Methods and devices to assist and improve cerebrospinal fluid drainage

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ABSTRACT Excessive accumulation of cerebrospinal flow (CSF) known as hydrocephalus affects about 1 million Americans of all ages, which is especially high in children (88 per 100,000) and older (175 per 100,000) populations. Hydrocephalus is frequently observed following central nervous system insults such as subarachnoid hemorrhage and traumatic brain injury. CSF has numerous important functional roles including maintenance of ionic and pH balance; waste removal; distribution of humoral factors; and providing a cushion for the brain. Thus, CSF homeostasis is critically important for normal brain function. Several exit routes for the CSF outflow have been identified, such as the arachnoid granulations, paravascular and paracranial nerves pathways and meningeal lymphatics. In the current project, we will leverage the drainage system of the CSF flow to decrease hydrocephalus and clear the cellular metabolic waste. Studies showed that up to 50% of CSF drains through the brain lymphatics and then the cervical lymph nodes. We propose that contraction of the neck muscles, by compressing the underlying cervical valve-equipped lymph vessels and nodes, is capable of accelerating CSF drainage resulting in the clearance of CSF excess and waste metabolites. Our preliminary results demonstrated that electrostimulation of the neck muscles decreases intracranial pressure (ICP), and accelerates cerebrospinal fluid flow, detected by dynamic contrast-enhancement magnetic resonance imaging (DCE-MRI). The main goal of this project is to investigate whether percutaneous electrostimulation of the mouse neck muscles accelerate CSF flow. We will monitor in vivo ICP changes in the ventricles during neck muscle stimulation, CSF distribution and drainage using dynamic contrast-enhancement MRI and macromolecule clearance using fluorescent tracers and fluorescent imaging. Employing known models of hydrocephalus, kaolin injection in the cisterna magna, we will evaluate the effects of chronic electromyostimulation (EMS) on the ventriculomegaly by T2-weighted anatomic MRI. We will also assess the overall well-being of the mice by locomotor and single-task cognitive test. The results of this project will provide new therapeutic venues for the treatment of hydrocephalus and potentially other neurological diseases in which glymphatic pathway is impaired.