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Role of the pupil response in night vision

Role of the pupil response in night vision


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What are the things that affect the reaction time of pupil light reflex? What I mean to say is, if you are in a bright room, and the light suddenly turns off. The time you spend to see things in the room (i.e.., night vision) is the reaction time.


Short answer
Pupil responses have little effect on dark adaptation. It is the retinal processes that govern the bulk of the dynamic range of the eye's light sensitivity.

Background
You are referring to dark adaptation of the eye, which is, according to the Universty of Calgary:

This change is called dark adaptation and refers to the process by which the eye becomes more sensitive to light under conditions of reduced illumination. [C]ones are primarily responsible for resolving fine detail (acuity) and colour vision in good light, while rods allow us to see more effectively in dim lighting conditions. The recovery of sensitivity in dark adaptation involves the regeneration of photoreceptor photo-pigments as well as neural changes.

See figure 1. The rods are way faster in gaining sensitivity than the photon-hungry cones.

In a typical clinical setting for diagnostical purposes of e.g. rod function, a typical dark adaptation period is about 20 minutes or so, which fits the below graph quite well. At the end of dark adaptation, the eye is about 100,000 times (i.e., 5 log units) more sensitive than it was at the beginning of the test, a level called dark adapted sensitivity (Universty of Calgary).

In contrast, the pupil response has only a minor effect on light sensitivity in dark adaptation. It does change its diameter in the dark for sure, but the amount of light that passes through doesn't change too drastically. Pupil diameters range between about 2 and 8 mm (Spector, 1990), say a factor of four. In terms of surface we are talking about 3 and 50 mm2, respectively using (pi*r2), hence a factor of 16, as opposed to 5 orders of magnitude in the process of retinal adaptation.


Fig. 1. Light sensitivity adaptation of rods and cones. source: Uni Calgary

Reference
- Spector. The Pupils. In: Walker et al. (eds.) Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths (1990)


The pupil is the opening in the center of the iris (the structure that gives our eyes their color). The function of the pupil is to allow light to enter the eye so it can be focused on the retina to begin the process of sight.

Typically, the pupils appear perfectly round, equal in size and black in color. The black color is because light that passes through the pupil is absorbed by the retina and is not reflected back (in normal lighting).

If the pupil has a cloudy or pale color, typically this is because the lens of the eye (which is located directly behind the pupil) has become opaque due to the formation of a cataract. When the cloudy lens is replaced by a clear intraocular lens (IOL) during cataract surgery, the normal black appearance of the pupil is restored.

There&aposs another common situation when the pupil of the eye changes color — when someone takes your photo using the camera&aposs flash function. Depending on your direction of gaze when the photo is taken, your pupils might appear bright red. This is due to the intense light from the flash being reflected by the red color of the retina. [Read more about red eyes in photos and how to avoid them.]


The Institute for Creation Research

Certain gecko lizards can see color in dim light. That means these geckos&rsquo eyes are about 350 times more sensitive than human eyes, which see only black and white in the same conditions. Can evolution account for the origin of the remarkable machinery that enables these nocturnal creatures to see so well?

Scientists studying the helmet gecko&rsquos eyes found distinct concentric zones, each with a different refractive power. Geckos also have a much higher density of oversized cone cells in their retinas that are responsible for detecting specific light wavelengths. In their study published in the Journal of Vision, the researchers found that together, these zones and cones form a &ldquomultifocal optical system.&rdquo Furthermore, the refractive powers of their lens array &ldquois of the same magnitude as needed to focus light of the wavelength range to which gecko photoreceptors are most sensitive.&rdquo 1 Thus, the various parts of this gecko&rsquos eyes are finely tuned to work together, allowing the animal to sharply focus on at least two different depth fields at the same time.

