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1700 nm optical coherence microscopy enables minimally invasive, label-free, in vivo optical biopsy deep in the mouse brain

Zhu, Jun; Freitas, Hercules Rezende; Maezawa, Izumi; Jin, Lee-Way; Srinivasan, Vivek J
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.
PMID: 34262015
ISSN: 2047-7538
CID: 4937532

Incoherent excess noise spectrally encodes broadband light sources

Kho, Aaron M; Zhang, Tingwei; Zhu, Jun; Merkle, Conrad W; Srinivasan, Vivek J
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.
PMCID:7538909
PMID: 33082941
ISSN: 2047-7538
CID: 4931862

Functional interferometric diffusing wave spectroscopy of the human brain

Zhou, Wenjun; Kholiqov, Oybek; Zhu, Jun; Zhao, Mingjun; Zimmermann, Lara L; Martin, Ryan M; Lyeth, Bruce G; Srinivasan, Vivek J
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.
PMCID:8115931
PMID: 33980479
ISSN: 2375-2548
CID: 4878402

Time-of-flight resolved light field fluctuations reveal deep human tissue physiology

Kholiqov, Oybek; Zhou, Wenjun; Zhang, Tingwei; Du Le, V N; Srinivasan, Vivek J
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.
PMCID:6971031
PMID: 31959896
ISSN: 2041-1723
CID: 4355842

From Soma to Synapse: Imaging Age-Related Rod Photoreceptor Changes in the Mouse with Visible Light OCT

Chauhan, Pooja; Kho, Aaron M; Srinivasan, Vivek J
PURPOSE/UNASSIGNED:Although the outer nuclear layer (ONL) and outer plexiform layer (OPL) each exhibit a complex internal organization, near-infrared OCT depicts both as monolithic bands. Here, using visible light OCT in the C57BL/6J mouse retina, sublaminar age-related changes in photoreceptor features were imaged and interpreted. These features were (1) oscillations in reflectivity, or striations, in the ONL and (2) a moderately reflective subband in the OPL. DESIGN/UNASSIGNED:Cross-sectional study. PARTICIPANTS/UNASSIGNED:Pigmented mice (C57BL/6J, n = 14). METHODS/UNASSIGNED:A 1.0-μm axial resolution visible light spectral/Fourier domain OCT system was used for in vivo retinal imaging. Light and electron microscopy were performed ex vivo. Linear mixed effects models or regression were employed for statistical analysis. MAIN OUTCOME MEASURES/UNASSIGNED:Comparison of OCT subbands with corresponding histological features, as well as quantification of subband thickness and reflectivity. RESULTS/UNASSIGNED:Corresponding histological comparisons confirm that striations in the ONL arise from the rowlike arrangement of photoreceptor nuclei and reveal that the moderately reflective OPL subband arises from rod spherules. Compression of outer ONL striations with age suggests changes in soma organization. Thinning of the moderately reflective OPL subband with age supports a reduction of synapses in the OPL. Critically, the ONL somas are tightly correlated with the purported spherule layer but not with the rest of the OPL. CONCLUSIONS/UNASSIGNED:Visible light OCT imaging of the mouse OPL resolves postsynaptic and synaptic differences. Visible light OCT can study rod photoreceptor changes from the soma to the synapse in the living mouse retina. FINANCIAL DISCLOSURES/UNASSIGNED:Proprietary or commercial disclosure may be found after the references.
PMCID:10302163
PMID: 37388138
ISSN: 2666-9145
CID: 5540552

Interferometric diffusing wave spectroscopy imaging with an electronically variable time-of-flight filter

