Faculty Bibliography

In vivo, minimally invasive microscopy in deep cortical and sub-cortical regions of the mouse brain has been challenging. To address this challenge, we present an in vivo high numerical aperture optical coherence microscopy (OCM) approach that fully utilizes the water absorption window around 1700 nm, where ballistic attenuation in the brain is minimized. Key issues, including detector noise, excess light source noise, chromatic dispersion, and the resolution-speckle tradeoff, are analyzed and optimized. Imaging through a thinned-skull preparation that preserves intracranial space, we present volumetric imaging of cytoarchitecture and myeloarchitecture across the entire depth of the mouse neocortex, and some sub-cortical regions. In an Alzheimer's disease model, we report that findings in superficial and deep cortical layers diverge, highlighting the importance of deep optical biopsy. Compared to other microscopic techniques, our 1700 nm OCM approach achieves a unique combination of intrinsic contrast, minimal invasiveness, and high resolution for deep brain imaging.

Across optics and photonics, excess intensity noise is often considered a liability. Here, we show that excess noise in broadband supercontinuum and superluminescent diode light sources encodes each spectral channel with unique intensity fluctuations, which actually serve a useful purpose. Specifically, we report that excess noise correlations can both characterize the spectral resolution of spectrometers and enable cross-calibration of their wavelengths across a broad bandwidth. Relative to previous methods that use broadband interferometry and narrow linewidth lasers to characterize and calibrate spectrometers, our approach is simple, comprehensive, and rapid enough to be deployed during spectrometer alignment. First, we employ this approach to aid alignment and reduce the depth-dependent degradation of the sensitivity and axial resolution in a spectrometer-based optical coherence tomography (OCT) system, revealing a new outer retinal band. Second, we achieve a pixel-to-pixel correspondence between two otherwise disparate spectrometers, enabling a robust comparison of their respective measurements. Thus, excess intensity noise has useful applications in optics and photonics.

Cerebral blood flow (CBF) is essential for brain function, and CBF-related signals can inform us about brain activity. Yet currently, high-end medical instrumentation is needed to perform a CBF measurement in adult humans. Here, we describe functional interferometric diffusing wave spectroscopy (fiDWS), which introduces and collects near-infrared light via the scalp, using inexpensive detector arrays to rapidly monitor coherent light fluctuations that encode brain blood flow index (BFI), a surrogate for CBF. Compared to other functional optical approaches, fiDWS measures BFI faster and deeper while also providing continuous wave absorption signals. Achieving clear pulsatile BFI waveforms at source-collector separations of 3.5 cm, we confirm that optical BFI, not absorption, shows a graded hypercapnic response consistent with human cerebrovascular physiology, and that BFI has a better contrast-to-noise ratio than absorption during brain activation. By providing high-throughput measurements of optical BFI at low cost, fiDWS will expand access to CBF.

Red blood cells (RBCs) transport oxygen to tissues and remove carbon dioxide. Diffuse optical flowmetry (DOF) assesses deep tissue RBC dynamics by measuring coherent fluctuations of multiply scattered near-infrared light intensity. While classical DOF measurements empirically correlate with blood flow, they remain far-removed from light scattering physics and difficult to interpret in layered media. To advance DOF measurements closer to the physics, here we introduce an interferometric technique, surmounting challenges of bulk motion to apply it in awake humans. We reveal two measurement dimensions: optical phase, and time-of-flight (TOF), the latter with 22 picosecond resolution. With this multidimensional data, we directly confirm the unordered, or Brownian, nature of optically probed RBC dynamics typically assumed in classical DOF. We illustrate how incorrect absorption assumptions, anisotropic RBC scattering, and layered tissues may confound classical DOF. By comparison, our direct method enables accurate and comprehensive assessment of blood flow dynamics in humans.

