CENTRAL THALAMIC DEEP BRAIN STIMULATION MODELS

描述（由申请人提供）：拟定研究的目的是开发两种互补的动物模型，以推进中央丘脑（CT）脑深部电刺激（DBS）作为治疗创伤性脑损伤（TBI）导致的获得性认知障碍的治疗策略。 每年大约有4,000名美国人遭受创伤性脑损伤（TBI），每年有多达10万人患有长期认知障碍。 我们将形成一个多学科的研究计划，利用系统神经科学和生物工程方法，以提高中央丘脑脑刺激（CT/DBS）的疗效。 该研究小组将由威尔-康奈尔医学的研究人员领导，与洛克菲勒大学和威斯康星州医学院的研究人员合作。 Nicholas Schiff博士（Weill-Cornell）是CT/DBS和人脑损伤研究领域的领先神经学家/神经科学家，他将担任P.I.与基思Purpura博士（Weill-Cornell）沿着，一位系统神经生理学家，在完整的警觉，行为的猴子身上进行了一系列的实验研究。 对猴子的研究将检查不同模式的电刺激对丘脑嘴侧中央神经元的影响。 这些神经元将控制唤醒的脑干中心与大脑皮层联系起来，并在整合皮层，纹状体和丘脑方面发挥关键作用。 在两个基本认知任务的执行过程中，将评估连续刺激和在特定时间施加的短暂脉冲的行为效应。 还将检查刺激期间和刺激后猴子额叶中的神经活动。 唐纳德·普法夫博士（洛克菲勒），一位世界知名的行为细胞基础专家，将调整他为小鼠开发的一套经过审查的唤醒试验，以研究CT/DBS。 他实验室的初步结果表明，小鼠中的CT/DBS可以促进诱导创伤性脑损伤后的行为表现。 Christopher Butson博士（威斯康星州医学院）是一名生物工程师，也是脑电刺激计算建模方面的专家，他将在威尔康奈尔和洛克菲勒的动物实验中开发出激活组织体积的详细模型。 他还将监督概率图谱的开发和分析，以确定CT/DBS的最佳应用部位。 该图谱将有助于构建可用于治疗非进展性脑损伤的人类图谱。 因此，这项工作的长期目标是优化神经调节策略，采用中央丘脑的电刺激来治疗TBI后的认知障碍。 公共卫生相关性：严重脑损伤后的获得性认知障碍每年使多达10万美国人患有毁灭性残疾。 这里提出的研究将有助于推进必要的知识，以推进和进一步开发脑电刺激的新应用，旨在改善患有这些终身挑战的患者的生活。

DESCRIPTION (provided by applicant): The goal of the proposed studies is to develop two complementary animal models to advance deep brain stimulation (DBS) of the central thalamus (CT) as a therapeutic strategy for the treatment of acquired cognitive disabilities resulting from traumatic brain injury (TBI). Each day of the year approximately 4,000 Americans suffer a traumatic brain injury (TBI), leaving as many as 100,000 persons/year with long-term cognitive disabilities. We will form a multidisciplinary research program utilizing systems neuroscience and bioengineering methods to improve the efficacy of central thalamic brain stimulation (CT/DBS). The research team will be lead by investigators at Weill- Cornell Medical in partnership with researchers at The Rockefeller University and Medical College of Wisconsin. Dr. Nicholas Schiff (Weill-Cornell), a leading neurologist/neuroscientist in the fields of CT/DBS and human brain injury studies, will act as P.I. of the R01 along with Dr. Keith Purpura (Weill-Cornell), an expert systems neurophysiologist, to carry out a series of experimental studies in intact alert, behaving monkeys. The work with monkeys will examine the influence of different patterns of electrical stimulation on rostral central thalamic neurons. These neurons link the brain stem centers that control arousal with the cerebral cortex, and play a crucial role in integrating cortex, striatum and thalamus. Behavioral effects of continuous stimulation and of brief pulses applied at specific times will be evaluated during the performance of two elementary cognitive tasks. Neural activity in the monkey's frontal lobe during and following stimulation will also be examined. Dr. Donald Pfaff (Rockefeller), a world- renowned expert on the cellular basis of behavior, will adapt a vetted set of arousal assays he developed for the mouse to studies of CT/DBS. Preliminary results in his laboratory have shown that CT/DBS in the mouse can facilitate behavioral performance following induced traumatic brain injury. Dr. Christopher Butson (Medical College of Wisconsin), a bioengineer and expert in computational modeling of brain electrical stimulation will develop detailed models of the volume of tissue activated in the animal experiments at Weill-Cornell and Rockefeller. He will also supervise the development and analysis of a probabilistic atlas to identify the sites of optimal application of CT/DBS. This atlas will assist in the construction of a human atlas that could be used in the treatment of non-progressive brain injuries. Thus, the long-range goal of this work is to optimize neuromodulation strategies employing electrical stimulation of the central thalamus to treat cognitive impairment following TBI. PUBLIC HEALTH RELEVANCE: Acquired cognitive impairment following severe brain injury leave as many as 100,000 Americans each year with devastating disabilities. The studies proposed here will help to advance the necessary knowledge to advance and further develop a novel application of electrical brain stimulation aimed at improving the lives of patients suffering with these lifelong challenges.