Improving CBF through direct control of CSF pulsations

通过直接控制脑脊液脉动改善 CBF

• 批准号: 7915821
• 负责人: Mark Gregory Luciano
• 金额: $ 70.95万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915821
• 关键词: Acute; Affect; Alzheimer' s Disease; Amyloidosis; Anatomy; Animal Model; Animals; Area; Arteries; Atherosclerosis; Blood; Blood Circulation; Blood Gas Analysis; Blood Pressure; Blood Vessels; Blood capillaries; Blood flow; Bolus Infusion; Brain; Brain Edema; Brain Injuries; Cardiac; Cephalic; Cerebral perfusion pressure; Cerebrospinal Fluid; Cerebrospinal Fluid Pressure; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Chronic; Clinical; Clinical Research; Closed head injuries; Congestive Heart Failure; Control Animal; Coupled; Coupling; Dementia; Devices; Diastole; Disease; Economic Inflation; Energy Transfer; Enzyme-Linked Immunosorbent Assay; Excision; Experimental Animal Model; Experimental Models; Frequencies; Functional disorder; Goals; Hour; Hydrocephalus; Hypercapnic respiratory failure; Hypertension; Hyperventilation; Immunohistochemistry; Infusion procedures; Injury; Intracranial Hypertension; Intracranial Pressure; Investigation; Ischemia; Laboratories; Measures; Methods; Monitor; Morphology; Nervous System Physiology; Nervous System Trauma; Neuroglia; Neurologic; Neuron-Specific Enolase; Neurons; Obstructive Hydrocephalus; Organ; Oxygen; Patients; Phase; Physiologic pulse; Physiological; Play; Property; Pseudotumor Cerebri; Pump; Regulation; Risk; Role; Serum; Shapes; Shock; Side; Spinal; Staining method; Stains; Stroke; Structure; System; Systole; Tidal Volume; Time; Tissues; Trauma; Traumatic Brain Injury; VEGF165; Variant; Vascular Dementia; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-2; Vascular System; Vasospasm; Veins; Venous; Western Blotting; Width; Work; base; capillary; cell injury; cerebrovascular; cranium; design; electric impedance; improved; in vivo; nervous system disorder; neurotrophic protein S100beta; non-compliance; pressure; public health relevance; research study; single photon emission computed tomography; transmission process

DESCRIPTION (provided by applicant): Many neurological disorders, including hydrocephalus, result in brain injury and dysfunction in part through decreased cerebral blood flow (CBF). Evidence from clinical and experimental studies indicates that reduced CBF may be, in part, caused by impaired vascular and cerebrospinal fluid (CSF) compliance and resultant abnormal intracranial pressure (ICP) pulsatility. Therefore, vascular-CSF compliance coupling and importantly CSF space may play a significant role in regulating CBF. It has been hypothesized that the CSF may be important in the transfer of pulsatile, non-continuous flow to non-pulsatile, continuous flow in capillaries, a term referred to as the brain's Windkessel mechanism. We hypothesize that changes in CSF space compliance and pulsatility result in changes in vascular compliance, pulsatility and CBF. Furthermore, we hypothesize that through direct CSF volume changes synchronous to the cardiac cycle, we can alter CBF without changing mean systemic or intracranial pressure. The goal of the proposed study is to improve CBF through direct, controlled CSF space manipulation. The current investigation employs an experimental animal model of chronic hydrocephalus that mimics the same clinical condition having decreased CBF and CSF compliance. A surgically implantable and adjustable cranial balloon device and oscillating pump system designed specifically to synchronize with the cardiac cycle with the ability to change amplitude, frequency, phase and inflation/deflation rate has been developed to directly control (increase or decreased) CBF. Balloon inflation/deflation will coincide with the body's own physiological properties (i.e., systole/diastole), therefore matching closely the underlying Windkessel mechanism. The purpose of this oscillating balloon device is to: (1) increase CBF by improving CSF compliance, and (2) protect the brain from the trauma of unabsorbed arterial pulsations entering the closed cranial cavity. In this study, we will use the cranial balloon device to augment or reduce CSF pulsations under normal physiologic conditions, during acute (hyper/hypoventilation, CSF removal/infusion) changes, and after chronic hydrocephalus. Primary endpoint is CBF as measured quantitatively by tissue and flow probes and SPECT imaging, with changes in CSF pulsatility. Secondary endpoints will include brain oxygen delivery, and the assessment of parenchymal and blood vessel injury using immunohistochemistry, ELISA, and Western blot methods for neuron specific enolase (NSE), astrocytic protein S100B, and ischemia marker vascular endothelial growth factor (VEGF) receptor 2. The significance of this study will be to improve CBF through cardiac-synchronized CSF volume manipulation. If this approach works, then our understanding of the pathophysiology of hydrocephalus is changed from the traditional view of CSF accumulation to that of dynamic pulsation abnormality. New treatments based on this understanding may be applied to various neurological disease with diminished CBF including Alzheimer's and vascular type dementia, vascular diseases such as vasospasm, amyloidosis, atherosclerosis, venous hypertension, and CSF hydrodynamic disorders such as hydrocephalus and pseurdotumor cerebri. In addition, this method may also be used effectively to control abberant CSF pulsations observed in other clinical diseases including stroke, closed head injury, and congestive heart failure which may be at risk for further neurological damage related to decreased CBF and abnormal CSF pulsatility. PUBLIC HEALTH RELEVANCE: The goal of the current research study is to improve cerebral blood flow (CBF) through direct, controlled cerebrospinal fluid (CSF) manipulation. In an animal model of chronic hydrocephalus that mimics the same clinical condition with decreased CBF, we will use a surgically implantable and adjustable cranial balloon device and oscillating pump system designed specifically to inflate/deflate with the cardiac cycle to control vascular-CSF compliance, act as a "shock absorber" to dampen incoming arterial pulsations, and ultimately improve CBF. If proven effective, this approach may be used to treat millions of patients with diminished CBF including Alzheimer's and vascular type dementia, vascular diseases such as venous hypertension, and CSF disorders such as hydrocephalus. In addition, this method may also be used effectively to normalize abnormal CSF pulsations observed in other clinical diseases including stroke, closed head injury, and congestive heart failure which may be at risk for further brain injury.

