Project Grant F31NS151410

QUANTIFYING DRIVERS OF CSF DYNAMICS AND THEIR IMPORTANCE IN BRAIN WASTE CLEARANCE - PROJECT SUMMARY CEREBROSPINAL FLUID (CSF) DYNAMICS PLAY A CRUCIAL ROLE IN THE CLEARANCE OF BRAIN WASTE AND HAVE BEEN FOUND TO BE ALTERED IN MANY NEUROLOGICAL DISEASES, INCLUDING TRAUMATIC BRAIN INJURY AND ALZHEIMER'S. UNDERSTANDING WHAT DRIVES CSF MOVEMENT WOULD IMPROVE OUR TREATMENT OF NEUROLOGICAL DISEASES. CSF MOVEMENT HAS BEEN SHOWN TO BE DRIVEN BY CARDIAC PULSATION, SLEEP, RESPIRATION, AND STIMULI. THE MOVEMENT OF CSF IS DRIVEN BY VOLUME DISPLACEMENT IN THE SKULL, SO DRIVERS THAT INFLUENCE CSF DYNAMICS ACT ON BLOOD FLOW INFLOW AND OUTFLOW. HOWEVER, THE MAGNITUDE OF, AND CSF RESPONSE TO, DRIVERS HAS NOT BEEN QUANTIFIED IN A REPEATABLE WAY. CSF MOVEMENT REMAINS LARGELY UNUSED IN THE CLINICAL SETTING BECAUSE IT HAS NOT BEEN LINKED TO QUANTITATIVELY TO DISEASE OR DRUG DELIVERY. MAGNETIC RESONANCE IMAGING (MRI) CAN BE USED TO QUANTIFY BLOOD AND CSF FLOW NON-INVASIVELY IN HUMANS. THE PROPOSED EXPERIMENTS COMPARE A BLOOD-OXYGEN-LEVEL-DEPENDENT (BOLD-EPI) SEQUENCE WITH PHASE- CONTRAST MAGNETIC RESONANCE (PCMR) IN-VITRO, THEN USE PCMR TO MEASURE BOTH VASCULAR AND CSF VELOCITY AND DISPLACEMENT ENCODING WITH STIMULATED ECHOES (DENSE) TO MEASURE BRAIN TISSUE MOTION IN-VIVO. AIM 1 COMPARES THE ACCURACY AND SENSITIVITY OF PCMR AND BOLD-EPI ON A FLOW PHANTOM. AIM 2 USES PCMR TO MEASURE THE CSF RESPONSE TO ARTERIAL AND VENOUS FLOW CHANGES DRIVEN BY HYPERCAPNIA AND DEPTH OF RESPIRATION IN HEALTHY HUMAN VOLUNTEERS. AIM 3 USES PCMR AND DENSE TO CREATE A MODEL OF CSF RESPONSE IN HEALTHY HUMANS. THEN IN CHIARI TYPE 1 MALFORMATION PATIENTS WHERE CSF OUTFLOW IS OBSTRUCTED, THE MODEL IS USED TO CALCULATE THEIR INDIVIDUAL DEFICIT IN FLOW, WHICH IS A NEW METRIC OF CHIARI-1 SEVERITY. THIS PROJECT DEVELOPS A MODEL CHARACTERIZING CSF DYNAMICS WHICH WOULD HAVE DIRECT CLINICAL APPLICATION AS A METHOD TO MEASURE CSF FLOW DEFICIT IN CHIARI-1 PATIENTS AND CAN BE USED TO FURTHER STUDY THE IMPORTANCE OF PHYSIOLOGICAL STATES ON BRAIN WASTE CLEARANCE. THE PROPOSED TRAINING PLAN PREPARES THE APPLICANT FOR A CAREER AS A PHYSICIAN-SCIENTIST BY COMBINING TRADITIONAL SCIENTIFIC TRAINING WITH CLINICAL TRAINING AND TRANSLATIONAL RESEARCH. THE PLAN FOCUSES ON OPPORTUNITIES FOR THE APPLICANT TO DEVELOP SKILLS IN SCIENTIFIC REASONING, COMMUNICATION, AND TECHNICAL MASTERY IN ADDITION TO LONGITUDINAL CLINICAL EXPOSURE. THESE INCLUDE AUTHORSHIP, CONFERENCE ATTENDANCE, TEACHING, DEDICATED INDIVIDUAL MENTORSHIP, AND PROFESSIONAL DEVELOPMENT OPPORTUNITIES. THE FELLOWSHIP IS SUPERVISED BY TWO SPONSORS - A PHD IN MRI AND FLUID MECHANICS, AND A NEUROSURGEON WITH ESTABLISHED RESEARCH IN NEUROVASCULAR DISORDERS - AND INCLUDES A TEAM OF SUPPORTING FACULTY FOR THE AREAS OF SPECIALTY IN THE PROPOSED RESEARCH.