Sub-cortical systems for stopping

我们通常认为运动是一个积极的过程，需要一个积极的决定。然而，在某些情况下，大脑必须主动阻止一个动作的发生-例如，当一个行人即将步入道路，但随后看到一辆正在接近的汽车。对抑制运动的神经回路的研究较少，但这些系统的缺陷可能是几种重要临床疾病的基础。中风后的痉挛，帕金森氏病的僵硬和肌张力障碍都是肌肉过度收缩的例子。在这个项目中，我们试图了解一组重要的抑制运动的途径，这些途径从大脑底部传递到脊髓-“网状脊髓束”。几乎所有关于这些途径的现有数据都来自大鼠或猫，它们与人类有重要差异。我们将在猕猴中研究这些通路，猕猴控制运动的系统与人类非常接近，使数据与人类患者直接相关。我们将首先在麻醉动物中研究这些通路的组织。我们将使用具有多个位点的复杂电极阵列来记录网状结构和脊髓中大量细胞的活动。我们将使用数学分析方法来评估这些细胞是如何相互连接的，我们将测试它们如何对来自肌肉的感觉受体的刺激以及大脑皮层的不同部分做出反应。这将向我们展示灵长类动物中存在哪些不同的运动抑制网状脊髓通路。通过确定这些中枢接收到什么样的输入，我们将来也许能够设计出调节它们的方法，例如通过对感觉输入的特定安排。这可能会导致改善运动障碍的治疗方法，这些疾病在运动抑制方面存在缺陷。该项目的下一阶段是测量这些系统如何实际用于抑制运动。我们将训练猴子完成一项任务，要求它们通过按下按钮来对“通行”灯做出反应。在某些试验中，另一个“停止”灯也会亮起，表明他们不应该做出反应。通过改变信号灯和停止信号灯之间的延迟，我们可以控制猴子如何有效地防止不适当的运动。一旦猴子接受训练，我们将记录大脑皮层、脑干和脊髓运动区细胞的活动。通过比较这些中心的活动时间与停止和前进线索，我们将能够确定它们如何合作停止运动。最后，我们将通过传递微弱的电刺激或直接向这些中心注射非常少量的药物来操纵神经活动。如果某个大脑区域参与了运动抑制，我们预测刺激它会使停止计划的运动变得更容易，但是用药物阻断活动会使停止变得更难，所以即使停止的信号及时传递，运动也会发生。这项实验将为我们提供确凿的证据，证明哪些神经中心与运动抑制有因果关系。这项基础研究将提供一个关键框架，以了解人类患者的各种运动障碍。抑制运动或肌肉收缩的缺陷可能是许多临床症状的基础，但尚不清楚是什么不同的神经系统产生特定的缺陷。例如，中风后的痉挛状态与帕金森病的僵硬状态非常不同;这些可能来自不同的子系统。了解这些是如何工作的，以及疾病中出现了什么问题，可以让我们提出新的干预措施来改善症状。

We normally think of movement as an active process, requiring a positive decision to move. However, in some circumstances the brain must actively stop a movement from taking place - for example, when a pedestrian is about to step into the road but then sees an approaching car. The neural circuits for inhibiting movement have been less well studied, but deficits in these systems could underlie several important clinical disorders. Spasticity after stroke, rigidity in Parkinson's disease and dystonia are all examples of excess muscle contraction. In this project, we seek to understand an important set of pathways for inhibiting movement which pass from the base of the brain to the spinal cord - the 'reticulospinal tract'. Almost all existing data on these pathways comes from rat or cat, which have important differences from humans. We will study them in macaque monkeys, where the systems for controlling movement are very close to those in man, making data directly relevant to human patients.We will first study the organisation of these pathways in anaesthetised animals. We will use sophisticated electrode arrays with many sites to record the activity of a large number of cells in the reticular formation and spinal cord. We will assess how these cells are interconnected using mathematical analysis methods, and we will test how they respond to stimulation of sensory receptors from muscles, and to different parts of the cerebral cortex. This will show us what different reticulospinal routes exist in primates for movement inhibition. By determining what inputs these centres receive, we might in future be able to design ways of modulating them, for example by specific arrangements of sensory inputs. This could lead to improved therapies for movement disorders where there is a deficit in inhibition of movement.The next stage of the project is to measure how these systems are actually used to inhibit movement. We will train monkeys to perform a task requiring them to respond to a 'go' light by pressing a button. On some trials, another 'stop' light will also illuminate, indicating that they should not respond. By varying the delay between go and stop lights, we can manipulate how effectively the monkeys can prevent an inappropriate movement. Once the monkeys are trained, we will record from the activity of cells in motor areas of the cerebral cortex, brainstem and spinal cord. By comparing the timing of activity in these centres with the stop and go cues, we will be able to determine how they cooperate to stop a movement. Finally, we will manipulate neural activity either by delivering weak electrical stimuli, or injecting very small amounts of drugs directly into these centres. If a brain area is involved in movement inhibition, we predict that stimulating it will make it easier to stop a planned movement, but blocking activity with a drug will make stopping harder, so that movements are made even when the signal to stop is delivered in good time. This experiment will give us firm evidence of which neural centres causally contribute to motor inhibition.This basic research will provide a key framework in which to understand a wide range of movement disorders in human patients. Deficits in inhibiting movement or muscle contraction probably underlie many clinical signs, but it is not clear what different neural systems produce particular deficits. For example, spasticity after stroke is quite different from rigidity in Parkinson's disease; these are likely to arise from different sub-systems. Understanding how these work, and what goes wrong in disease, may allow us to suggest novel interventions to ameliorate symptoms.