In addition to seeing color in the dark, the geckos have built-in correctional abilities for blurred images caused by longitudinal chromatic aberration, or the failure to focus all colors to the same point. Studying these features in gecko eyes may offer clues to improving camera technology. 2

The authors of the study asserted that &ldquoat some point in evolution a group of lizards, the geckos, turned to a nocturnal lifestyle. In response to the demands of nocturnal vision without rods, the cones of nocturnal geckos have become much larger and more light&ndashsensitive than those of their diurnal relatives.&rdquo 1 However, there is no evidence that the mere presence of an environmental demand can cause the coordinated physiological changes required to bridge the differences between monofocal eyes and this gecko&rsquos multifocal, supersensitive eyes. Nor is there any evidence that mutations can do anything but corrupt existing genetic information, the opposite process to what is needed to invent the required whole sets of genetic material that specify the various interdependent parts that comprise these eyes.

Also, many creatures are successful night hunters without color vision. This indicates that the nighttime environment alone is an insufficient cause for developing these particular gecko eyes, which apparently did not &ldquoneed&rdquo to exist for survival. Indeed, other nocturnal geckos have monofocal eyes like humans, and they have survived quite well without major changes. 3

There is strong evidence that evolution by mutations could not possibly build these amazing eyes. 4 A more feasible explanation involves the creative power and genius of God, who on day six of the creation week implemented all of the design requirements for nocturnal helmet geckos with their specialized visual system.

  1. Roth, L. S. V. et al. 2009. The pupils and optical systems of gecko eyes. Journal of Vision. 9 (3): 27, 1-11.
  2. &ldquoGecko Vision&rdquo: Key to the Multifocal Contact Lens of the Future? The Association for Research in Vision and Ophthalmology press release, May 11, 2009.
  3. Thomas, B. Fossilized Gecko Fits Creation Model. ICR News. Posted on icr.org September 8, 2008, accessed May 8, 2009.
  4. Sanford, J. et al. 2008. Mendel&rsquos Accountant: A New Population Genetics Simulation Tool for Studying Mutation and Natural Selection. Proceedings of the Sixth International Conference on Creationism. Pittsburgh, PA: Creation Science Fellowship, and Dallas, TX: Institute for Creation Research, 87-98.

* Mr. Thomas is Science Writer at the Institute for Creation Research.


A Sixth Sense, and Beyond

April 2007--Hearing, sight, smell, taste and touch. Growing up, we all learned about the five tools we use to perceive the outside world. While this pentad clearly plays a principal part in processing the abundance of stimuli surrounding us, it’s not the whole story. We also rely on senses that detect more subtle changes, and within the IBBS Center for Sensory Biology, Hopkins researchers are deciphering these less renowned, but no less vital, systems.

One such system resides in the retina, behind the rods and cones that enable us to see in vivid color by day and find the bathroom at night. There, neurons known as ganglion cells connect the eyes to the brain. While most ganglion cells link to the centers of image-forming vision, a small subset travels to the hypothalamus—the center of our circadian clock.

For years, scientists believed that the hypothalamus processed light information from the rods and cones to reset the clock as needed, as when we adjust to new time zones. “The intriguing thing about that,” says neuroscience professor King-Wai Yau , “is that some blind people can still overcome jetlag.”

To solve this circadian mystery, Yau, along with former postdoc and now Hopkins professor Samer Hattar and student Hsi-Wen “Rock” Liao, poked around mouse retinal ganglion cells and found that about 1 percent contain melanopsin, a pigment that enables these cells to absorb light just like rods and cones. These photosensitive ganglion cells are the same subset that connects to the brain regions not involved in image-forming vision.

Like a light meter on photography equipment, Yau notes, photosensitive ganglion cells relay the amount of ambient light to the brain so it can sync up our internal clock when we fly to Europe, for example, or constrict the aperture of our pupils in response to bright light.

Both Yau and Hattar continue to study these photosensitive ganglion cells to better understand how they develop, how they work and how they evolved. “Evolutionarily, these cells are more similar to most photoreceptors in lower animals than to our own rods and cones,” says Yau.

