comorbid postherpetic neuralgia (PHN), who underwent a right-sided pallidotomy. Besides a substantial improvement in her Parkinson's symptoms, she reported an immediate and complete disappearance of PHN. This neuralgia had been long-standing, pharmacologically refractory, and severe (preoperative Brief Pain Inventory [BPI] pain severity score of 8.0, BPI pain interference score of 7.3, short-form McGill Pain Questionnaire sensory pain rating index of 7 and affective pain rating index of 10, Present Pain Intensity rank value of 4, and visual analog scale score of 81 mm; all postoperative scores were 0). She continued to be pain free at 16 months postoperatively.This peculiar finding adds substantially to the largely unrecognized evidence for the role of the pallidum in pain processing, based on previous electrophysiological, metabolic, anatomical, pharmacological, and clinical observations. Therefore, the potential of the pallidum as a neurosurgical target for neuropathic pain warrants further investigation.