Zhao, Mingjun; Zhou, Wenjun; Aparanji, Santosh; Mazumder, Dibbyan; Srinivasan, Vivek J.
Diffuse optics (DO) is a light-based technique used to study the human brain, but it suffers from low brain specificity. Interferometric diffuse optics (iDO) promises to improve the quantitative accuracy and depth specificity of DO, and particularly, coherent light fluctuations (CLFs) arising from blood flow. iDO techniques have alternatively achieved either time-of-flight (TOF) discrimination or highly parallel detection, but not both at once. Here, we break this barrier with a single iDO instrument. Specifically, we show that rapid tuning of a temporally coherent laser during the sensor integration time increases the effective linewidth seen by a highly parallel interferometer. Using this concept to create a continuously variable and user-specified TOF filter, we demonstrate a solution to the canonical problem of DO, measuring optical properties. Then, with a deep TOF filter, we reduce scalp sensitivity of CLFs by 2.7 times at 1 cm source-collector separation. With this unique combination of desirable features, i.e., TOF-discrimination, spatial localization, and highly parallel CLF detection, we perform multiparametric imaging of light intensities and CLFs via the human forehead.
SCOPUS:85152433292
ISSN: 2334-2536
CID: 5461112

Visible light optical coherence tomography reveals age-related photoreceptor changes in the mouse

Chapter by: Chauhan, Pooja; Kho, Aaron M.; Yiu, Glenn; Dang, Brian Q.; Srinivasan, Vivek J.
in: Progress in Biomedical Optics and Imaging - Proceedings of SPIE by
[S.l.] : SPIE, 2023
pp. ?-?
ISBN: 9781510658257
CID: 5501982

Dual-wavelength interferometric near-infrared spectroscopy (iNIRS)

Chapter by: Mazumder, Dibbyan; Kholiqov, Oybek; Srinivasan, Vivek J.
in: Bio-Optics: Design and Application in Proceedings Biophotonics Congress: Optics in the Life Sciences 2023, OMA, NTM, BODA, OMP, BRAIN 2023 by
[S.l.] : Optical Society of America, 2023
pp. ?-?
ISBN: 9781957171210
CID: 5662522

Decoding diffuse light scattering dynamics in layered tissues: path length versus fluctuation time scale

Aparanji, Santosh; Zhao, Mingjun; Srinivasan, Vivek J.
Dynamic multiple light scattering (DMLS) has found numerous applications, including soft matter physics and biomedical optics. Yet biological tissues may have complex internal geometries, presenting a challenge for noninvasive measurements. Deciphering laminar dynamics is crucial to accurately interpret tissue or organ physiology. Seminal DMLS work noted that one can probe deeper layers indirectly by analyzing light fluctuations on shorter time scales. Recent technologies have enabled probing deeper layers directly by analyzing fluctuations at longer path lengths. The following question arises: are the indirect and direct approaches synergistic or redundant? Here, by adding an optical switch to path-length-filtered interferometric diffusing wave spectroscopy, we experimentally address this question in the context of a forearm occlusion study. We find that both approaches afford better distinction of light scattering dynamics in layered tissues than either approach alone. This motivates further development of methods that integrate both decorrelation time scale and light path length to probe layered tissues.
SCOPUS:85178166023
ISSN: 0146-9592
CID: 5622922

Interferometric diffuse optics: recent advances and future outlook

Zhou, Wenjun; Zhao, Mingjun; Srinivasan, Vivek J
The field of diffuse optics has provided a rich set of neurophotonic tools to measure the human brain noninvasively. Interferometric detection is a recent, exciting methodological development in this field. The approach is especially promising for the measurement of diffuse fluctuation signals related to blood flow. Benefitting from inexpensive sensor arrays, the interferometric approach has already dramatically improved throughput, enabling the measurement of brain blood flow faster and deeper. The interferometric approach can also achieve time-of-flight resolution, improving the accuracy of acquired signals. We provide a historical perspective and summary of recent work in the nascent area of interferometric diffuse optics. We predict that the convergence of interferometric technology with existing economies of scale will propel many advances in the years to come.
PMCID:9587754
PMID: 36284601
ISSN: 2329-423x
CID: 5359422