Mechanisms of Distorted Inputs in Chronic Spinal Injury

慢性脊柱损伤中输入失真的机制

• 批准号: 9055781
• 负责人: Charles Heckman
• 金额: $ 33.8万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055781
• 关键词: Affect; Animals; Ankle; Behavior; Chronic; Clinical; Coupling; Data; Diffuse; Electrodes; Environmental Wind; Equilibrium; Exhibits; Experimental Designs; Felis catus; Freedom; Goals; Health; Hindlimb; Hip region structure; Human; Interneurons; Involuntary Movements; Joints; Knee; Link; Measurement; Measures; Methods; Motor; Motor Neurons; Motor output; Movement; Muscle; Muscle Spindles; Nature; Neurons; Output; Pain; Pattern; Play; Population; Preparation; Process; Robotics; Role; Rotation; Sensory; Sensory Process; Skin; Source; Spasm; Spinal; Spinal Injuries; Spinal cord injury; Synapses; System; Techniques; Therapeutic Intervention; Translating; Translations; arm; base; human subject; injured; limb movement; novel; novel therapeutic intervention; receptive field; research study; response; restoration; sensory input; translational approach; voltage clamp

DESCRIPTION (provided by applicant): In spinal injury, the loss of descending input not only impairs motor commands but also damages descending control of spinal excitability. The goal of this proposal is to understand the cellular and synaptic mechanisms of the resulting distortions in the behavior of spinal circuits, which can generate aberrant muscle activation patterns and unintended movements like spasms. To achieve this goal, we use our chronic spinal cat preparation to develop a novel translational approach, in which we link cellular mechanisms to system behaviors. Our results potentially provide clear predictions for experiments to evaluate whether these same mechanisms occur in human spinal injured subjects. In the intact state, considerable data show that the effects of sensory inputs on motor outputs are focused, reciprocal and consistent. These effects are focused in the sense that sensory input from one joint primarily induces motor output at that same joint, reciprocal in that sensory inputs generate opposite actions on antagonists and consistent in that sensory inputs generate stable responses to repeated activations. The basic concept underlying this proposal is that the loss of descending control of spinal excitability induces precisely the opposite sensory processing state, one that is diffuse, co- active and inconsistent. Although likely overly simple this concept provides clearly testable hypotheses and moreover is supported by significant data, including our recent preliminary studies. The translational nature of our experimental design arises from two novel techniques that link intracellular measurements to the "real world": 1) synaptic currents are measured during voltage clamp in response to precise movements of the entire hindlimb via a 6 degree of freedom robotic arm and 2) firing patterns from intracellular recordings are compared to firing patterns of populations of motor units recorded by a newly developed electrode array placed on muscle. Both the robotic and the array techniques are already in use in human subjects, thus providing the basis for our proposed predictions for human experiments. Aim 1 seeks to identify the mechanisms of expanded receptive fields by identifying the types of sensory afferents involved. Aim 2 examines the balance of excitation versus inhibition, primarily relying on intracellular recordings. Aim 3 investigates wind-up, both n terms of quantifying its strength and in terms of determining its source in motoneurons versus interneurons. The proposed experiments will provide a new depth of understanding of the distortions in spinal processing of sensory input that emerge in spinal injury. Each aim will provide information critical for developing specific therapeutic interventions, focusing on restoration of normal functional connections and minimization of wind- up.

描述(申请人提供)：在脊髓损伤中，下行输入的丧失不仅损害运动指令，还损害对脊髓兴奋性的下行控制。这项提议的目标是了解导致脊髓回路行为扭曲的细胞和突触机制，这种扭曲可能会产生异常的肌肉激活模式和痉挛等意外运动。为了实现这一目标，我们利用我们的慢性脊髓CAT准备工作来开发一种新的翻译方法，在该方法中，我们将细胞机制与系统行为联系起来。我们的结果可能为评估这些相同的机制是否发生在人类脊柱损伤受试者的实验中提供明确的预测。在完整状态下，大量数据表明感觉输入对运动输出的影响是集中的、相互的和一致的。这些影响集中在这样的意义上，即来自一个关节的感觉输入主要诱导同一关节的运动输出，在该感觉输入产生的交互作用下 对拮抗剂的相反作用和一致性在于，感觉输入对重复激活产生稳定的反应。这一建议的基本概念是，失去对脊髓兴奋性的下行控制会导致恰好相反的感觉处理状态，一种弥漫的、协同的和不一致的感觉处理状态。尽管这个概念可能过于简单 提供了明确可检验的假设，而且得到了重要数据的支持，包括我们最近的初步研究。我们实验设计的平移性源于两项将细胞内测量与“真实世界”联系起来的新技术：1)通过6自由度机械臂，在电压钳期间测量突触电流，以响应整个后肢的精确运动；2)将细胞内记录的放电模式与新开发的放置在肌肉上的电极阵列记录的运动单位群体的放电模式进行比较。机器人和阵列技术都已经在人类受试者中使用，因此为我们提出的人体实验预测提供了基础。目的1试图通过识别所涉及的感觉传入的类型来确定扩大感受野的机制。目标2主要依靠细胞内的记录，研究兴奋与抑制的平衡。目标3研究缠绕，既包括量化其强度，也包括确定其来源是运动神经元还是中间神经元。拟议的实验将为理解脊柱损伤中出现的感觉输入在脊柱处理中的扭曲提供新的深度。每个目标都将为制定具体的治疗干预措施提供至关重要的信息，重点是恢复正常的功能连接和最大限度地减少缠绕。