Improving CBF through direct control of CSF pulsations

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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.