Project Grant R44MH144943

SBIR PHASE II: MULTI-PROBE MINIMALLY INVASIVE ENDOMICROSCOPE - PROJECT SUMMARY THIS PROJECT SEEKS TO CONTINUE THE DEVELOPMENT OF A MULTI-PROBE ULTRATHIN ENDOMICROSCOPE TO ENABLE HIGH- RESOLUTION IMAGING AND PHOTO-STIMULATION AT MULTIPLE SITES WITHIN CURRENTLY INACCESSIBLE REGIONS OF THE BRAIN. THE INSTRUMENT WILL BE AMENABLE TO SCIENTIFIC STUDIES IN MODEL ANIMALS AND A STEPPING STONE FOR FUTURE MEDICAL INSTRUMENTATION TARGETED AT DIAGNOSIS AND DISEASE TREATMENT IN HUMANS. THE COMPANY ADDRESSES THE CRITICAL NEED IN THE SCIENTIFIC AND MEDICAL FIELDS FOR ENDOSCOPES THAT ARE MINIMALLY INVASIVE, WITH A CROSS SECTION IN THE ORDER OF 100 MM. THE PROPOSED SYSTEM PROTOTYPE WILL BE DIGITALLY PROGRAMMED AND SIMULTANEOUSLY ADDRESS MULTIPLE PROBES THAT PENETRATE TISSUE WITH NEGLIGIBLE DAMAGE. THE TARGET APPLICATION IS DEEP BRAIN IMAGING AND PHOTO-STIMULATION SIMULTANEOUSLY IN MULTIPLE REGIONS OF THE BRAIN. THE SYSTEM WILL ENABLE IMAGING DIFFICULT-TO-REACH BRAIN AREAS, SUCH AS THE BRAIN STEM OR THE OLFACTORY BULB, WITH NEGLIGIBLE TRAUMA TO THE ANIMAL. THE POSSIBILITY OF INSERTING MULTIPLE IMAGING PROBES TO CORRELATE STIMULATION AND ACTIVITY IN DIFFERENT REGIONS OF THE BRAIN COULD PROVIDE NEW UNDERSTANDING OF THE CONNECTOME AND HELP OBSERVE DIFFERENCES BETWEEN HEALTHY AND DISEASED BRAINS. CURRENT ENDOSCOPIC SOLUTIONS ARE APPROPRIATE FOR INSERTION IN LARGE CAVITIES BUT THEY PRODUCE EXCESSIVE DAMAGE IN APPLICATIONS SUCH AS DEEP BRAIN IMAGING. THIS PROJECT WILL CREATE A MINIMALLY-INVASIVE, ROBUST, FLEXIBLE, AND COMPACT PROTOTYPE FOR MULTI-PROBE ENDOMICROSCOPY. THE KEY INNOVATION IS IN ACHIEVING THE FUNDAMENTALLY THINNEST MECHANISM TO TRANSMIT A HIGH INFORMATION CONTENT IMAGE IN REAL TIME AND IN PARALLELIZING IT TO MULTIPLE BRAIN SITES. THE INDIVIDUAL PROBES HAVE A CROSS-AREA 10 TIMES SMALLER THAN THE THINNEST EXISTING ENDOSCOPES. FURTHER, EACH OF THE PROBES WILL BE ABLE TO DELIVER MULTIPLE FUNCTIONS: 3D IMAGING WITH MICROMETER RESOLUTION, FLUORESCENCE AND REFLECTION IMAGING, AS WELL AS LASER PATTERN GENERATION FOR PHOTO-STIMULATION AND ABLATION. THE IMAGING APPROACH IMPLEMENTS WAVEFRONT SHAPING IN VARIOUS MULTIMODE FIBER PROBES SIMULTANEOUSLY, USING ADVANCED MACHINE LEARNING AND SIGNAL PROCESSING METHODS, TO GENERATE ARBITRARY DIGITALLY-REPROGRAMMABLE LIGHT PATTERNS AND 3D IMAGES. THE SYSTEM USES A SPATIAL LIGHT MODULATOR TO FIRST CALIBRATE EACH FIBER AND THEN SCAN LIGHT AT HIGH SPEED, COMPENSATING FOR THE INHERENT MODAL DISPERSION AND INTERMODAL COUPLING. DURING PHASE I WE DEMONSTRATED THE FIRST IN-VIVO MULTIPROBE IMAGING EXPERIMENTS, SHOWING POPULATIONS OF NEURONS INDIVIDUALLY IMAGED AT DEPTH, WITH SUBCELLULAR RESOLUTION, AND WITH MINIMAL TISSUE DAMAGE OPENING EXCITING OPPORTUNITIES FOR EXPANSION AND DEVELOPMENT INTO MULTI-SITE SIMULTANEOUS ACTIVITY RECORDING AND NEURONAL MANIPULATION USING OPTOGENETICS. THE COMPANY'S INITIAL FOCUS IS ON DE-RISKING AND VALIDATING THE USE OF MULTIPLE MULTIMODE FIBER PROBES IN ANIMAL FUNCTIONAL NEURO-IMAGING. THE LONG-TERM VISION IS TO TRANSLATE THE TECHNOLOGY TOWARDS MEDICAL APPLICATIONS.