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)
Project #
Application #
Study Section
Special Emphasis Panel (ZNS1-SRB-G (77))
Program Officer
Talley, Edmund M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
California Institute of Technology
Engineering (All Types)
Schools of Engineering
United States
Zip Code
Jang, Mooseok; Horie, Yu; Shibukawa, Atsushi et al. (2018) Wavefront shaping with disorder-engineered metasurfaces. Nat Photonics 12:84-90
Liu, Yan; Shen, Yuecheng; Ruan, Haowen et al. (2018) Time-reversed ultrasonically encoded optical focusing through highly scattering ex vivo human cataractous lenses. J Biomed Opt 23:1-4
Chan, Ken Y; Jang, Min J; Yoo, Bryan B et al. (2017) Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat Neurosci 20:1172-1179
Xu, Jian; Ruan, Haowen; Liu, Yan et al. (2017) Focusing light through scattering media by transmission matrix inversion. Opt Express 25:27234-27246
Ruan, Haowen; Brake, Joshua; Robinson, J Elliott et al. (2017) Deep tissue optical focusing and optogenetic modulation with time-reversed ultrasonically encoded light. Sci Adv 3:eaao5520
Qureshi, Muhammad Mohsin; Brake, Joshua; Jeon, Hee-Jae et al. (2017) In vivo study of optical speckle decorrelation time across depths in the mouse brain. Biomed Opt Express 8:4855-4864
Jang, M; Yang, C; Vellekoop, I M (2017) Optical Phase Conjugation with Less Than a Photon per Degree of Freedom. Phys Rev Lett 118:093902
Ruan, Haowen; Haber, Tom; Liu, Yan et al. (2017) Focusing light inside scattering media with magnetic-particle-guided wavefront shaping. Optica 4:1337-1343
Cua, Michelle; Zhou, Edward Haojiang; Yang, Changhuei (2017) Imaging moving targets through scattering media. Opt Express 25:3935-3945
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

Showing the most recent 10 out of 18 publications