Cerebellar stimulation for the treatment of dystonia: preclinical studies

小脑刺激治疗肌张力障碍：临床前研究

• 批准号: 8458057
• 负责人: ELLEN J. HESS
• 金额: $ 18.82万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458057
• 关键词: Ablation; Address; Affect; Animal Experiments; Animal Model; Animals; Autopsy; Basal Ganglia; Botulinum Toxins; Brain; Case Study; Cerebellar Diseases; Cerebellum; Cerebral Palsy; Cervical Dystonia; Cervix Neoplasms; Clinical Research; Deep Brain Stimulation; Disease; Dyskinetic syndrome; Dystonia; Dystonic Disorder; Electric Stimulation; Epilepsy; FOS gene; Frequencies; Functional Imaging; Globus Pallidus; Goals; Human; Image; Injection of therapeutic agent; Link; Location; Maps; Measures; Modeling; Movement; Movement Disorders; Mus; Muscle; Muscle Contraction; Patients; Pharmaceutical Preparations; Physiologic pulse; Posture; Rattus; Reporter; Reporting; Secondary Dystonia; Signal Transduction; Smooth Muscle; Testing; Width; effective therapy; experience; motor disorder; mouse model; novel; novel therapeutics; palliative; pre-clinical; preclinical study; small molecule; success; treatment strategy

DESCRIPTION (provided by applicant): Dystonia is characterized by excessive involuntary muscle contractions that cause abnormal postures and twisting movements. Current treatments for dystonia are largely unsatisfactory or palliative. Small molecule drugs are ineffective in most patients. Botulinum toxin is effective but requires injection into affected muscles, limiting its ue to the treatment of dystonias that affect a small number of muscles. Deep brain stimulation (DBS) of the internal globus pallidus is another treatment option. Some patients, particularly those suffering from primary generalized dystonia experience tremendous benefits from pallidal DBS. However, many other patients, particularly those with secondary dystonias, experience little or no improvement, demonstrating a need for the identification and exploration of new treatment targets. Strong evidence implicates cerebellar abnormalities in dystonia and supports the idea that electrical stimulation of the cerebellum is an effective treatment for dystonia. Autopsy studies established a link between cervical dystonia and tumors of the cerebellum. Further, abnormal activity of the cerebellum is observed in many different forms of dystonia additionally, some cerebral palsy patients, who also often suffer from dystonia in addition to spasticity, have experienced improvement after cerebellar electrical stimulation. However, there are currently no studies examining the use of cerebellar stimulation in dystonia per se. Animal studies demonstrate that cerebellar abnormalities can cause dystonia. Abnormal cerebellar activity is observed in mouse and rat models of dystonia. In rat and mouse models, ablation of the cerebellum ameliorates dystonia. The effects of cerebellar stimulation have not yet been explored in animal models to test the idea that dystonia can be ameliorated using the non-ablative approach of electrical stimulation to interrupt abnormal signaling. Although cerebellar stimulation has been used in humans for decades, the use of cerebellar stimulation for the treatment of dystonia is surprisingly limited despite the strong evidence linking cerebellar dysfunction to dystonia in both human and animal studies. This proposal will systematically examine cerebellar stimulation for the treatment of dystonia in mouse models as preclinical proof-of-concept. The specific aims of this proposal are: Aim 1. To determine parameters of cerebellar stimulation that ameliorates dystonia. The effects of methodically varying stimulation parameters, including location, frequency, and amplitude and pulse width on dystonic and baseline activity are assessed in alert unrestrained mouse models of dystonia. Aim 2. to map the anatomical extent of stimulation. Because c-fos expression is routinely used to map electrical stimulation in brain, we will use the fos reporter TetTag mice to map extent of cerebellar stimulation. The success of this proposal will provide preclinical evidence to support an exploratory clinical study in humans for the use of cerebellar stimulation as a treatment for dystonia.

描述（由申请人提供）：肌张力障碍的特征是过量的非自愿性肌肉收缩，引起异常的姿势和扭曲运动。目前对肌张力障碍的治疗基本上是不令人满意的或姑息的。小分子药物在大多数患者中无效。肉毒杆菌毒素是有效的，但需要注射到受影响的肌肉中，将其UE限制在影响少量肌肉的肌张力蛋白酶的治疗中。内部球粒内部的深脑刺激（DB）是另一种治疗选择。一些患者，尤其是患有原发性肌张力障碍的患者，从苍白的DBS上经历了巨大的好处。但是，许多其他患者，特别是患有继发性肌张力障碍的患者，几乎没有改善或没有改善，表明需要鉴定和探索新的治疗靶标。有力的证据表明，肌张力障碍的小脑异常，并支持小脑电刺激是肌张力障碍的有效治疗方法。尸检研究建立了宫颈肌张力障碍与小脑肿瘤之间的联系。此外，在许多不同形式的肌张力障碍中也观察到小脑的异常活性，另外一些脑性麻痹患者除痉挛外还经常患有肌张力障碍，在小脑电刺激后也经历了改善。但是，目前尚无研究在肌张力障碍中使用小脑刺激的使用。动物研究表明，小脑异常会导致肌张力障碍。在小鼠和大鼠肌张力障碍模型中观察到异常的小脑活性。在大鼠和小鼠模型中，小脑的消融可改善肌张力障碍。在动物模型中尚未探索小脑刺激的作用，以测试可以使用电刺激的非开采方法改善肌张力障碍来中断异常信号传导的方法。尽管几十年来已在人类中使用小脑刺激，但尽管在人类和动物研究中，小脑功能障碍与肌张力障碍联系在一起，但使用小脑刺激来治疗肌张力障碍。该建议将系统地检查小脑刺激，以作为临床前概念验证小鼠模型治疗肌张力障碍。该提案的具体目的是：目标1。确定小脑刺激的参数可以改善肌张力障碍。有条不紊地改变刺激参数的影响，包括位置，频率以及脉冲宽度对肌张力障碍和基线活性的影响。目标2。绘制刺激的解剖学范围。由于C-FOS表达通常用于绘制大脑中的电刺激，因此我们将使用FOS报告基因TETTAG小鼠来绘制小脑刺激的程度。该提案的成功将提供临床前证据，以支持人类使用小脑刺激作为肌张力障碍治疗的探索性临床研究。