The resemblance, he notes, arises from the fact that the photosensitive ganglion cells appear to convert light energy to nerve signals by means of a cellular signaling pathway more akin to that found in lower animals. It has also been suggested that these cells may function through proteins known as TRP channels, gates on the plasma membrane that, in lower animals such as flies, open up when triggered by light and let in a wave of sodium and calcium ions. Regular vision operates on a different signaling pathway, using protein gates called cyclic-nucleotide-gated ion channels.

Fellow sensory scientist Michael Caterina knows all about TRP channels, as they play a pivotal role in his studies of heat sensation. When we transition from the comforts of an air-conditioned house to a sweltering summer day, specialized nerves in our skin report this change to the brain. They do so with the help of temperature-responsive TRP channels that act as tiny molecular thermometers. “We have a whole series of TRP temperature sensors, each calibrated to open at a different temperature,” Caterina says, “ranging from bitter cold to fiery hot.”

Caterina has been exploring how these thermosensors relate to classical pain/touch receptors one TRP channel that responds to extreme heat (above 42 C) also responds to capsaicin, the chemical that gives chili peppers their “kick” (and explains why spicy foods are associated with burning).

“Some of these sensory nerves are pulling double duty by sensing both heat and pain,” Caterina says, “but we also find some segregation.” For example, most pain nerves activate regions of the brain that direct us to pull our hands away from a hot stovetop, but other heat- and cold-sensitive nerves send signals to the hypothalamus, which processes these temperature readings to adjust subconscious heat responses like sweating.

Caterina has also found that some skin cells, not the nerves intermingled with them, contain heat channels triggered to respond to modest temperature increases (between 30 and 40 C). “We think of our skin as just a physical barrier to the outside world, but now it seems that it might also be a first-line responder to encroaching heat,” he says, “warning us that things are about to get uncomfortable.”

The parallel themes permeating Caterina’s and Yau’s work apply to most sensory systems, notes Craig Montell , who discovered the first TRP channel in fruit flies many years ago. “Back then, I didn’t think that one protein would explode into a whole field,” he says. “But we now know that these channels exist in animals from worms to people and are involved in every sense. And this use of similar ion channels is just one example of the intriguing similarities underlying the different senses.”


The pupil near response

Profile

The pupil near response (PNR), also called the pupil near reflex, is the constriction of the pupil in response to looking at a nearby object, and the dilation of the pupil in response looking at a far-away object. The PNR is certainly the least studied, and perhaps the least understood of all pupil responses. The profile of the PNR, shown in Figure ​ Figure5, 5 , is similar to that of the pupil light response (PLR).

The profile of a typical pupil near response. This figure shows data of myself while I’m shifting gaze from a far-away to a nearby point (prompted by an auditory cue at 0 s) and back again (prompted by another auditory cue at 10 s N = 10 trials). The x axis indicates time since the onset of the auditory cue to shift gaze. The y axis indicates pupil size as a proportion of pre-stimulus pupil size. Errors bars reflect the standard error. All data shown in this figure and others is available through the URL provided at the end of the article.

In the example data, again from myself, shown in Figure ​ Figure5, 5 , the PNR is elicited by an auditory cue at 0 s to shift gaze from far (଒ m) to near (ଐ.1 m), and a second auditory cue at 10 s to shift back from near to far. This shift of gaze was such that, except for vergence eye movements, eye position did not change. The profile of the resulting PNR looks as follows:

[Far to near] 0𠄰.6s: This is the latency period of the PNR, relative to the cue onset. This time comprises both the time it takes to process the cue and to shift focus from far to near, and the latency of the PNR proper.

[Far to near] 0.6s𠄲s: The pupil constricts strongly until it reaches its minimum size.

[Far to near] 2s�s: The pupil remains fully constricted. There is no notable pupil escape in the PNR.

[Near to far] 10s�s: The pupil recovers to its original size. This redilation is slower than the constriction however, it is faster than the redilation after a light response (see Figure ​ Figure4 4 ).

