Mechanism of CMPf Deep Brain Stimulation for Tourette Syndrome

项目总结 Tourette综合征(TS)是一种神经发育障碍，其特征是两个运动的慢性存在 还有声带抽搐。最近的流行病学研究表明，超过10万名学龄儿童受到这种综合征的影响， 通常伴随有干扰学习成绩和社交能力的行为并存 发展。虽然主要是一种儿童疾病，随着年龄的增长而改善，但部分患者是难治性的。 接受药物治疗，并继续遭受痛苦，直到成年。脑深部刺激(DBS)已经成为一种 这些严重影响患者的治疗选择，虽然DBS治疗的许多目标是 确定的主要目标是丘脑的中央正中-束旁复合体(CMPF)。最大的 Tourette的DBS临床试验发现，到目前为止，针对CMPF的Yale Global Tic严重程度降低了52% 规模，这是一个显示其潜力的有希望的结果。尽管有这种临床益处，但神经生物学机制 CMPF的DBS通过什么机制缓解TS的症状尚不清楚。此前的研究表明， 纹状体细胞外多巴胺水平升高与本病和OUR的病理生理关系 CMPF DBS期间快速扫描循环伏安(FSCV)的初步结果表明，CMPF可以 调节这些水平。这些结果表明，CMPF的DBS可能改变了细胞外纹状体多巴胺 水平，这可能与减少抽动行为有关。为了测试这一点，我们试图澄清CMPF 刺激导致背侧纹状体的多巴胺能反应。我们将采用光伏发电和电动发电。 并用FSCV和FSCV记录细胞外多巴胺的时相和紧张性变化 多次循环方波伏安法。将使用TS的大鼠模型来表征 CMPF DBS对纹状体细胞外多巴胺水平和抽动行为的影响药理操作 将被应用于机械评估是否需要CMPF刺激引起的多巴胺释放的变化 用于改善TS相关抽动行为。

PROJECT SUMMARY Tourette syndrome (TS) is a neurodevelopmental disorder characterized by the chronic presence of both motor and vocal tics. Recent epidemiologic studies show over 100,000 school children are affected by this syndrome, often with associated behavioral comorbidities that interfere with scholastic performance and social development. While primarily a disease of childhood that improves with age, a subset of patients are refractory to medication and continue to be afflicted into adulthood. Deep brain stimulation (DBS) has emerged as a treatment option for these severely affected patients and while many targets for DBS therapy have been identified, the primary target is the centromedian-parafascicular complex (CMPf) of the thalamus. The largest Tourette’s DBS clinical trial to date targeting the CMPf found a 52% reduction in the Yale Global Tic Severity Scale, a promising result that shows its potential. Despite this clinical benefit, the neurobiological mechanism by which DBS of the CMPf alleviates symptoms of TS is not understood. Previous studies have implicated increased extracellular dopamine levels in the striatum with the pathophysiology of this disease and our preliminary results using fast scan cyclic voltammetry (FSCV) during CMPf DBS suggest the CMPf can modulate these levels. These findings indicate that DBS of the CMPf may alter extracellular striatal dopamine levels and this may be correlated with reduced tic behavior. To test this, we seek to elucidate if CMPf stimulation leads to a dopaminergic response in the dorsal striatum. We will employ optogenetic and electrical stimulation to do so and record extracellular levels of phasic and tonic changes in dopamine with FSCV and multiple cyclic square wave voltammetry, respectively. A rat model of TS will be employed to characterize the effects of CMPF DBS on extracellular striatal dopamine levels and tic behavior. Pharmacological manipulations will be applied to mechanistically assess if CMPf stimulation-evoked changes in dopamine release are required for amelioration of TS-related tic behavior.