Diffusion tensor imaging of the injured spinal cord

描述(由申请人提供)： 摘要假设：我们假设在脊髓损伤后的恢复过程中，脊髓的扩散特性和显微结构会发生变化。此外，我们假设扩散测量和组织保留可以用来评估感觉运动功能。此外，我们假设DTI对再生性干预很敏感。初步数据：初步研究已经证明了使用高场(9.4T)小动物磁铁获取损伤和非损伤大鼠脊髓的DTI图像的可行性。DTI图像似乎遵循慢性人类脊髓损伤图像所预测的预期模式，损伤部位和远离损伤的区域的扩散系数都发生了变化。特别值得注意的是，弥散减少出现在脊髓远离损伤部位的区域，这与组织学数据显示相应灰质神经元的细胞反应相关联。此外，试点数据表明，扩散模式与脊髓的功能连通性有关，与脊髓体感诱发电位(SSEP)的相关性证明了这一点。在单独的研究中，我们还展示了胸部挫伤和干细胞移植治疗的大鼠脊髓颈背侧的特殊结构变化。这些结构变化与疼痛纤维的增殖增加有关，这在功能上导致了前肢痛觉异常的发展。我们建议使用这一治疗范例，结合充分记录的结构和功能变化，来测试DTI的诊断和预后能力。研究目的：本项目的总体目标是确定DTI是否能提供损伤和再生治疗后大鼠脊髓结构和功能的无创性成像。我们计划通过三个具体目标来实现这一目标。(1)描述脊髓损伤恢复过程中弥散率的区域性变化。(2)探讨脊髓损伤恢复过程中脊髓DTI的功能相关性。(3)检测脊髓损伤后DTI对神经干细胞治疗的敏感性。我们的方法将使用体内和体外OTI来确定脊髓损伤恢复期间的组织学相关性。然后，我们将确定DTI的行为和电生理功能与组织学和轴突形态测量的相关性。最后，我们将确定DTI对已知结构和功能变化的再生干预的敏感性。如果DTI被发现能够检测到损伤脊髓中组织学上可验证的形态变化，该项目的翻译性质将通过未来在人类中的直接应用得到反映。 公共卫生相关性： 对退伍军人医疗保健的潜在影响：脊髓损伤(SCI)是一个人或他们的家人可能经历的最具破坏性的灾难之一。随着美国目前在全球进行几项军事努力，脊髓损伤可能会成为退伍军人中日益严重的问题。这项研究将验证新的磁共振成像技术(扩散张量成像，DTI)用于监测损伤后脊髓的结构完整性和功能状态。我们预计这些信息将被证明对进一步了解脊髓损伤的病理和建立DTI作为一种准确的、非侵入性的诊断和预后工具的使用至关重要。此外，关于损伤程度和随后对感觉运动功能的影响的详细信息将在涉及药物和物理治疗的康复策略中被证明是非常宝贵的。在过去的两年里，我们专注于开发和保留脊髓损伤治疗和成像的“团队”方法，其中使用了工程专家(Schmit博士)、图像采集和分析专家(Ulmer博士)和脊髓干细胞干预专家(Kurpad博士、Alexania和Crowe博士)。此外，库尔帕德博士还是退伍军人管理局Zablocki神经外科服务的负责人，他对脊髓损伤患者的临床护理有着浓厚的兴趣。他对SCI临床护理和研究的这种承诺还体现在他从BL R&D功绩审查计划获得的研究支持上。这个“团队”的存在和有希望的初步数据最终在今年发表了五篇文章，预计将产生最终的数据，这些数据可以成功地转化为SCI退伍军人的护理。

DESCRIPTION (provided by applicant): ABSTRACT Hypothesis: We hypothesize the diffusion properties and microstructure change across the entire length of the spinal cord during recovery from SCI. Also, we postulate that diffusion measurements and tissue sparing can be used to estimate sensorimotor function. In addition, we hypothesize that DTI is sensitive to regenerative interventions. Preliminary Data: Pilot studies have demonstrated the feasibility of obtaining DTI images of the injured and non-injured rat spinal cord using a high field (9.4T) small animal magnet. DTI images appear to follow expected patterns predicted by images obtained in chronic human SCI, with changes in diffusivity both at the injury site and in regions distant from the injury. Of particular note, reductions in diffusion appear in regions o fthe spinal cord distant from the injury site that correlate with histological data indicating cellular responses in neurons ofthe corresponding gray matter. Further, pilot data indicate that diffusion patterns are related to functional connectivity of the spinal cord, evidenced by correlations with spinal somatosensory evoked potentials (SSEPs). In separate studies, we have also demonstrated specific structural changes in the cervical dorsal hom of the rat spinal cord subjected to thoracic contusion injury and treated with stem cell grafts. These structural changes correlated with increased proliferation of pain fibers, which functionally resulted in the development of forelimb allodynia. We propose using this treatment paradigm, with well documented structural and functional changes, to test the diagnostic and prognostic abilities of DTI. Research Objectives: The overall goal of this project is to determine whether DTI can provide a non invasive imaging correlate of spinal cord structure and function following injury and regenerative therapies in a rat model of SCI. We plan to pursue this goal through three specific objectives. (1) Characterize region-specific changes in diffusivity during recovery from SCI. (2) Characterize functional correlates to DTI in the spinal cord during recovery from SCI. (3) Determine the sensitivity ofDTI to neuronal stem cell treatments following SCI. Our approach will use in vivo and ex vivo OTI to detemi.ine histological correlates during recovery from SCI. We will then determine the behavioral and electrophysiological functional correlates to DTI to histology and axonal morphometry. Lastly, we will determine the sensitivity of DTI to regeneration interventions with known changes in structure and function. The translational nature of this project is reflected by direct future application in humans if DTI is found to be able to detect histologically verifiable changes in morphology in the injured spinal cord. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans' Health Care: Spinal cord injury (SCI) constitutes one of the most devastating calamities that a person or their family can experience. With the United States currently engaged in several military efforts globally, SCI is likely to be an increasingly significant problem in the veteran population. This study will result in the validation of novel magnetic resonance imaging techniques (Diffusion Tensor Imaging, DTI) for monitoring the structural integrity and functional status of the spinal cord following an injury. We anticipate this information will prove vital to further understanding the pathology of SCI and establishing the use of DTI as an accurate, non-invasive diagnostic and prognostic tool. In addition, detailed information of the extent of injury and subsequent impact on sensorimotor function will prove invaluable in rehabilitative strategies involving pharmacological and physical therapies. We have focused in the last two years in the development and retention of a "team" approach to SCI treatment and imaging which uses experts in engineering (Dr Schmit), image acquisition and analysis (Dr Ulmer) and spinal cord interventions with stem cells (Dr Kurpad, Alexanian and Crowe). Dr Kurpad additionally is the Chief of the Neurosurgical Service at the Zablocki VA and has a strong interest in the clinical care of patients with SCI. This commitment to SCI clinical care and research is additionally reflected by his research support from the BL R&D MERIT Review Program. The presence of this "team" and the promising preliminary data that have culminated in five publications this year are expected to generate definitive data that can be translated successfully for the care of Veterans with SCI.