The near triad

The PNR is part of three eye movements, the near triad, that usually (but not necessarily, e.g. Stakenburg, 1991) occur together (Mays & Gamlin, 1995 McDougal & Gamlin, 2008). Besides the PNR, the near triad includes: vergence, the inward rotation of the eyes to look at something nearby and the outward rotation of the eyes to look at something far away and accomodation, the curving of the eye’s lens to focus on a nearby object and the flattening of the lens to focus on a far-away object.

Neural basis

The output pathway of the PNR is the same as that of the PLR, projecting from the Edinger-Westphal nucleus (EWN) to the iris sphincter muscle (see Figure ​ Figure3a). 3a ). However, unlike the PLR, the PNR does not appear to be driven directly by a subcortical pathway, but rather by cortical projections to the EWN (McDougal & Gamlin, 2008). Which cortical areas are involved in the PNR is not entirely clear however, there are projections from the frontal eye fields (FEF) and parietal cortex to the EWN that are involved in vergence movements (Gamlin, 2002). Because of the strong association between vergence and the PNR, and the central role of the EWN in pupil constriction, it is possible that these projections also play a role in the PNR.

Cognitive influences

To my knowledge, only two studies have directly investigated cognitive influences on the PNR: one published study by Enright (1987) and one of our own studies that we are currently finalizing (Van der Mijn & Mathôt, 2017). The results of these studies are interesting yet puzzling, and more research is certainly needed.

Enright (1987) asked participants to look at two-dimensional drawings of three-dimensional boxes (i.e. drawings that conveyed a sense of perspective). Participants viewed these drawings monocularly, with one eye covered. Participants fixated either on the corner of the box that appeared nearby, or on the corner that appeared far away. Even though the drawing was in a single plane, participants nevertheless made vergence movements as if they looked at the nearby or far-away corner of a real three-dimensional box. But there were no corresponding pupil-size changes: the pupil was not smaller when participants looked at the nearby corner, indicating that vergence was not accompanied by a PNR.

However, the results were very different when participants viewed so-called Neckercubes. A Neckercube is an ambiguous box-like drawing, in which the same corner can be perceived as either nearby or far away. Participants looked at this corner, and indicated whether they subjectively perceived it as the nearby or far-away corner. The results for vergence movements were more-or-less the same as for the regular box drawings (although slightly weaker), but vergence was now accompanied by exceptionally large pupil responses: the pupil was smaller when the corner was subjectively nearby as compared to when it was subjectively far away. However, while the direction of the effect was consistent with a PNR, the size of the effect was unrealistically large, casting doubt on whether it truly was a PNR, or rather an artifact of some unrecognized confound.

In one of our own experiments (Van der Mijn & Mathôt, 2017), we used a setup consisting of three separate displays: a central fixation display at an intermediate distance, a display on the left that was nearby, and a display on the right that was far away (or vice versa). Participants either covertly attended to the nearby or far-away display (while keeping gaze on the central display), or, in a different condition, made an eye movement to the nearby or far-away display. In the covert-attention condition, we found that pupil size did not change as a function of whether participants covertly attended to the nearby or far-away display this suggests that, unlike the PLR (e.g. Binda et al., 2013a Mathôt et al., 2013), the PNR is not modulated by covert shifts of attention. In the eye-movement condition, we found that the pupil responded to the distance of the to-be-looked-at display, and, importantly, did so with an extremely low latency this is reminiscent of the effect of eye-movement preparation on the PLR (Ebitz et al., 2014 Mathôt et al., 2015b). However, these results should be interpreted with caution, because distance is related to other factors that might also affect pupil size, such as brightness and size (i.e. from a retinal point of view, nearby things are generally brighter and larger than far-away things).

In conclusion, it is unclear whether the PNR is affected by cognitive influences. Results from the, as far as I know, only two studies that have investigated this issue suggest that, if cognitive influences on the PNR exist, they are likely smaller than similar influences on the PLR (Enright, 1987 Van der Mijn & Mathôt, 2017).

