Project Grant R01NS134577

CALCIUM IMAGING-BASED INSIGHTS AND GUIDANCE OF DEEP BRAIN STIMULATION TO ENHANCE CHRONIC, POST-STROKE REHABILITATION IN A RODENT MODEL OF ISCHEMIA - PROJECT SUMMARY CURRENT POST-STROKE REHABILITATION TREATMENTS ASSIST ONLY ~50% OF PATIENTS, RESULTING IN AN URGENT NEED TO DEVELOP NEW THERAPIES FOR THE MILLIONS OF INDIVIDUALS WHO SUFFER FROM CHRONIC MOTOR DEFICITS. A RECENTLY-COMPLETED PHASE I CLINICAL TRIAL LED BY OUR TEAM (EDEN), SHOWED PROMISING RESULTS FOR A NEW DEEP BRAIN STIMULATION (DBS) REHABILITATION TREATMENT, WITH SOME HETEROGENEITY IN RECOVERY OUTCOMES ACROSS PATIENTS. TO ANSWER WHY SOME PATIENTS RESPOND TO THE TREATMENT WHILE OTHERS DON'T, A BETTER MECHANISTIC UNDERSTANDING OF HOW DBS CONTRIBUTES TO POST-STROKE REHABILITATION IS ESSENTIAL. OUR CENTRAL HYPOTHESIS IS THAT PATIENT-SPECIFIC CUSTOMIZATION OF DBS PARAMETERS SUCH AS AMPLITUDE, FREQUENCY AND DURATION ARE REQUIRED TO ADDRESS UNIQUE DIFFERENCES IN BRAIN CONDITIONS AND TO MAXIMIZE THE POTENTIAL OF THIS NEW TREATMENT. THE PROJECT'S GOALS ARE TO STUDY HOW REORGANIZATION OF THE PERILESIONAL BRAIN TISSUE AFTER INJURY IS PROMOTED BY DBS, AND TO DEVELOP A SUBJECT-SPECIFIC APPROACH FOR TUNING THE DBS PARAMETERS TO ENHANCE RECOVERY. FOR ACHIEVING OUR GOALS, WE WILL USE A RAT MODEL OF ISCHEMIA, WHERE WE CAN SYSTEMATICALLY VARY THE STROKE INJURY PARAMETERS USING THE ENDOTHELIN-1 VASOCONSTRICTION MODEL AND VISUALIZE THE INJURY AND THE BRAIN FUNCTIONAL ACTIVITY BEFORE AND DURING RECOVERY ACROSS MOST OF THE DORSAL CORTEX USING TWO-PHOTON MICROSCOPY AND CALCIUM IMAGING. OUR LONG-TERM GOAL IS TO TRANSLATE SIMILAR INTERVENTIONS TO PATIENTS, BASED ON THE LESSONS FROM RATS. THE PROJECT RATIONALE: THIS PROJECT 1) PROVIDES A COMPREHENSIVE PLATFORM FOR RIGOROUS STUDY OF BASIC MECHANISMS OF BRAIN REORGANIZATION AND GENERATION OF NEW FUNCTIONAL PROPERTIES FOLLOWING ISCHEMIC INJURY IN A PRECLINICAL ANIMAL MODEL, 2) PROVIDES ANIMAL-SPECIFIC INFORMATION ON REORGANIZATION OF CORTICAL CIRCUITS DURING POST-STROKE RECOVERY TO ADDRESS HETEROGENEITY ACROSS ANIMALS, AND 3) ENABLES DIRECT COMPARISON ACROSS DIFFERENT REHABILITATION APPROACHES. AIM 1 WILL DETERMINE THE CONTRIBUTION OF DIFFERENT TREATMENTS TO CIRCUIT REORGANIZATION AND MOTOR RECOVERY AFTER INJURY AND AIM 2 WILL DEMONSTRATE MULTI-FACET OPTIMIZATION OF SUBJECT-SPECIFIC DBS PARAMETERS TO ENHANCE BRAIN REORGANIZATION AND MOTOR REHABILITATION IN MIDDLE-AGED MALE AND FEMALE RATS FOR DIFFERENT INJURY TYPES. IMPACT: THE PROPOSED PROJECT WILL PROVIDE US WITH MECHANISTIC UNDERSTANDING ON THE REORGANIZATION PROCESS OF CORTICAL NEURONS FOLLOWING AN ISCHEMIC STROKE, AND HOW EFFICIENT DBS TREATMENT MAY PROMOTE IT BEYOND CURRENT REHABILITATION TREATMENTS. SUCH KNOWLEDGE WILL ASSIST IN OPTIMIZING NEW NEUROMODULATION-BASED REHABILITATION APPROACHES, SUCH AS THE EDEN CLINICAL TRIALS, TO ASSIST PATIENTS. MOREOVER, THE PROPOSED QUANTITATIVE ASSESSMENT APPROACH CAN BE EXPANDED TO COMPARATIVELY ASSESS THE EFFICACY OF OTHER REHABILITATION TREATMENTS AND OTHER STROKE MODELS IN AN UNBIASED WAY. THEREFORE, THE PROPOSED WORK WILL PROMOTE BETTER UNDERSTANDING OF THE CORTICAL REORGANIZATION PROCESS DURING RECOVERY AND HAS THE POTENTIAL TO ASSIST IN IMPROVING PATIENT QUALITY OF LIFE.