Using ultrasound-guided optical wavefront shaping, the authors show enhanced optogenetic control in thick acute brain slices.

Optical scattering has traditionally limited the ability to focus light inside scattering media such as biological tissue. Recently developed wavefront shaping techniques promise to overcome this limit by tailoring an optical wavefront to constructively interfere at a target location deep inside scattering media. To find such a wavefront solution, a “guidestar” mechanism is required to identify the target location. However, developing guidestars of practical usefulness is challenging, especially in biological tissue, which hinders the translation of wavefront shaping techniques. Here, we demonstrate a guidestar mechanism that relies on magnetic modulation of small particles. This guidestar method features an optical modulation efficiency of 29% and enables micrometer-scale focusing inside biological tissue with a peak intensity-to-background ratio (PBR) of 140; both numbers are one order of magnitude higher than those achieved with the ultrasound guidestar, a popular guidestar method. We also demonstrate that light can be focused on cells labeled with magnetic particles, and to different target locations by magnetically controlling the position of a particle. Since magnetic fields have a large penetration depth even through bone structures like the skull, this optical focusing method holds great promise for deep-tissue applications such as optogenetic modulation of neurons, targeted light-based therapy, and imaging.

Focusing light inside scattering media in a freely addressable fashion is challenging, as the wavefront of the scattered light is highly disordered. Recently developed ultrasound-guided wavefront shaping methods are addressing this challenge, albeit with relatively low modulation efficiency and resolution limitations. In this paper, we present a new technique, time-reversed ultrasound microbubble encoded (TRUME) optical focusing, which can focus light with improved efficiency and sub-ultrasound wavelength resolution. This method ultrasonically destroys microbubbles, and measures the wavefront change to compute and render a suitable time-reversed wavefront solution for focusing. We demonstrate that the TRUME technique can create an optical focus at the site of bubble destruction with a size of ∼2 μm. We further demonstrate a twofold enhancement in addressable focus resolution in a microbubble aggregate target by exploiting the nonlinear pressure-to-destruction response of the microbubbles. The reported technique provides a deep tissue-focusing solution with high efficiency, resolution, and specificity.

For the past decade, optical wavefront shaping has been the standard technique to control light through scattering media. Implicit in this dominance is the assumption that manipulating optical interference is a necessity for optical control through scattering media. In this paper, we challenge this assumption by reporting on an alternate approach for light control through a disordered scattering medium – optical-channel-based intensity streaming (OCIS). Instead of actively tuning the interference between the optical paths via wavefront shaping, OCIS controls light and transmits information through scattering media through linear intensity operations. We demonstrate a set of OCIS experiments that connect to some wavefront shaping implementations, i.e. iterative wavefront optimization, digital optical phase conjugation, image transmission through transmission matrix, and direct imaging through scattering media. We experimentally created focus patterns through scattering media on a sub-millisecond timescale. We also demonstrate that OCIS enables a scattering medium mediated secure optical communication application.

The Time-Reversed Ultrasound-Encoded (TRUE) light technique enables noninvasive focusing deep inside scattering media. However, the time-reversal procedure usually has a low signal-to-noise ratio because the intensity of ultrasound-encoded light is intrinsically low. Consequently, the contrast and resolution of TRUE focus is far from ideal, especially in the backscattering geometry, which is more practical in many biomedical applications. To improve the light intensity and resolution of TRUE focus, we developed an iterative TRUE (iTRUE) light focusing technique that employs the TRUE focus itself as a signal source (rather than diffused light) for subsequent TRUE procedures. Importantly, this iTRUE technique enables light focusing in backscattering mode. Here, we demonstrate the concept by focusing light in between scattering layers in a backscattering configuration and show that the light intensity at the focus is progressively enhanced by a factor of ~20. By scanning across a fluorescent bead between these two scattering layers, the focusing resolution in the ultrasound axial and lateral directions was improved ~2-fold and ~3-fold, respectively. We further explored the application of iTRUE in biological samples by focusing light between 1 mm thick chicken tissue and cartilage, and light intensity enhancements of the same order were also observed.