Function

The main function of the PNR is likely to increase depth of field for near vision. As described in the section on the PLR, you can see sharply across a wider range of distances with a small pupil than you can with a large pupil (Campbell, 1957 Charman & Whitefoot, 1977). The reason that a large depth of field is especially useful for near vision, is that depth of field is much smaller for nearby than far-away objects that is, you can simultaneously and sharply see two objects at ten and eleven meters distance, but you cannot simultaneously and sharply see two objects at half and one-and-a-half meters distance.


Eye-Opener: Why Do Pupils Dilate in Response to Emotional States?

What do an orgasm, a multiplication problem and a photo of a dead body have in common? Each induces a slight, irrepressible expansion of the pupils in our eyes.

For more than a century scientists have known that our eyes' pupils respond to more than changes in light. They also betray mental and emotional commotion. In fact, pupil dilation correlates with arousal so consistently that researchers use pupil size, or pupillometry, to investigate a wide range of psychological phenomena. And they do this without knowing exactly why our eyes behave this way.

"Nobody really knows for sure what these changes do," says Stuart Steinhauer, director of the Biometrics Research Lab at the University of Pittsburgh School of Medicine. He views the dilations as a by-product of the nervous system processing important information.

The visual cortex in the back of the brain assembles the actual images we see. But a different, older part of the nervous system&mdashthe autonomic&mdashmanages the continuous tuning of pupil size (along with other involuntary functions such as heart rate and perspiration). Specifically, it dictates the movement of the iris to regulate the amount of light that enters the eye, similar to a camera aperture. The iris is made of two types of muscle: a ring of sphincter muscles that encircle and constrict the pupil down to a couple of millimeters across to prevent too much light from entering and a set of dilator muscles laid out like bicycle spokes that can expand the pupil up to eight millimeters&mdashapproximately the diameter of a chickpea&mdashin low light.

Stimulation of the autonomic nervous system's sympathetic branch, known for triggering "fight or flight" responses when the body is under stress, induces pupil dilation. Whereas stimulation of the parasympathetic system, known for "rest and digest" functions, causes constriction. Inhibition of the latter system can therefore also cause dilation. The size of the pupils at any given time reflects the balance of these forces acting simultaneously.

The pupil response to cognitive and emotional events occurs on an even smaller scale than the light reflex, with changes generally less than half a millimeter. By recording subjects' eyes with infrared cameras and controlling factors that might affect pupil size, such as ambient brightness, color and distance, scientists can use pupil movements as a proxy for other processes, like mental strain.

Princeton University psychologist Daniel Kahneman showed several decades ago that pupil size increases in proportion to the difficulty of a task at hand. Calculate nine times 13 and your pupils will dilate slightly. Try 29 times 13 and they will widen further and remain dilated until you reach the answer or stop trying. Kahneman says in his book, Thinking Fast and Slow, that he could divine when someone gave up on a multiplication problem simply by watching for pupil contraction during the experiment.

"The pupils reflect the extent of mental effort in an incredibly precise way," Kahneman said in an interview with the German news magazine Der Spiegel, adding, "I have never done any work in which the measurement is so precise." When he instructed subjects to remember and recite a series of seven digits, their pupils grew steadily as the numbers were presented one by one and shrunk steadily as they unloaded the digits from memory.

Subsequent research found that the pupils of more intelligent people (as defined by their Scholastic Aptitude Test scores) dilated less in response to cognitive tasks compared with those of lower-scoring participants, indicating more efficient use of brainpower.

Scientists have since used pupillometry to assess everything from sleepiness, introversion and sexual interest to race bias, schizophrenia, moral judgment, autism and depression. And whereas they haven't been reading people's thoughts per se, they've come pretty close.