描述（由申请人提供）：许多神经系统疾病，包括脑积水，部分通过脑血流量（CBF）减少导致脑损伤和功能障碍。临床和实验研究的证据表明，CBF 减少可能部分是由血管和脑脊液 (CSF) 顺应性受损以及由此导致的异常颅内压 (ICP) 搏动引起的。因此，血管-脑脊液顺应性耦合以及重要的脑脊液空间可能在调节CBF中发挥重要作用。据推测，脑脊液可能在毛细血管中脉动、非连续流向非脉动、连续流的转移中发挥重要作用，这一术语被称为大脑的 Windkessel 机制。我们假设脑脊液空间顺应性和搏动性的变化导致血管顺应性、搏动性和CBF的变化。此外，我们假设通过与心动周期同步的直接脑脊液体积变化，我们可以在不改变平均全身压或颅内压的情况下改变CBF。本研究的目标是通过直接、受控的 CSF 空间操纵来改善 CBF。目前的研究采用了慢性脑积水的实验动物模型，该模型模拟了 CBF 和 CSF 顺应性降低的相同临床状况。一种可通过手术植入、可调节的颅球囊装置和振荡泵系统，专门设计用于与心动周期同步，能够改变振幅、频率、相位和充气/放气率，以直接控制（增加或减少）CBF。气球充气/放气将与人体自身的生理特性（即收缩/舒张）一致，因此与潜在的 Windkessel 机制紧密匹配。这种振荡球囊装置的目的是：(1) 通过改善脑脊液顺应性来增加 CBF，(2) 保护大脑免受进入闭合颅腔的未吸收动脉搏动造成的创伤。在这项研究中，我们将使用颅球装置来增强或减少正常生理条件下、急性（通气过度/通气不足、脑脊液取出/输注）变化期间以及慢性脑积水后的脑脊液搏动。主要终点是通过组织和流量探针以及 SPECT 成像定量测量的 CBF，以及 CSF 搏动的变化。次要终点包括脑氧输送，以及使用免疫组织化学、ELISA 和蛋白质印迹法对神经元特异性烯醇化酶 (NSE)、星形细胞蛋白 S100B 和缺血标记物血管内皮生长因子 (VEGF) 受体 2 评估实质和血管损伤这项研究的意义在于通过心脏同步脑脊液容量操作来改善 CBF。如果这种方法有效，那么我们对脑积水病理生理学的理解就会从传统的脑脊液积聚观点转变为动态搏动异常观点。基于这一认识的新疗法可应用于各种CBF减少的神经系统疾病，包括阿尔茨海默氏症和血管型痴呆，血管疾病如血管痉挛、淀粉样变性、动脉粥样硬化、静脉高血压，以及脑脊液流体动力障碍如脑积水和假性脑瘤。此外，该方法还可以有效地用于控制在其他临床疾病中观察到的异常脑脊液搏动，包括中风、闭合性颅脑损伤和充血性心力衰竭，这些疾病可能面临与CBF减少和异常脑脊液搏动相关的进一步神经损伤的风险。公共健康相关性：当前研究的目标是通过直接、受控的脑脊液 (CSF) 操作来改善脑血流量 (CBF)。在模拟相同临床状况但 CBF 减少的慢性脑积水动物模型中，我们将使用可通过手术植入的可调节颅球囊装置和专门设计用于随心动周期充气/放气的振荡泵系统，以控制血管-脑脊液顺应性，作为“减震器”来抑制传入的动脉搏动，并最终改善 CBF。如果被证明有效，这种方法可用于治疗数百万 CBF 减少的患者，包括阿尔茨海默病和血管型痴呆、静脉高压等血管疾病以及脑积水等脑脊液疾病。此外，该方法还可有效用于使在其他临床疾病中观察到的异常脑脊液搏动正常化，包括中风、闭合性颅脑损伤和充血性心力衰竭，这些疾病可能有进一步脑损伤的风险。

项目成果

Epidural Oscillating Cardiac-Gated Intracranial Implant Modulates Cerebral Blood Flow.

硬膜外振荡心门控颅内植入物调节脑血流。

• 发表时间: 2020
• 影响因子: 4.8
• 作者: Luciano, Mark G;Dombrowski, Stephen M;El;Yang, Jun;Thyagaraj, Suraj;Qvarlander, Sara;Khalid, Syed;Suk, Ian;Manbachi, Amir;Loth, Francis
• 通讯作者: Loth, Francis

Novel method for dynamic control of intracranial pressure.

动态控制颅内压的新方法。

• 发表时间: 2017-05
• 影响因子: 4.1
• 作者: Luciano, Mark G;Dombrowski, Stephen M;Qvarlander, Sara;El;Yang, Jun;Thyagaraj, Suraj;Loth, Francis
• 通讯作者: Loth, Francis

Modifying the ICP pulse wave: effects on parenchymal blood flow pulsatility.

修改 ICP 脉冲波：对实质血流脉动的影响。

• 发表时间: 2023-02-01
• 作者: Qvarlander, Sara;Dombrowski, Stephen M;Biswas, Dipankar;Thyagaraj, Suraj;Loth, Francis;Yang, Jun;Luciano, Mark G
• 通讯作者: Luciano, Mark G