The function of descending and ascending pathways in spastic hypertonia and hyperreflexia after stroke

这项研究将针对我们对上皮层神经机制的理解中的一个关键知识缺口， 中风后肢体痉挛，通过直接评估下行运动和上行感觉通路， 手功能痉挛是中风后出现的主要运动障碍之一 中风后几周，阻碍上肢功能恢复，并引起并发症，如 虚弱挛缩和疼痛它的传统特征是肌肉的速度依赖性增加 张力（张力亢进）和脊髓牵张反射（反射亢进）增加。尽管外周和脊髓 痉挛的特征已被广泛研究，其潜在的脑机制和脑脊髓 路径仍然存在争议。这种理解对于解决当前的限制是至关重要的， 痉挛状态的临床管理与其早期诊断、预后因素的识别以及缺乏 有效的治疗针对损伤的起源，而不是其症状。临床前研究已经 包括网状脊髓束（recticulosporinal tract，简称RST）在内的下行运动通路的损伤可能导致痉挛性 中风后肌张力增高相反，脊髓感觉-运动回路和上行感觉回路的变化 投射可能是中风后反射亢进的基础。然而，目前还不清楚中风后的大脑病变是如何导致这些的。 脊髓回路的远程变化。早期电生理学工作支持的几种理论模型 在猫中，背侧和内侧腹侧的抑制性和兴奋性投射的不平衡 在痉挛中起着关键作用。然而，在灵长类动物中出现的证据表明， （抑制性/兴奋性）不遵循背侧/内侧组织，如在当前痉挛模型中所假设的， 而是取决于投射的偏侧性。在这项提案中，我们的目标是将这些新发现转化为人类， 并检查它们与中风后痉挛的相关性。我们的中心假设是， 痉挛状态，同侧与对侧脊髓的不平衡激活与痉挛性张力亢进直接相关， 背柱躯体感觉投射亢进与痉挛性反射亢进有关。测试 基于这一假设，我们将采用一种强大的神经成像方法， 功能磁共振成像（fMRI）在慢性脑卒中偏瘫患者中的应用 肢体痉挛，以及健康对照。用这种方法，我们将评估大降支的功能， （皮质脊髓，脊髓束）和上行（背柱，前外侧束）途径， 感官功能任务我们将确定这些神经影像学标记物与痉挛性肌张力亢进的关系， 反射亢进，如通过可靠的生物力学和电生理测量所评估的。总体看 拟议的项目将促进我们对中风后痉挛的神经生物学基础的理解， 新的定量神经影像学标记物，用于准确预测痉挛并发症，并提供结果 评估哪些治疗方法最直接针对痉挛的神经起源。

This study will target a critical knowledge gap in our understanding of the neural mechanisms underlying upper limb poststroke spasticity, by directly assessing the descending motor and ascending sensory pathways in hand function. Spasticity is one of the major motor impairments after stroke that typically begins to emerge several weeks poststroke, impedes upper limb functional recovery, and gives rise to complications such as weakness, contractures, and pain. It is traditionally characterized by a velocity-dependent increase in muscle tone (hypertonia) and increased spinal stretch reflex (hyperreflexia). Although the peripheral and spinal signatures of spasticity have been extensively studied, its underlying brain mechanisms and brain-spinal pathways are still controversial. This understanding is critically needed for resolving the current limitations in clinical management of spasticity related to its early diagnosis, identification of prognostic factors, and lack of effective treatments targeting the origin of the impairments rather than its symptoms. Preclinical studies have shown that lesions of descending motor pathways including the reticulospinal tract (RST) may lead to spastic hypertonia after stroke. In contrast, changes in the spinal sensory-motor circuits and the ascending sensory projections may underlie hyperreflexia after stroke. Yet it is unclear how brain lesions after stroke lead to these remote changes in the spinal cord circuit. Several theoretical models backed by early electrophysiological work in cats propose that an imbalance of inhibitory and excitatory projections from the dorsal and medial RST plays a critical role in spasticity. However, emerging evidence in primates suggests that the type of RST projections (inhibitory/excitatory) does not follow a dorsal/medial organization, as presumed in current models of spasticity, but depends on the laterality of projections. In this proposal, we aim to translate these new findings to humans, and examine their relevance in poststroke spasticity. Our central hypothesis is that in stroke survivors with spasticity, the imbalanced activation of ipsilateral vs contralateral RST is directly related to spastic hypertonia, while the hyperactivity of dorsal column somatosensory projections is related to spastic hyperreflexia. To test this hypothesis, we will employ a powerful neuroimaging method using simultaneous spinal cord–brain functional magnetic resonance imaging (fMRI) in chronic hemiplegic stroke patients with and without upper limb spasticity, as well as healthy controls. Using this method, we will assess the function of major descending (corticospinal, RST) and ascending (dorsal column, anterolateral tract) pathways during hand motor and sensory functional tasks. We will determine how these neuroimaging markers relate to spastic hypertonia and hyperreflexia, as evaluated by reliable biomechanical and electrophysiological measurements. Overall, the proposed projects will advance our understanding of the neurobiological basis of poststroke spasticity, offer new quantitative neuroimaging markers for accurate prognosis of spastic complications, and provide outcome measures for evaluating what treatments most directly target the neural origins of spasticity.