Oxygen levels (pO2) in the brain play a significant role in influencing the function of single neurons and neuronal networks during normal and pathological states. Mechanisms of such interactions between neuronal function and oxygen supply and consumption are not well understood relying largely on theoretical models and qualitative measurements. In addition, current and emerging neural implants disrupt the local blood-brain barrier as they penetrate the brain during placement potentially leading to oxidative stress in brain tissue along the path of the implant. Such oxidative stress indicative of energy imbalances can trigger multiple pathways to tissue damage. Many of the current technologies for measuring oxygen are qualitative and therefore do not provide a direct measure of oxygen partial pressure in the brain. Those that do measure oxygen quantitatively are either point measurements that do not give a spatial map, or require very specialized equipment or can only map the superficial areas. We propose here a novel PISTOL (Proton Imaging of Siloxane Tissue Oxygen Levels) based magnetic resonance (MR) imaging approach to create dynamic, quantitative spatial maps of pO2 levels with microscale resolution in the brain around implanted neural interfaces in anesthetized and conscious, head-restrained animals. We will develop a siloxane contrast agent that will be loaded in a polydimethylsiloxane (PDMS) matrix encapsulating the neural interface for long-term stability in brain tissue.
The specific aims of this proposal are: 1). Develop, test and validate the sensitivity, detection limits, of 3 different embodiments of a siloxane sensor that will create quantitative spatial maps of pO2 along the length of a single microscale implant in the brain under ?no stimulation? and electrical/optical stimulation conditions in rodent experiments. 2). We will develop and test a generalizable process that will encapsulate individual shanks in 16- and 256-channel custom MR compatible microelectrode arrays and Utah microelectrode arrays with a PDMS matrix loaded with siloxane contrast agent. Subsequently, we will scale the PISTOL imaging technique to create spatial maps of pO2 around multiple implant sites in the brain and 3). We will test and validate the siloxane contrast agents for their ability to map pO2 levels around multi-channel microelectrodes in chronic rodent experiments. Successful development of the proposed technology will yield unprecedented information and discoveries on (a) dynamics of oxygen supply and consumption during neuronal function and dysfunction and (b) mechanisms of tissue injury leading to failure of chronic implants. The proposed siloxane based technique is also expected to be readily translatable leading to immediate clinical impact in patients with epilepsy, stroke, hemorrhage etc.
This proposal seeks to develop a novel imaging technique that will enable simultaneous monitoring of electrical activity of single neurons and neuronal networks along with quantitative spatial mapping at the microscale level of oxygen changes with time. Such unprecedented quantitative measurements of oxygen levels and neuronal function will accelerate discoveries about how local oxygenation influences neuronal function and dysfunction and how blood flow is regulated to different brain regions particular in metabolic disorders such as stroke, ischemia etc.
