Time-resolved laser speckle contrast imaging of resting-state functional connectivity in neonatal brain

ABSTRACT Continuous monitoring of neonatal brain development is crucial for effective management of brain injury and associated complications, thus reducing healthcare burden and costs. One rapidly developing method for early characterization of abnormal brain development is to map resting-state functional connectivity (rs-FC) across distinct regions of the brain. However, currently available neuroimaging technologies are either expensive and difficult to use continuously (fMRI and PET) or lack the combination of temporal-spatial resolution and large field- of-view (FOV) to image distributed rs-FC (EEG and near-infrared spectroscopy and tomography). In collaboration with University of Kentucky inventors, Bioptics Technology is developing, validating, and commercializing a revolutionary time-resolved laser speckle contrast imaging (TR-LSCI) technology that enables noncontact, fast, high-resolution imaging of cerebral blood flow (CBF) over a large FOV. TR-LSCI illuminates picosecond-pulsed, widefield, coherent, near-infrared light onto the brain and synchronizes a newly developed, picosecond-gated, high-resolution, single-photon avalanche diode (SPAD) camera for 2D mapping of cerebral blood flow (CBF) at different depths into the head. By applying the time-gated strategy, TR-LSCI differentiates short and long photon paths through the layered head tissues at different depths, thus eliminating the need for time-consuming complex 3D reconstruction in near-infrared diffuse optical tomography technologies. In preliminary studies, continuous mapping of CBF at different depths has been demonstrated by a lab-made benchtop TR-LSCI prototype in flow- simulating phantoms and in vivo rodents. In this Fast Track STTR proposal through two phases, we will develop, optimize, validate, and commercialize a user-friendly portable TR-LSCI device for fast, high-solution, and multiscale imaging of CBF and rs-FC in neonatal rodents (Phase 1) and neonatal piglets (Phase 2). Specifically, Phase 1 will optimize and assess the benchtop TR-LSCI prototype for imaging CBF and extracting rs-FC (derived from time-course CBF images) in neonatal rodents with perinatal hypoxic-ischemic encephalopathy (HIE). Neonatal rats are used in this Phase 1 feasibility test to de-risk the TR-LSCI before its full-scale development in neonatal piglets during Phase 2. HIE is selected to study as it affects 2-9 babies per 1000 term births and is associated with severe neurodevelopmental problems and mortality. Phase 2 will develop, optimize, and assess a user-friendly portable TR-LSCI device for continuous imaging of CBF and rs-FC in neonatal piglets with HIE. Neonatal piglets are selected to study as their head size and post-HIE pathology are analogous to human neonates. TR-LSCI results will be correlated with MRI results and clinical outcomes to identify biomarkers for assessing neonatal brain injury after HIE. While this proposal tests it on HIE models of neonatal rats and piglets as the first step for preclinical commercialization, the TR-LSCI device is broadly applicable to investigate many neurovascular diseases beyond HIE occurring in human neonates, thereby providing a significant opportunity for future clinical development and commercialization.