Cerebellar stimulation for the treatment of dystonia: preclinical studies

描述（由申请人提供）：肌张力障碍的特征是过度的不随意肌收缩，导致异常的姿势和扭曲运动。目前对肌张力障碍的治疗大多不能令人满意或只能起到缓解作用。小分子药物对大多数病人无效。肉毒杆菌毒素是有效的，但需要注射到受影响的肌肉，限制其用于治疗影响少数肌肉的肌张力障碍。深部脑刺激（DBS）的内部苍白球是另一种治疗方案。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pallidal DBS中获得了巨大的好处。然而，许多其他患者，特别是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。强有力的证据暗示小脑异常在肌张力障碍和支持的想法，电刺激小脑是一个有效的治疗肌张力障碍。尸检研究证实了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都观察到小脑异常活动。此外，一些脑瘫患者，除了痉挛之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，目前还没有研究检查小脑刺激在肌张力障碍本身的应用。动物研究表明，小脑异常可引起肌张力障碍。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。小脑刺激的效果尚未在动物模型中进行探索，以验证使用电刺激的非消融方法来中断异常信号传导来改善肌张力障碍的想法。尽管小脑刺激已经在人类中应用了几十年，但令人惊讶的是，尽管在人类和动物研究中都有强有力的证据表明小脑功能障碍与肌张力障碍有关，但小脑刺激治疗肌张力障碍的应用却有限。本提案将系统地检查小脑刺激治疗肌张力障碍的小鼠模型作为临床前概念验证。本建议的具体目标是：目标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、幅度和脉冲宽度对肌张力障碍和基线活动的影响在无约束的小鼠肌张力障碍模型中进行了评估。目标2。绘制刺激的解剖范围。由于c-fos表达通常用于绘制脑电刺激图，因此我们将使用fos报告基因TetTag小鼠来绘制小脑刺激程度图。该建议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.