Cerebellar stimulation for the treatment of dystonia: preclinical studies

描述(申请人提供)：肌张力障碍的特征是过度的不自主肌肉收缩，导致不正常的姿势和扭曲的运动。目前对肌张力障碍的治疗大多不令人满意或姑息治疗。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中，仅限于治疗影响少数肌肉的肌张力障碍。苍白球内侧脑深部刺激(DBS)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，体验到了苍白球DBS的巨大好处。然而，许多其他患者，特别是那些继发性肌张力障碍患者，几乎没有改善，这表明需要确定和探索新的治疗靶点。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的观点。尸检研究确定了颈性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都可以观察到小脑活动的异常。此外，一些脑瘫患者除了痉挛外，还经常患有肌张力障碍，在小脑电刺激后症状有所改善。然而，目前还没有研究考察小脑刺激在肌张力障碍本身中的应用。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小脑活动异常。在大鼠和小鼠模型中，切除小脑可以改善肌张力障碍。小脑刺激的影响还没有在动物模型中进行探索，以测试使用电刺激的非消融性方法来中断异常信号可以改善肌张力障碍的想法。虽然小脑刺激在人类中已经使用了几十年，但在人类和动物研究中，尽管有强有力的证据表明小脑功能障碍与肌张力障碍有关，但小脑刺激用于治疗肌张力障碍的应用令人惊讶地有限。这项建议将系统地检查小脑刺激治疗小鼠肌张力障碍的模型，作为临床前的概念验证。本方案的具体目的是：目的1.确定改善肌张力障碍的小脑刺激参数。系统地改变刺激参数，包括位置、频率、幅度和脉冲宽度，在警觉的不受限制的肌张力障碍小鼠模型中评估了刺激参数对肌张力障碍和基线活动的影响。目的2.绘制刺激的解剖范围图。因为c-fos的表达通常被用来定位大脑中的电刺激，所以我们将使用FOS报告基因TetTag小鼠来定位小脑刺激的范围。这项提议的成功将提供临床前证据，支持在人类中使用小脑刺激作为治疗肌张力障碍的探索性临床研究。

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.