PURPOSE/UNASSIGNED:We aim to study a case of pathologic myopia with visible light OCT. DESIGN/UNASSIGNED:Case report. SUBJECTS/UNASSIGNED:We recruit 1 patient with pathologic myopia presenting with an acute lacquer crack with submacular hemorrhage (SMH) in the right eye and a chronic lacquer crack in the left eye. METHODS/UNASSIGNED:We acquire visible light OCT images with 1 μm axial resolution. Images are processed to depict spectral centroid shift, and spectral fitting is performed to determine oxygen saturation. Results are compared to clinical imaging. MAIN OUTCOME MEASURES/UNASSIGNED:Visible light OCT images, spectral centroid shift (redshift), oximetry, and spectral fitting. RESULTS/UNASSIGNED:with spectral evidence of an overlying RPE deficit (deficient red shift) and photoreceptor abnormalities. CONCLUSIONS/UNASSIGNED:As visible light OCT technology advances, its application toward well-characterized human retinal pathology can clarify its utility. We describe the first case of visible light OCT applied to pathologic myopia, a primary RPE-BM-choriocapillaris interface disease. We confirm that extravascular hemoglobin can be subject to spectral fitting, and we quantify the oxygen saturation of acute SMH. We further show that structural changes in chronic lacquer cracks can be characterized with this new technology. FINANCIAL DISCLOSURES/UNASSIGNED:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Interferometric diffuse optics (iDO) has recently emerged as a promising class of near-infrared (NIR) light technologies for monitoring human brain signals associated with coherent light fluctuations. In this work, we demonstrate a line scan interferometric diffusing wave spectroscopy (iDWS) system at 1060 nm, a wavelength that has a multitude of benefits for high-speed cerebral blood flow index (BFI) monitoring. Pulsatile BFI measurements on the forehead of a moderately dark-skinned (Fitzpatrick Type V) subject with medium-length black hair up to a source-collector (S-C) separation of 5.5 cm on the forehead and 4.0 cm over the parietal cortex are demonstrated in continuous wave (CW) mode. On this high-throughput platform, we further implement a simple time-of-flight filter (TOF) via source wavelength tuning. The TOF filter can be turned on and off, and its width can be changed electronically, enabling probing different sample depths without requiring multiple S-C separations. At 4 cm S-C separation, an electronic TOF filter afforded a 2.92-fold reduction in scalp sensitivity over CW mode. With further optimization, the combination of TOF filtering with highly parallel detection in the 1060 nm range promises to improve depth sensitivity and signal-to-noise ratio of iDO in neuromonitoring applications.

SIGNIFICANCE/UNASSIGNED:Noninvasive optical measurements of blood flow have many applications. Measurements have been demonstrated with diffuse correlation spectroscopy (DCS), interferometric diffusing wave spectroscopy (iDWS), and speckle contrast optical spectroscopy (SCOS) techniques, but concurrent measurements with all three techniques in the same experiment have not been compared. AIM/UNASSIGNED:We aim to evaluate the comparative strengths and weaknesses of SCOS, iDWS, and DCS methods in controlled experiments. APPROACH/UNASSIGNED:arm cuff occlusion experiments using SCOS, iDWS, and DCS concurrently and in the same geometry. RESULTS/UNASSIGNED: CONCLUSIONS/UNASSIGNED:The experiments demonstrate the equivalency of absolute flow measures from iDWS and DCS and improved precision of pulsatile waveforms from SCOS. These results emphasize the need for rapid development and adoption of iDWS and SCOS.

Light speckle fluctuations provide a means for noninvasive measurements of cerebral blood flow index (CBFi). While conventional Diffuse Correlation Spectroscopy (DCS) quantifies these fluctuations to provide marginal brain sensitivity for CBFi in adult humans, new techniques have emerged to improve diffuse light throughput and brain sensitivity. Here we further optimize one such approach, interferometric diffusing wave spectroscopy (iDWS), with respect to the number of independent channels, camera duty cycle and full well capacity, incident laser power, noise and artifact mitigation, and data processing. We build the system on a cart and define conditions for stable operation. We show pulsatile CBFi monitoring at 4-4.5 cm source-collector separation in adults with moderate pigmentation (Fitzpatrick 4). We also report preliminary clinical measurements of patient CBFi in the Neuro Intensive Care Unit (Neuro ICU). These results push the boundaries of iDWS CBFi monitoring performance beyond previous reports.

A feature issue is being presented by a team of guest editors containing papers based on contributed submissions including studies presented at Optics and the Brain, held April 24-27, 2023 as part of Optica Biophotonics Congress: Optics in the Life Sciences, in Vancouver, Canada.

Blood flow index (BFI) is an optically accessible parameter, with unit distance-squared-over-time, that is widely used as a proxy for tissue perfusion. BFI is defined as the dynamic scattering probability (i.e. the ratio of dynamic to overall reduced scattering coefficients) times an effective Brownian diffusion coefficient that describes red blood cell (RBC) motion. Here, using a wavelength division multiplexed, time-of-flight- (TOF) - resolved iNIRS system, we obtain TOF-resolved field autocorrelations at 773 nm and 855 nm via the same source and collector. We measure the human forearm, comprising biological tissues with mixed static and dynamic scattering, as well as a purely dynamic scattering phantom. Our primary finding is that forearm BFI increases from 773 nm to 855 nm, though the magnitude of this increase varies across subjects (23% ± 19% for N = 3). However, BFI is wavelength-independent in the purely dynamic scattering phantom. From these data, we infer that the wavelength-dependence of BFI arises from the wavelength-dependence of the dynamic scattering probability. This inference is further supported by RBC scattering literature. Our secondary finding is that the higher-order cumulant terms of the mean squared displacement (MSD) of RBCs are significant, but decrease with wavelength. Thus, laser speckle and related modalities should exercise caution when interpreting field autocorrelations.