As the development of new methods that quickly discern brain structures and neural pathways becomes a pressing need, we work actively on optical techniques for visualizing and mapping the brain at high resolution.  Large-scale or whole brain imaging and mapping at microscopic resolution is feasible with intrinsic optical contrasts.  We combined multi-contrast optical coherence tomography and a tissue slicer to form a serial optical coherence scanner (SOCS).  It distinguishes white matter and gray matter and visualizes nerve fiber tracts that are as small as a few tens of micrometers.  Axonal birefringence highlights the location and myelination of nerve fibers, while the axis orientation contrast indicates the fiber alignment in the plane. In-plane measurements of SOCS and diffusion MRI were co-validated, and we also reported a method to extract the inclination angle of fibers to complete the 3D orientation. SOCS could reveal biomarkers for disease onset and progression in cerebrum and cerebellum, and support development of therapeutics.

We have demonstrated label-free depth-resolved optical imaging of neural action potentials by measuring sub-nanometer range transient structural changes. Fast signals detected by phase-sensitive optical coherence tomography (OCT) are coincident with the action potential arrival to the measurement site.  Among other unmyelinated nerve models, we used squid giant axon preparation to study these changes in presence of different environmental (i.e. temperature) and physiological (i.e. ionic concentrations) conditions.  Cooling the nerve slows and increases the amplitude of the electrical and optical responses. Increasing the NaCl concentration bathing the axon decreases the diameter of the axon, but yields a larger response during activity.  Experiments with voltage sensitive dyes allowed us to compare the phase and intensity signals at several depths.  Then, we have reported a functional OCT cross-sectional scanner to detect neural activity using unmyelinated nerve bundles.  The advantage compared to monitoring a single depth profile is a dramatic increase in the number of available sites that can be measured in two spatial dimensions with lateral scanning; therefore, the study demonstrated that two-dimensional monitoring of small-scale functional activity would also be feasible.

We introduced the polarization-maintaining-fiber (PMF) based OCT systems to the field. These systems are phase and polarization sensitive and are implemented in time-domain, in spectral-domain, and with swept-source technology.  Conventional OCT is useful; however, often times the reflectivity images are not descriptive enough to indicate different structures in complex tissue.  Polarization-sensitive OCT (PS-OCT), on the other hand, provides additional contrasts based on birefringence, which is the optical anisotropy shared by many tissues including muscle, tendon and nerve. The PMF based PS-OCT devices are capable of generating reflectivity, birefringence/retardance and axis orientation images of tissue, as well as the bidirectional blood flow, all simultaneously.  These systems combine the advantages of fiber technology with the straight forward operation and analyses of bulk setups.  Other benefits include (i) single measurement for multiple contrasts (the fastest fiber systems in its kind), (ii) retardance image does not require compensation (simple analysis), (iii) no need for polarization modulators or controllers (easy operation and cheaper implementation), (iv) external disturbances such as fiber movement and rotation do not cause polarization transformations in PMF (accurate images), and (v) axis orientation and blood flow images are calculated from the phase of the same data set (multi-functional data).

We reported on several differential phase sensors based on low-coherence interferometry. The sensors are capable of measuring extremely small (Angstrom level) optical path length changes at specific depths. The applications include imaging tissue response to electrical or photothermal stimulation, and detection of neural activity.  We also reported reflection-mode measurement of Faraday rotation with a small field-depth factor.