Posted on by Dr. Francis Collins
Each morning, more than 2 million Americans start their rise-and-shine routine by remembering to take their eye drops. The drops treat their open-angle glaucoma, the most-common form of the disease, caused by obstructed drainage of fluid where the eye’s cornea and iris meet. The slow drainage increases fluid pressure at the front of the eye. Meanwhile, at the back of the eye, fluid pushes on the optic nerve, causing its bundled fibers to fray and leading to gradual loss of side vision.
For many, the eye drops help to lower intraocular pressure and prevent vision loss. But for others, the drops aren’t sufficient and their intraocular pressure remains high. Such people will need next-level care, possibly including eye surgery, to reopen the clogged drainage ducts and slow this disease that disproportionately affects older adults and African Americans over age 40.
Sally Baxter, a physician-scientist with expertise in ophthalmology at the University of California, San Diego (UCSD), wants to learn how to predict who is at greatest risk for serious vision loss from open-angle and other forms of glaucoma. That way, they can receive more aggressive early care to protect their vision from this second-leading cause of blindness in the U.S..
To pursue this challenging research goal, Baxter has received a 2020 NIH Director’s Early Independence Award. Her research will build on the clinical observation that people with glaucoma frequently battle other chronic health problems, such as high blood pressure, diabetes, and heart disease. To learn more about how these and other chronic health conditions might influence glaucoma outcomes, Baxter has begun mining a rich source of data: electronic health records (EHRs).
In an earlier study of patients at UCSD, Baxter showed that EHR data helped to predict which people would need glaucoma surgery within the next six months . The finding suggested that the EHR, especially information on a patient’s blood pressure and medications, could predict the risk for worsening glaucoma.
In her NIH-supported work, she’s already extended this earlier “Big Data” finding by analyzing data from more than 1,200 people with glaucoma who participate in NIH’s All of Us Research Program . With consent from the participants, Baxter used their EHRs to train a computer to find telltale patterns within the data and then predict with 80 to 99 percent accuracy who would later require eye surgery.
The findings confirm that machine learning approaches and EHR data can indeed help in managing people with glaucoma. That’s true even when the EHR data don’t contain any information specific to a person’s eye health.
In fact, the work of Baxter and other groups have pointed to an especially important role for blood pressure in shaping glaucoma outcomes. Hoping to explore this lead further with the support of her Early Independence Award, Baxter also will enroll patients in a study to test whether blood-pressure monitoring smart watches can add important predictive information on glaucoma progression. By combining round-the-clock blood pressure data with EHR data, she hopes to predict glaucoma progression with even greater precision. She’s also exploring innovative ways to track whether people with glaucoma use their eye drops as prescribed, which is another important predictor of the risk of irreversible vision loss .
Glaucoma research continues to undergo great progress. This progress ranges from basic research to the development of new treatments and high-resolution imaging technologies to improve diagnostics. But Baxter’s quest to develop practical clinical tools hold great promise, too, and hopefully will help one day to protect the vision of millions of people with glaucoma around the world.
 Machine learning-based predictive modeling of surgical intervention in glaucoma using systemic data from electronic health records. Baxter SL, Marks C, Kuo TT, Ohno-Machado L, Weinreb RN. Am J Ophthalmol. 2019 Dec; 208:30-40.
 Predictive analytics for glaucoma using data from the All of Us Research Program. Baxter SL, Saseendrakumar BR, Paul P, Kim J, Bonomi L, Kuo TT, Loperena R, Ratsimbazafy F, Boerwinkle E, Cicek M, Clark CR, Cohn E, Gebo K, Mayo K, Mockrin S, Schully SD, Ramirez A, Ohno-Machado L; All of Us Research Program Investigators. Am J Ophthalmol. 2021 Jul;227:74-86.
 Smart electronic eyedrop bottle for unobtrusive monitoring of glaucoma medication adherence. Aguilar-Rivera M, Erudaitius DT, Wu VM, Tantiongloc JC, Kang DY, Coleman TP, Baxter SL, Weinreb RN. Sensors (Basel). 2020 Apr 30;20(9):2570.
Glaucoma (National Eye Institute/NIH)
Video: Sally Baxter (All of Us Research Program)
Sally Baxter (University of California San Diego)
Baxter Project Information (NIH RePORTER)
NIH Director’s Early Independence Award (Common Fund)
NIH Support: Common Fund
Posted on by Dr. Francis Collins
Recently, I’ve highlighted just a few of the many amazing advances coming out of the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. And for our grand finale, I’d like to share a cool video that reveals how this revolutionary effort to map the human brain is opening up potential plans to help people with disabilities, such as vision loss, that were once unimaginable.
