Our bodies appear optically opaque because biological tissue scatters light strongly. Although advances such as multiphoton excitation have enabled deeper access for optical imaging by gating out scattered light, these strategies are still fundamentally limited to superficial depths (~ 1 mm). Yang's group at Caltech has pioneered time-reversal symmetry of optical scattering as a direct strategy to 'turn off'tissue scattering. n 2012, Yang's group demonstrated a time-reversal ultrasound-encoded (TRUE) focusing strategy based on the use of digital optical phase conjugation to flexibly and controllably deliver high optical power in ex vivo tissues. Here we propose to realize a digital TRUE focusing in vivo with rapid wavefront sensing and wavefront modulation. If successful, this novel approach will enable light focusing up to a depth of 4 mm in a living rodent brain, with a focal minimal width close to single-cell level (30 ?m). This ability to render a tight laser focus within biological tissues can be translated into powerful new methods for functional imaging and manipulation of the brain. We can scan the focus spot to perform fluorescence, Raman, and other types of imaging. We can also use the focus spot to selectively ablate tissues with high precision. This technology will also enable non-invasive focused light delivery for optogenetics - a key application area that is the focus of our proposed research. The use of digital TRUE would enable the extension of optogenetic techniques to the deep brain for non-invasive, spatially specific, excitation/inhibition. For this project, we will complement the power of optogenetic control of defined brain circuits with real-time circuit activity feedback, via in vivo anaesthetizd recordings, to establish digital TRUE as a new, noninvasive optical tool for optogenetic studies. This proposed work represents a powerful enabling technology for optogenetics - potentially opening up new applications and new methods for optogenetics. In addition to optogenetics, digital TRUE promises broader impacts on biomedical research and diagnosis. Digital TRUE's unique capability to focus light in deep tissues holds tremendous potential in enabling in vivo deep tissue optical imaging and biochemical analysis. Although there are significant technical challenges to be tackled, our proposed project is an important and necessary step in advancing TRUE to reach its full potential.

Public Health Relevance

We propose to implement a novel and fast time-reversal based deep tissue optical focusing method with the specific goal of enabling a new optogenetic format. This project will allow us to controllably and flexibly focus light through optically opaqu brain tissue to stimulate neurons. More broadly, the optical focus can be used to perform high-resolution deep brain imaging and serve as an incisionless optical cutting tool.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZNS1-SRB-G (77))
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Talley, Edmund M
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California Institute of Technology
Engineering (All Types)
Schools of Engineering
United States
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Ryu, Jihee; Jang, Mooseok; Eom, Tae Joong et al. (2016) Optical phase conjugation assisted scattering lens: variable focusing and 3D patterning. Sci Rep 6:23494
Brake, Joshua; Jang, Mooseok; Yang, Changhuei (2016) Analyzing the relationship between decorrelation time and tissue thickness in acute rat brain slices using multispeckle diffusing wave spectroscopy. J Opt Soc Am A Opt Image Sci Vis 33:270-5
Deverman, Benjamin E; Pravdo, Piers L; Simpson, Bryan P et al. (2016) Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol 34:204-9
Xiao, Cheng; Cho, Jounhong Ryan; Zhou, Chunyi et al. (2016) Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways. Neuron 90:333-47
Treweek, Jennifer B; Chan, Ken Y; Flytzanis, Nicholas C et al. (2015) Whole-body tissue stabilization and selective extractions via tissue-hydrogel hybrids for high-resolution intact circuit mapping and phenotyping. Nat Protoc 10:1860-96
Horstmeyer, Roarke; Ruan, Haowen; Yang, Changhuei (2015) Guidestar-assisted wavefront-shaping methods for focusing light into biological tissue. Nat Photonics 9:563-571
Wang, Daifa; Zhou, Edward Haojiang; Brake, Joshua et al. (2015) Focusing through dynamic tissue with millisecond digital optical phase conjugation. Optica 2:728-735
Ruan, Haowen; Jang, Mooseok; Yang, Changhuei (2015) Optical focusing inside scattering media with time-reversed ultrasound microbubble encoded light. Nat Commun 6:8968