Thalamic infusions as a treatment of limbic epilepsy

目前正在广泛寻找治疗难治性癫痫的新疗法。尽管具有多种机制的药物仍然是治疗开发的重要焦点，但目前技术的发展已经开辟了新的可能性。刺激神经系统的几个区域已经引起了极大的兴趣，这种方法现在包括识别程序，以在任何早期阶段检测癫痫发作，并提供编程刺激来打破癫痫发作。这种发展在一定程度上是由于电子产品的逐步小型化而成为可能的。这种方法的一个潜在优势是，治疗被输送到大脑的一个单一区域，这种技术可以避免可能来自全身给药的药物进入大脑的所有部分的副作用。通常考虑将药物递送至单个点，并且已经显示在一些癫痫发作的动物模型中具有效果，并且这种靶向特定区域的治疗是治疗癫痫的NINDS基准之一。然而，临床前筛选的实用和可靠的方法和长期交付的手段还没有。最近，我们一直在研究丘脑内侧背侧区在边缘系统癫痫发作中的潜在作用，并有证据表明，该区域可能代表了初始癫痫发作回路中的一个关键点。在这个项目中，我们将测试整体假设，即药物输注到丘脑背内侧核将控制自发性边缘癫痫发作，而没有显着的行为副作用。为了验证这一假设，我们将使用大鼠边缘系统癫痫模型与自发性癫痫发作和注入药物到丘脑的内侧背侧区域，并确定这种干预对自发性癫痫发作的影响。在该项目的过程中，我们将定义最佳靶点和药物。由于任何癫痫治疗导致的认知障碍问题都是一个值得关注的问题，我们还将确定癫痫发作抑制方面的成功治疗是否也会影响复杂行为。在本项目结束时，我们将确定脑内药物输注到特定区域的方法是否具有通过抑制癫痫发作而没有明确的认知成本的临床开发潜力。将本研究的结果转移到临床将通过CNS长期连续药物输注技术的存在而得到促进。最后，如果成功的话，我们还将创造一种技术，通过这种技术，我们可以识别出其他毒性较小的化合物，这些化合物可能比本研究中测试的化合物更有效，行为成本更低。

There is an ongoing wide ranging search for new therapies for intractable epilepsy. Although drugs with a variety of mechanisms remain a significant focus of therapy development, the current evolution in technology has opened up new possibilities. Stimulation of several regions of the nervous system has attracted significant interest and this approach now includes recognition programs to detect seizures at any early stage and deliver a programmed stimulus to break the seizure. This development has been made possible in part by the progressive miniaturization of electronics. A potential advantage of this approach is that therapy is delivered to a single area of the brain, a technique that may avoid the side effects that can come from the systemic administration of a drug that goes to all parts of the brain. Delivery of a drug to a single point has often been considered and has been shown to have effect in some animal models of seizures, and such therapy targeted to a specific region is one of the NINDS benchmarks for treating epilepsy. However, a practical and reliable method for preclinical screening and a means for chronic delivery have not been available. Recently we have been examining the potential role of the medial dorsal region of the thalamus in limbic seizures and have evidence that suggests that this area may represent a key point in the initial seizure circuit. In this project we will be testing the overall hypothesis that drug infusion into the medial dorsal thalamic nucleus will control spontaneous limbic seizures without significant behavioral side effects. To test this hypothesis we will use a rat model of limbic epilepsy with spontaneous seizures and infuse drugs into the medial dorsal region of the thalamus and determine the effects of this intervention on spontaneous seizures. In the course of this project we will define optimal targets and drugs. Because the issue of cognitive impairment as a consequence of any epilepsy treatment is a concern, we will also determine whether successful treatment with regard to seizure suppression also affects complex behaviors. At the end of this project we will have determined whether the approach of intracerebral drug infusion into a specific region has potential for clinical development by suppressing seizures with no clear cognitive cost. Moving the results of this study to the clinic will be facilitated by the presence of technology for long term continuous drug infusions into the CNS. Finally, if successful we will also have created a technique with which we might identify other, less toxic compounds that may be more effective than the ones tested in this study with less behavior cost.