This video, produced by Jordi Chanovas and narrated by Stephen Macknik, State University of New York Downstate Health Sciences University, Brooklyn, outlines a new strategy aimed at restoring loss of central vision in people with age-related macular degeneration (AMD), a leading cause of vision loss among people age 50 and older. The researchers’ ultimate goal is to give such people the ability to see the faces of their loved ones or possibly even read again.
In the innovative approach you see here, neuroscientists aren’t even trying to repair the part of the eye destroyed by AMD: the light-sensitive retina. Instead, they are attempting to recreate the light-recording function of the retina within the brain itself.
How is that possible? Normally, the retina streams visual information continuously to the brain’s primary visual cortex, which receives the information and processes it into the vision that allows you to read these words. In folks with AMD-related vision loss, even though many cells in the center of the retina have stopped streaming, the primary visual cortex remains fully functional to receive and process visual information.
About five years ago, Macknik and his collaborator Susana Martinez-Conde, also at Downstate, wondered whether it might be possible to circumvent the eyes and stream an alternative source of visual information to the brain’s primary visual cortex, thereby restoring vision in people with AMD. They sketched out some possibilities and settled on an innovative system that they call OBServ.
Among the vital components of this experimental system are tiny, implantable neuro-prosthetic recording devices. Created in the Macknik and Martinez-Conde labs, this 1-centimeter device is powered by induction coils similar to those in the cochlear implants used to help people with profound hearing loss. The researchers propose to surgically implant two of these devices in the rear of the brain, where they will orchestrate the visual process.
For technical reasons, the restoration of central vision will likely be partial, with the window of vision spanning only about the size of one-third of an adult thumbnail held at arm’s length. But researchers think that would be enough central vision for people with AMD to regain some of their lost independence.
As demonstrated in this video from the BRAIN Initiative’s “Show Us Your Brain!” contest, here’s how researchers envision the system would ultimately work:
• A person with vision loss puts on a specially designed set of glasses. Each lens contains two cameras: one to record visual information in the person’s field of vision; the other to track that person’s eye movements enabled by residual peripheral vision.
• The eyeglass cameras wirelessly stream the visual information they have recorded to two neuro-prosthetic devices implanted in the rear of the brain.
• The neuro-prosthetic devices process and project this information onto a specific set of excitatory neurons in the brain’s hard-wired visual pathway. Researchers have previously used genetic engineering to turn these neurons into surrogate photoreceptor cells, which function much like those in the eye’s retina.
• The surrogate photoreceptor cells in the brain relay visual information to the primary visual cortex for processing.
• All the while, the neuro-prosthetic devices perform quality control of the visual signals, calibrating them to optimize their contrast and clarity.
While this might sound like the stuff of science-fiction (and this actual application still lies several years in the future), the OBServ project is now actually conceivable thanks to decades of advances in the fields of neuroscience, vision, bioengineering, and bioinformatics research. All this hard work has made the primary visual cortex, with its switchboard-like wiring system, among the brain’s best-understood regions.
OBServ also has implications that extend far beyond vision loss. This project provides hope that once other parts of the brain are fully mapped, it may be possible to design equally innovative systems to help make life easier for people with other disabilities and conditions.
Age-Related Macular Degeneration (National Eye Institute/NIH)
Macknik Lab (SUNY Downstate Health Sciences University, Brooklyn)
Martinez-Conde Laboratory (SUNY Downstate Health Sciences University)
Show Us Your Brain! (BRAIN Initiative/NIH)
NIH Support: BRAIN Initiative
Posted on by Dr. Francis Collins
The retina, like this one from a mouse that is flattened out and captured in a beautiful image, is a thin tissue that lines the back of the eye. Although only about the size of a postage stamp, the retina contains more than 100 distinct cell types that are organized into multiple information-processing layers. These layers work together to absorb light and translate it into electrical signals that stream via the optic nerve to the brain.
In people with inherited disorders in which the retina degenerates, an altered gene somewhere within this nexus of cells progressively robs them of their sight. This has led to a number of human clinical trials—with some encouraging progress being reported for at least one condition, Leber congenital amaurosis—that are transferring a normal version of the affected gene into retinal cells in hopes of restoring lost vision.
To better understand and improve this potential therapeutic strategy, researchers are gauging the efficiency of gene transfer into the retina via an imaging technique called large-scale mosaic confocal microscopy, which computationally assembles many small, high-resolution images in a way similar to Google Earth. In the example you see above, NIH-supported researchers Wonkyu Ju, Mark Ellisman, and their colleagues at the University of California, San Diego, engineered adeno-associated virus serotype 2 (AAV2) to deliver a dummy gene tagged with a fluorescent marker (yellow) into the ganglion cells (blue) of a mouse retina. Two months after AAV-mediated gene delivery, yellow had overlaid most of the blue, indicating the dummy gene had been selectively transferred into retinal ganglion cells at a high rate of efficiency .