CENTRAL THALAMIC DEEP BRAIN STIMULATION MODELS

描述（由申请人提供）：拟议研究的目标是建立两个互补的动物模型，以推进中央丘脑（CT）的深部脑刺激（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。一年中每天大约有4000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。我们将建立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来提高中央丘脑脑刺激（CT/DBS）的疗效。该研究小组将由威尔-康奈尔医学院的研究人员领导，并与洛克菲勒大学和威斯康星医学院的研究人员合作。Nicholas Schiff博士（Weill-Cornell）是CT/DBS和人类脑损伤研究领域的顶尖神经学家/神经科学家，他将与系统神经生理学专家Keith Purpura博士（Weill-Cornell）一起担任R01的私家侦探，在完整、警觉、行为良好的猴子身上进行一系列实验研究。这项以猴子为对象的研究将检验不同模式的电刺激对丘脑吻侧中央神经元的影响。这些神经元将控制觉醒的脑干中心与大脑皮层连接起来，在整合皮层、纹状体和丘脑方面发挥着至关重要的作用。在两个基本认知任务的执行过程中，将评估持续刺激和特定时间施加短脉冲的行为效果。在刺激期间和之后，猴子额叶的神经活动也将被检查。Donald Pfaff博士（洛克菲勒）是世界著名的行为细胞基础专家，他将把他为老鼠开发的一套经过审查的唤醒分析方法应用于CT/DBS研究。他实验室的初步结果表明，CT/DBS可以促进小鼠在诱导创伤性脑损伤后的行为表现。Christopher Butson博士（威斯康辛医学院）是一名生物工程师和脑电刺激计算建模专家，他将在威尔-康奈尔和洛克菲勒的动物实验中开发组织激活体积的详细模型。他还将监督概率图谱的开发和分析，以确定CT/DBS的最佳应用地点。该图谱将有助于构建可用于治疗非进行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，利用中央丘脑的电刺激来治疗脑外伤后的认知障碍。

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.