Sub-cortical systems for stopping

用于停止的皮层下系统

• 批准号: MR/P012922/1
• 负责人: Stuart Baker
• 金额: $ 90.45万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP012922%2F1
• 关键词: Sub; cortical; systems; stopping

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.

我们通常认为移动是一个积极的过程，需要一个积极的决定才能移动。然而，在某些情况下，大脑必须主动阻止运动的发生--例如，当一个行人正要走上马路，但随后看到一辆汽车驶来。抑制运动的神经回路研究较少，但这些系统中的缺陷可能是几个重要的临床疾病的基础。中风后的痉挛、帕金森氏症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通路，这些通路从大脑底部传递到脊髓--网状脊髓束。这些通路上现有的几乎所有数据都来自老鼠或猫，它们与人类有重要的区别。我们将在猕猴身上进行研究，猕猴控制运动的系统与人类非常接近，从而使数据直接与人类患者相关。我们将首先研究麻醉动物的这些通路的组织。我们将使用具有多个位置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评估这些细胞是如何相互连接的，并测试它们对肌肉和大脑皮层不同部分的感觉受体刺激的反应。这将向我们展示灵长类动物存在哪些不同的运动抑制的网状脊髓途径。通过确定这些中心接受什么输入，我们未来可能能够设计出调制它们的方法，例如通过特定的感觉输入安排。这可能会改进运动障碍的治疗方法，因为运动障碍在抑制运动方面存在缺陷。该项目的下一阶段是测量这些系统是如何实际用于抑制运动的。我们将训练猴子执行一项任务，要求它们通过按下一个按钮来对“GO”灯做出反应。在一些试验中，另一个“停止”灯也会亮起，表明他们不应该做出反应。通过改变红绿灯和红绿灯之间的延迟，我们可以控制猴子如何有效地防止不适当的动作。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。通过将这些中心的活动时间与停止和开始提示进行比较，我们将能够确定它们如何合作来阻止运动。最后，我们将通过传递微弱的电刺激，或者直接向这些中心注射非常少量的药物来操纵神经活动。如果大脑的某个区域涉及运动抑制，我们预测刺激它会使停止计划的运动变得更容易，但用药物阻断活动会使停止变得更难，因此即使在及时发出停止信号的情况下也会做出动作。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关。这项基础研究将提供一个关键框架，用于了解人类患者的广泛运动障碍。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了特定的缺陷。例如，中风后的痉挛与帕金森氏症的强直有很大的不同；它们很可能来自不同的子系统。了解这些机制是如何起作用的，以及疾病中哪里出了问题，可能会让我们提出新的干预措施来改善症状。

项目成果

The Existence of the StartReact Effect Implies Reticulospinal, Not Corticospinal, Inputs Dominate Drive to Motoneurons during Voluntary Movement.

• DOI: 10.1523/jneurosci.2473-21.2022
• 发表时间: 2022-10-05
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Tapia, Jesus A.;Tohyama, Takamichi;Poll, Annie;Baker, Stuart N.
• 通讯作者: Baker, Stuart N.

Classification of Cortical Neurons by Spike Shape and the Identification of Pyramidal Neurons.

• DOI: 10.1093/cercor/bhab147
• 发表时间: 2021-10-01
• 期刊: Cerebral cortex (New York, N.Y. : 1991)
• 作者: Lemon RN;Baker SN;Kraskov A
• 通讯作者: Kraskov A

Effects of Diazepam on Reaction Times to Stop and Go.

• DOI: 10.3389/fnhum.2020.567177
• 发表时间: 2020
• 期刊: Frontiers in human neuroscience
• 影响因子: 2.9
• 作者: Sarkar S;Choudhury S;Islam N;Chowdhury MSJH;Chowdhury MTI;Baker MR;Baker SN;Kumar H
• 通讯作者: Kumar H

Stop Signal Reaction Time measured with a portable device validates optimum STN-DBS programming.

使用便携式设备测量的停止信号反应时间可验证最佳 STN-DBS 编程。

• DOI: 10.1016/j.brs.2020.09.007
• 发表时间: 2020
• 期刊: Brain stimulation
• 影响因子: 7.7
• 作者: Roy A

Abnormal Blink Reflex and Intermuscular Coherence in Writer's Cramp.

• DOI: 10.3389/fneur.2018.00517
• 发表时间: 2018
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Choudhury S;Singh R;Chatterjee P;Trivedi S;Shubham S;Baker MR;Kumar H;Baker SN
• 通讯作者: Baker SN