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Trigeminal nerve stimulation to modulate cortical spreading depolarizations after brain injury

三叉神经刺激调节脑损伤后皮质扩散去极化

基本信息

批准号：
10058295
负责人：
Chunyan Li
金额：
$ 25.13万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058295
关键词：
Acute Acute Brain Injuries Adenosine Aftercare Animal Model Blood Preservation Blood Vessels Brain Brain Injuries Brain hemorrhage Brain region Cerebral cortex Cerebrovascular Circulation Cerebrovascular system Cerebrum Clinical Coupled Cranial Nerves Depressed mood Development Disease Dose Electric Stimulation Functional disorder Glucose Glutamates Goals Heart Hemorrhagic Shock Incidence Infarction Injury Ischemic Stroke Knowledge Lead Lesion Light Long-Term Effects Malignant - descriptor Measures Meningeal Metabolic Methods Middle Cerebral Artery Occlusion Mind Neuraxis Neurologic Deficit Nitric Oxide Oxygen Patients Pharmaceutical Preparations Pharmacology Phase Play Production Rattus Recovery Research Role Site Specificity Stroke Subarachnoid Hemorrhage System Therapeutic Time Tissues Traumatic Brain Injury Trigeminal nerve structure Vasodilation Vasodilator Agents brain tissue diving reflex improved innovation nervous system disorder neurophysiology precision medicine preservation prevent response side effect stroke model systemic intervention targeted treatment vasoconstriction

项目摘要

Project Summary Cortical spreading depolarization (CSD) is a phenomenon of depressed electrical activity in the brain that has been clinically associated with a variety of acute brain injuries, including 100% of patients with malignant hemispheric ischemic stroke. In addition to being a real-time marker of brain damage, CSDs are also believed to be a mechanism of secondary injury in the compromised tissue of acute brain injuries. Accumulating evidence proves that the expansion of ischemic territory is closely coupled to the occurrence of CSDs, due to the increased metabolic demand of repolarization (oxygen depletion associated with vasoconstriction). Thus, recent studies have focused on the use of various drugs to create complete cessation of CSDs in the injured brain as a method of preventing further tissue loss. However, these pharmacological approaches are systemic and typically have significant side effects. Therefore, new strategies are needed to selectively reduce the deleterious consequences of CSDs. Whether or not injury occurs after CSDs depends greatly on the capacity of tissues to re-establish ionic gradients in the aftermath of CSDs. This capacity is influenced mainly by the availability of ATP and the ability of a brain region to profoundly increase cerebral blood flow (CBF) to match the energy demands. The trigeminal nerve is the largest cranial nerve forming an extensive network throughout the central nervous system (CNS), and is unique because of its intimate connection with the cerebral and meningeal blood vessels, referred to as the trigemino-cerebrovascular system. It is also capable of activating the diving reflex, whose primary role is to conserve oxygen for sensitive brain and heart tissue. We have previously shown that electrical stimulation of the trigeminal nerve (TNS) not only increases CBF but also significantly increases brain oxygen tension in the brains of normal, traumatic brain injury, and hemorrhagic shock rats. Additionally, in our preliminary studies, TNS treatment in normal brains increased the threshold current required for eliciting CSD and slowed its propagation velocity. Furthermore, TNS treatment immediately before middle cerebral artery occlusion (MCAO) in rats decreased infarction volumes, and the numbers of CSDs. We therefore hypothesize that TNS can reduce the detrimental consequences of CSDs in the injured brain by initiating cerebral vasodilation and increasing energy substrate levels for quicker repolarization. In this proposal, we aim to: (1) Investigate the effects of TNS on the release of cerebral vasodilators and energy substrates in the normal brain; (2) Explore the effects of TNS in obtaining the ideal amount of cerebral vasodilators and energy substrates to reduce injury development after CSDs. The proposed study would be the first ever research to reduce deleterious consequences of CSDs on the basis of precision medicine for the injured brain. The information obtained from these studies will lead us to a better understanding of the therapeutic potential of TNS in the injured brain, and its mechanism of action on CSDs across the spectrum of mild, moderate and severe ischemic regions using validated animal models.

