“The basis of this work began with a clinical observation,” explained Dr. Aguirre. “Some patients with dysfunction of their rod and cone photoreceptors get migraines – and bright light makes it worse. And this was an enduring mystery. Without functioning photoreceptors, which cells were sensing light and making these headaches worse?”
These questions pointed towards a third class of light-sensing cells, which were reported in a series of papers by researchers at Brown University and Johns Hopkins University between 1999 and 2002. These researchers found that a small subset of retinal ganglion cells (RGCs) express a photopigment called melanopsin that can detect light. Melanopsin is involved in the constriction of the pupil in response to bright light, as well as regulation of the circadian clock, but its full functionality is not yet understood.
Around five years ago, Drs. Brainard and Aguirre began their collaboration to better understand how “melanopsin-containing RGCs” act in humans. Their first task was to figure out how to isolate and stimulate melanopsin and cone cells separately. This task was particularly difficult because melanopsin responds to blue light, so any light that stimulates melanopsin would also trigger cone cells that respond to this region of the spectrum.
After several months of development, Drs. Brainard and Aguirre successfully deployed a device that precisely controls the intensity of 56 bands of the visible spectrum of light. Using a processcalled “silent substitution,” they shined blue-green light (triggering melanopsin and cone cells) and subtracted off red light (triggering only cone cells) in a carefully balanced manner—ultimately leaving an isolated melanopsin signal. This discovery allowed Drs. Brainard and Aguirre to study what we “see” with melanopsin alone.
Using this technique, they began conducting experiments to investigate if (and how) melanopsin affects brain signals. They measured the visual cortex response to melanopsin-stimulating light via fMRI, which is a non-invasive MRI technology that detectsbrain function. To their surprise, Drs. Brainard and Aguirre initially found that a melanopsin light, flickering at rates typical of normal vision, does not produce a brain response. After this initial study was published in the Journal of Neuroscience, however, they extended their methods to study much slower stimulation, at temporal frequencies closer to what would be appropriate for control of the circadian clock and the pupil. Their preliminary finding is that this slow melanopsin stimulus does drive the visual cortex. “This brain response serves as a clue that these cells do not just affect circadian rhythms; they may also affect how you see,” explained Dr. Brainard.
In addition to exploring how melanopsin affects brain signals, Drs. Brainard and Aguirre are studying how healthy people actually see melanopsin. “In all of us—even those with normal sight—is part of what you perceive when you see being supplied by melanopsin cells? Do they influence what things look like?” asked Dr. Aguirre. To test this theory, healthy volunteers wereexposed to the melanopsin-stimulating light. They were then asked questions about how bright it looked, if it hurt, and so on. These results are currently submitted for publication, but Dr. Aguirre did reveal that “there are some hints that melanopsin looks like brightness.” The investigators are also examining the opposite situation: what cones cells perceive without melanopsin.
A future aim of this work is to provide benefit for patients with photophobia. As mentioned above, melanopsin contributes to the expansion and contraction of the pupil in response to changes in light intensity. Thus, a malfunctioning melanopsin system may contribute to conditions that involve sensing too much or too little light, such as migraine, concussion, insomnia, or seasonal affective disorder.
Drs. Brainard and Aguirre’s next steps will be to recruit patients with light sensitivity for their studies. “We plan to make the same measurements as in our previous studies and find out if people with light sensitivity have different melanopsin function,” said Dr. Aguirre. If this is the case, future studies could examine genetic variants of the melanopsin photopigment that may lead to these differences.
Patients with dysfunction in their rods or cones could also be positively impacted by this research. In some blinding conditions, patients lose function of their photoreceptors, while their RGCs are spared. “Some of these patients can still sense light – and one theory is that they still detect light because melanopsin cells are still working,” said Dr. Aguirre.
In support of this theory, Dr. Artur Cideciyan, a Research Professor of Ophthalmology and colleague of Drs. Brainard and Aguirre, recently showed that some patients with severe rod and cone dysfunction still have a pupil response to light, which is likely due to melanopsin (published in Investigative Ophthalmology & Visual Science). This data is valuable, as it can serve as an indicator that RGCs are still functioning and can transmit a signal from the retina to the brain. In the future, this information could be used to help select patients who would derive the greatest benefit from gene therapy clinical trials for photoreceptor disorders.
In a similar way, measures of melanopsin response could also be used as a clinical tool to evaluate the degree of RGC damage in diseases such glaucoma (in which RGCs degenerate). This information could help diagnose or pinpoint the severity of such diseases.
Look out for more publications in the coming year on what Dr. Aguirre calls “the additional feature of the visual system that adds to what we perceive of the world.”