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Phase-sensitive coherent imaging exploits changes in the phases of backscattered light to observe tiny alterations of scattering structures or variations of the refractive index. But moving scatterers or a fluctuating refractive index decorrelate the phases and speckle patterns in the images. It is generally believed that once the speckle pattern has changed, the phases are scrambled and any meaningful phase difference to the original pattern is removed. As a consequence, diffusion and tissue motion that cannot be resolved, prevent phase-sensitive imaging of biological specimens. Here, we show that a phase comparison between decorrelated speckle patterns is still possible by utilizing a series of images acquired during decorrelation. The resulting evaluation scheme is mathematically equivalent to methods for astronomic imaging through the turbulent sky by speckle interferometry. We thus adopt the idea of speckle interferometry to phase-sensitive imaging in biological tissues and demonstrate its efficacy for simulated data and imaging of photoreceptor activity with phase-sensitive optical coherence tomography. We believe the described methods can be applied to many imaging modalities that use phase values for interferometry.

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Imaging neuronal activity non-invasively in vivo is of tremendous interest, but current imaging techniques lack either functional contrast or necessary microscopic resolution. The retina is the only part of the central nervous system (CNS) that allows us direct optical access. Not only ophthalmic diseases, but also many degenerative disorders of the CNS go along with pathological changes in the retina. Consequently, functional analysis of retinal neurons could lead to an earlier and better diagnosis and understanding of those diseases. Recently, we showed that an activation of photoreceptor cells could be visualized in humans using a phase sensitive evaluation of optical coherence tomography data. The optical path length of the outer segments changes by a few hundred nanometers in response to optical stimulation. Here, we show simultaneous imaging of the activation of photoreceptor and ganglion cells. The signals from the ganglion cells are ten-fold smaller than those from the photoreceptor cells and were only visible using new algorithms for suppressing motion artifacts. This allowed us to generate a wiring diagram showing functional connections between photoreceptors and ganglion cells. We present a theoretical model that explains the observed intrinsic optical signals by osmotic volume changes, induced by ion influx or efflux. Since all neuronal activity is associated with ion fluxes, imaging osmotic induced size changes with nanometer precision should visualize activation in any neuron.