项目摘要皮层扩散去极化（CSD）是一种脑电活动抑制的现象，临床上与各种急性脑损伤相关，包括100%的恶性脑损伤患者。大脑半球缺血性中风除了作为脑损伤的实时标记，CSD还被认为是是急性脑损伤受损组织的继发性损伤机制。积累有证据表明，缺血区域的扩大与CSD的发生密切相关，复极化的代谢需求增加（与血管收缩相关的氧耗）。因此，在本发明中，最近的研究集中在使用各种药物使受伤者的CSD完全停止大脑作为防止进一步组织损失的方法。然而，这些药理学方法是全身性且通常具有显著的副作用。因此，需要新的战略，减少CSD的有害后果。CSD后是否发生损伤在很大程度上取决于组织在CSD后重建离子梯度的能力。这种能力受到影响主要是通过ATP的可用性和大脑区域深刻增加脑血流量的能力 (CBF)以满足能源需求。三叉神经是最大的脑神经，神经网络贯穿整个中枢神经系统（CNS），并且是独特的，因为它与大脑和脑膜血管，称为三叉神经-脑血管系统。也是能够激活潜水反射，其主要作用是为敏感的大脑和心脏保存氧气组织.我们以前已经表明，电刺激三叉神经（TNS）不仅增加了 CBF还显著增加正常脑、创伤性脑损伤脑中的脑氧张力，失血性休克大鼠此外，在我们的初步研究中，正常大脑中的TNS治疗增加了引起CSD所需的阈值电流，并减慢其传播速度。此外，TNS 在大鼠大脑中动脉闭塞（MCAO）之前立即治疗降低了梗塞体积，和CSD的数量因此，我们假设TNS可以减少通过启动脑血管舒张和增加能量底物水平，复极化本研究的目的是：（1）研究TNS对脑缺血再灌注损伤大鼠脑组织中神经递质释放的影响。（2）探讨TNS在获得理想的脑内血管扩张因子和能量底物中的作用脑血管扩张剂和能量底物的量，以减少CSD后的损伤发展。的拟议的研究将是有史以来第一次研究，以减少CSD的有害后果的基础上，对受伤的大脑进行精准治疗从这些研究中获得的信息将使我们更好地了解TNS在脑损伤中的治疗潜力及其对CSD的作用机制使用经验证的动物模型，在轻度、中度和重度缺血区域的范围内。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CBF oscillations induced by trigeminal nerve stimulation protect the pericontusional penumbra in traumatic brain injury complicated by hemorrhagic shock.

DOI：
10.1038/s41598-021-99234-8
发表时间：
2021-10-04
期刊：
Scientific reports
影响因子：
4.6
作者：
Li C;Shah KA;Powell K;Wu YC;Chaung W;Sonti AN;White TG;Doobay M;Yang WL;Wang P;Becker LB;Narayan RK
通讯作者：
Narayan RK

Electrical Stimulation of the Infraorbital Nerve Induces Diving Reflex in a Dose-Controlled Manner.

眶下神经的电刺激以剂量控制的方式诱导潜水反射。

DOI：
10.1109/embc44109.2020.9176845
发表时间：
2020
期刊：
Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference
影响因子：
0
作者：
Shah,KevinA;Sonti,AnupN;Wu,Yi-Chen;Powell,Keren;Doobay,Mohini;Narayan,RajK;Li,Chunyan
通讯作者：
Li,Chunyan

Multi-Mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review.

多种力学方法治疗创伤性脑损伤：综述。

DOI：
10.3390/jcm12062179
发表时间：
2023-03-11
期刊：
JOURNAL OF CLINICAL MEDICINE
影响因子：
3.9
作者：
Lynch, Daniel G.;Narayan, Raj K.;Li, Chunyan
通讯作者：
Li, Chunyan

Trigeminal nerve stimulation: a current state-of-the-art review.

DOI：
10.1186/s42234-023-00128-z
发表时间：
2023-12-13
期刊：
Bioelectronic medicine
影响因子：
0
作者：
Powell, Keren;Lin, Kanheng;Tambo, Willians;Saavedra, Andrea Palomo;Sciubba, Daniel;Al Abed, Yousef;Li, Chunyan
通讯作者：
Li, Chunyan

Trigeminal Nerve Control of Cerebral Blood Flow: A Brief Review.