Bi-modal structure/function optical RetinAl Imaging in Neurodegenerative diseaseS – BRAINS

The BRAINS project is based on the development of advanced optical imaging methods that enable the observation of the human retina at micrometer-scale resolution, in a non-invasive manner and in living subjects. The approaches developed aim to overcome the limitations of conventional ophthalmic imaging techniques, particularly in terms of resolution, acquisition speed, and access to functional information.

A first approach relies on full-field optical coherence tomography (full-field OCT). Unlike conventional scanning OCT systems, full-field OCT enables the simultaneous acquisition of information over a large field of view, with very high spatial resolution. This technique is particularly well suited for imaging fine retinal structures and for extracting functional information from rapid acquisitions compatible with clinical use.

In addition, the project developed a phase-contrast imaging approach, enabling the visualization of weakly scattering and translucent retinal structures. This contrast is essential for studying the retinal vascular network, as it allows detailed observation of blood vessel walls and the circulation of red blood cells, without the need for contrast agents or exogenous markers.

The combination of full-field OCT and phase contrast, together with advanced image processing methods, thus provides access to both structural and functional information on retinal neurons and blood vessels, while favoring rapid, robust, and non-invasive acquisitions. These methodological choices were guided by the objective of making these approaches compatible with clinical and translational studies.

The BRAINS project has led to major scientific and technological results in high-resolution retinal imaging, enabling access to structural and functional information that was previously difficult, or even impossible, to observe in vivo in humans.

Through the development of imaging systems based on full-field optical coherence tomography (full-field OCT), the project made it possible to visualize key retinal structures at micrometer-scale resolution, notably photoreceptors located near the center of the fovea, a region essential for fine vision, as well as retinal nerve fibers connecting the retina to the brain. The first images of retinal ganglion cells were also obtained in living humans, representing an important step toward the direct observation of neurons involved at early stages of neurodegenerative diseases.

A particularly significant result concerns functional imaging. The project enabled the measurement of photoreceptor activity in response to light stimulation over a field of view approximately 25 times larger than the state of the art, a first at this scale. The developed methods make it possible to obtain functional maps at the level of individual photoreceptors in just a few seconds, with analysis times compatible with clinical use.

The project also led to the development of an original phase-contrast imaging approach, enabling detailed visualization of retinal blood vessels and the circulation of red blood cells without the use of contrast agents. Using this method, the project demonstrated and characterized neurovascular coupling in the human retina, a mechanism that has long been debated in the scientific literature. This characterization was performed in several healthy volunteers as well as in a patient with glaucoma, opening new perspectives for studying the interactions between neuronal activity and blood circulation.

The results obtained within the BRAINS project open up important scientific and medical perspectives for high-resolution functional retinal imaging and its application to the study of neurodegenerative diseases.

A first perspective concerns the improvement and generalization of the developed technologies in order to make functional imaging of retinal neurons more robust and reproducible. The advances achieved provide a solid foundation for the development of new imaging modalities that are even more sensitive and stable, enabling reliable access to early neuronal biomarkers in humans.

A second major perspective focuses on the extension of retinal neurovascular coupling studies to larger and more diverse cohorts. The demonstrations carried out in healthy volunteers constitute an essential first step and pave the way for future clinical studies aimed at evaluating the potential of these functional markers for the early diagnosis and monitoring of neurodegenerative and ophthalmic diseases, notably Alzheimer’s disease and glaucoma.

In addition, the development of advanced image processing tools, particularly for the automated analysis of retinal vascular networks over large fields of view, represents a key perspective to facilitate data exploitation and enable large-scale studies, while reducing analysis time.

Finally, all the results obtained within the BRAINS project have contributed to structuring a new high-potential research direction, ensuring the continuity and amplification of the work initiated. These perspectives are part of a long-term research dynamic aimed at making the retina a true functional window into the brain, with expected benefits for biomedical research and clinical practice.

As part of the central nervous system, the retina can be used to assess neurodegenerative diseases, e.g. Alzheimer’s disease and Parkinson’s disease. Thanks to the optical properties of the eye, the retina is directly accessible to optical imaging with cellular resolution, suggesting that the retina is a window to neurodegenerative diseases. Hope lies in monitoring cellular scale early neurodegenerative disease manifestations in individual ganglion cells, neurons connecting the retina to the brain. Despite advances in clinical imaging technology, ganglion cells visualization in patients remains elusive due to their optical translucency, the presence of ocular aberrations which degrade image resolution, and involuntary eye motion. These properties make these neurons extremely challenging to image in patients, therefore requiring a clinical imaging system with unprecedented performance, combining three competing parameters: (i) high sensitivity (-90dB), (ii) high 3D resolution (<2µm), and (iii) high acquisition speed (>2000Hz).

The BRAINS project aims to overcome this technological challenge by developing a bi-modal structure/function optical interferometric imaging technique based on Full-Field Optical Coherence Tomography (FFOCT). Compared to the current clinical point-scanning OCT, the FFOCT takes speed and resolution to the next level, i.e. millisecond and subcellular scales. To reach the highest sensitivity possible in FFOCT, Adaptive Optics will be incorporated to correct for ocular aberrations in real-time, thus enhancing the signal-to-noise ratio by a factor of 100. The proposed advanced FFOCT clinical system will present capabilities well beyond the state-of-the-art, gathering all three key imaging parameters, thus finally revealing the structure of ganglion cells in patients at subcellular and millisecond scales. In addition, owing to the unequalled achieved performance in terms of sensitivity and resolution, I aim to probe, for the first time, the functional activity of individual ganglion cells. This remarkable information will enable to have access to the physiological condition of neurons in both qualitative and quantitative ways. Finally, I will take advantage of the built clinical imaging system and developed image processing methods to extract valuable structure and functional biomarkers at multiple scales, over a large field of view. Biomarker extraction will lift the final hurdles for using the retina as a window to neurodegenerative disease, opening new avenues for a better interpretation of the physiological condition of neurons, which is essential for an accurate and early diagnosis of neurodegenerative diseases and treatment monitoring.