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度的不自主肌肉收缩，导致异常姿势和扭转运动。目前针对肌张力障碍的治疗在很大程度上不令人满意或姑息。小分子药物对大多数患者无效。肉毒杆菌毒素是有效的，但需要注射到受影响的肌肉，限制了它的使用影响少数肌肉肌张力障碍的治疗。深部脑刺激（DBS）的内部苍白球是另一种治疗选择。一些患者，特别是那些患有原发性全身性肌张力障碍的患者，从苍白球DBS中获得了巨大的益处。然而，许多其他患者，特别是那些继发性肌张力障碍，经验很少或没有改善，表明需要识别和探索新的治疗目标。强有力的证据表明小脑异常与肌张力障碍有关，并支持电刺激小脑是治疗肌张力障碍的有效方法。尸检研究证实了颈部肌张力障碍和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观察到小脑的异常活动。此外，除了痉挛状态之外，还经常患有肌张力障碍的一些脑瘫患者在小脑电刺激后经历了改善。然而，目前还没有研究检查使用小脑刺激肌张力障碍本身。动物研究表明，小脑异常可导致肌张力障碍。在肌张力障碍的小鼠和大鼠模型中观察到异常小脑活动。在大鼠和小鼠模型中，小脑消融可改善肌张力障碍。小脑刺激的作用尚未在动物模型中探索，以测试使用电刺激的非消融方法中断异常信号传导可以改善肌张力障碍的想法。尽管小脑刺激已经在人类中使用了几十年，但是尽管在人类和动物研究中有强有力的证据将小脑功能障碍与肌张力障碍联系起来，但是使用小脑刺激治疗肌张力障碍令人惊讶地有限。该提案将系统地检查小脑刺激用于治疗小鼠模型中的肌张力障碍，作为临床前概念验证。本提案的具体目标是：目标1。确定小脑刺激改善肌张力障碍的参数。在肌张力障碍的警觉无限制小鼠模型中评估了系统地改变刺激参数（包括位置、频率和振幅以及脉冲宽度）对肌张力障碍和基线活动的影响。目标2.来绘制刺激的解剖学范围。因为c-fos表达通常用于绘制脑中的电刺激，所以我们将使用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，以支持在人类中使用小脑刺激作为肌张力障碍治疗的探索性临床研究。