Subthalamic deep brain stimulation to modulate vestibular heading perception in Parkinson’s disease.

帕金森氏病(PD)是一种常见的影响人类运动的神经退行性疾病。警局不是 只是运动性疾病。它还会导致对自我编码至关重要的多感觉加工受损 定向力和自动性。最终，这会导致空间导航异常，行走时横向漂移 (转向)，姿势不稳，约70%的患者摔倒。常规药物治疗或脑深部治疗 对帕金森病的刺激(DBS)在治疗这些衰弱症状方面的效果各不相同。星展银行改善平衡 一些患者会出现功能障碍，而在一些患者中，它不会影响平衡，甚至会使情况恶化。定义一致性 治疗需要对帕金森病患者的航行障碍机制有一个正确的了解，并知道如何 星展银行调整平衡功能。我们研究计划的一个独特愿景是：1)揭示 DBS如何调节多感觉整合系统的过程的生理基础 控制自己对空间导航、步态和帕金森病平衡至关重要的运动感知。2)能够 丘脑底核DBS持续治疗帕金森病患者的航海障碍 同时保留其治疗震颤和增加肌肉张力的其他好处，并减少药物治疗 有烦人副作用的负担。出于这个目标，当前的Merit Review应用程序专注于前庭 系统-感知自身直线运动的关键系统，即前庭方向感知- 这项任务必须准确，才能正确控制平衡、导航和避免跌倒。我们 假设STN DBS对前庭航向知觉和转向的影响依赖于 STN内主动电极接触的特定位置和小脑-丘脑通路的调制 这是已知的携带前庭信号，并在物理上接近STN。为了检验这一假说 我们将客观地测量一个人感知直线运动方向的能力(即前庭方向感知)， 行走时的侧向漂移(即转向)在帕金森病中很常见，然后我们将比较这些目标 测量三种独立状态-背侧STN DBS、腹侧STN DBS和DBS关闭。目标1 将研究STN内组织激活体积的位置对前庭改变的影响 人类帕金森病患者的航向知觉和转向。我们将整理组织体积的物理位置 当发现前庭方向知觉和转向改变时，所有患者都会激活。这些 生成概率刺激地图集的地点将提供对STN区域的洞察，这些区域可能 影响帕金森病的平衡功能。目标2将检查轴突通路的招募指标 受STN DBS调制，与帕金森病患者前庭方向知觉和转向的变化相关 病人。它将直接检查参与小脑-丘脑通路的作用，这是已知的传递 前庭感知信息，并在STN附近。总之，通过采取自上而下的方法和 利用一个多学科的调查团队研究人类帕金森病患者的STN DBS，神经成像， 和计算模型；我们将揭开STN DBS调节前庭的机制 帕金森病患者的航向知觉。最后，我们将应用这种机械性的理解来设计一致和有效的 利用DBS预防PD跌倒的治疗策略。

Parkinson’s Disease (PD) is a common neurodegenerative disorder affecting human movements. PD is not just a motor disease. It also results in impaired multi-sensory processing that is critical for encoding self- orientation and self-motion. Ultimately, this leads to abnormal spatial navigation, lateral drifts while walking (veering), postural instability and falls in about 70% of patients. Conventional pharmacotherapy or deep brain stimulation (DBS) for PD are variably effective in treating these debilitating symptoms. DBS improves balance dysfunction in some patients, while in some it does not affect balance or even makes it worse. Defining consistent therapy requires a proper understanding of the mechanisms of navigational impairments in PD, and to know how DBS modulates the balance function. A singular vision of our research program is: 1) To reveal the physiological underpinnings of how DBS modulates the process by which multisensory integrated systems govern perception of one’s own motion critical for spatial navigation, gait and balance in PD. 2) To be able to consistently treat navigational impairments such as veering in PD patients with subthalamic nucleus (STN) DBS while preserving its other benefits of treating tremor and increased muscle tone, and reducing pharmacotherapy burden with bothersome side effects. With this goal the current Merit Review application focuses on the vestibular system – the critical system for the perception of one’s own linear motion, i.e. vestibular heading perception – the task that is has to be accurate for the proper control of balance, navigation, and averting falls. We hypothesize that effects of STN DBS on vestibular heading perception and veering are dependent upon the specific location of the active electrode contact within the STN and modulation of the cerebello-thalamic pathway that is known to carry the vestibular signal and is in physical vicinity of the STN. In order to test this hypothesis we will objectively measure one’s ability to perceive direction of linear motion (i.e., vestibular heading perception), lateral drifts while walking (i.e., veering) that is common in PD, and then we will compare these objective measures among three independent conditions – dorsal STN DBS, ventral STN DBS, and DBS off. The Aim 1 will examine the effects of the location of volume of tissue activation within the STN on the change in vestibular heading perception and veering in human PD patients. We will collate physical location of the volume of tissue activation from all patients when the change in vestibular heading perception and veering was found. These locations, generating the probabilistic stimulation atlas, will provide insights about areas of STN that could influence balance function in PD. The Aim 2 will examine the recruitment metrics of the axonal pathways modulated by the STN DBS that correlates with change in vestibular heading perception and veering in PD patients. It will directly examine the role of involvement of cerebello-thalamic pathway that is known to transmit vestibular perception information and is in vicinity of the STN. In summary, by taking a top-down approach and leveraging a multidisciplinary team of investigators studying human PD patients with STN DBS, neuroimaging, and computational modeling; we will unravel mechanisms through which STN DBS modulates the vestibular heading perception in PD. Finally we will apply this mechanistic understanding to design consistent and effective therapeutic strategies utilizing DBS to prevent falls in PD.