"Pupil dilation can betray an individual's decision before it is openly revealed," concluded a 2010 study led by Wolfgang Einhäuser-Treyer, a neurophysicist at Philipps University Marburg in Germany. Participants were told to press a button at any point during a 10-second interval, and their pupil sizes correlated with the timing of their decisions. Dilation began about one second before they pressed the button and peaked one to two seconds after.

But are pupils informative outside the lab? Can pupil size be used to "read" a person's intentions and feelings? According to Men's Health magazine a man can tell when it is "time to make your move" by watching his date's pupils, but some skepticism is warranted. "It is unclear to me to what extent this can be exploited in completely unrestrained settings," Einhäuser-Treyer wrote in an e-mail, pointing out that light conditions could easily interfere with amateur attempts at interpersonal pupillometry.

Other efforts to exploit pupil dilations for purposes beyond scientific research have failed. During the Cold War, Canadian government officials tried to develop a device they called the "fruit machine" to detect homosexuality among civil service employees by measuring how the pupils in their eyes responded to racy images of women and men. The machine, which never worked, was to aid the government's purge of gay men and lesbians from the civil service and thereby purportedly reduce vulnerability to Soviet blackmail.

A pupil test for sexual orientation remains as unlikely as it was in the 1960s. Researchers at Cornell University recently showed that sexual orientation correlated with pupil dilation to erotic videos of their preferred gender, but only on average and only for male subjects. Although pupillometry shows promise as a noninvasive measure of sexual response, they concluded, "not every participant&rsquos sexual orientation was correctly classified" and "an observable amount of variability in pupil dilation was unrelated to the participant's sexual orientation."

Pupillometry also became popular in the advertising industry during the 1970s as a way to test consumers' responses to television commercials, says Jagdish Sheth, a marketing professor at Emory University. But the practice was eventually abandoned. "There was no scientific way to establish whether it measured interest or anxiety," Sheth says.

Despite these limitations, pupillometry is a valuable tool for psychological research, says Pittsburgh's Steinhauer, because our eyes are easy to observe as well as provide a sensitive indicator of cognitive, emotional and sensory response. "It's like having an electrode permanently implanted in the brain," he says. "And all we can do is watch the change at the end. We can't monitor everything going into it."

This article is provided by Scienceline, a project of New York University's Science, Health and Environmental Reporting Program.

ABOUT THE AUTHOR(S)

Joss is the video production intern at Scientific American and a graduate student in the Science, Health and Environmental Reporting program at New York University. Follow on twitter at @jossfong


Blind humans lacking rods and cones retain normal responses to nonvisual effects of light

In addition to allowing us to see, the mammalian eye also detects light for a number of "non-visual" phenomena. A prime example of this is the timing of the sleep/wake cycle, which is synchronized by the effects of light on the circadian pacemaker in the hypothalamus.

In a study published online on December 13th in Current Biology, researchers have identified two totally blind humans whose non-visual responses to light remain intact, suggesting that visual and non-visual responses to light are functionally distinct. Indeed, this separation was suggested by earlier studies in mice that demonstrated that circadian rhythms and other non-visual responses remain sensitive to light in the absence of rods and cones, the two photoreceptor types that are responsible for vision.

It turns out that mammals have an additional light-sensitive photoreceptor in the retinal ganglion cell layer (pRGCs) that is directly sensitive to light and is primarily responsible for mediating these responses. These cells are most sensitive to short-wavelength light with a peak sensitivity at

480 nm, in the visible blue light range. While these studies and others in sighted subjects suggested that this non-rod, non-cone photoreceptor might play an important role in human photoreception, this had yet to demonstrated unequivocally until now.

To address whether the cells identified in rodents and primates also exist in humans, Zaidi and colleagues first had to find patients who lacked functional rods and cones, but retained pRGCs--a formidable task, given that fewer than 5% of totally blind people are thought to retain this response.

This group of researchers was able to identify two such rare patients, allowing them to perform a series of complementary experiments to address whether non-visual responses are possible in the absence of rods and cones and to determine the most effective wavelength, or color, of light that induced a response. In the first patient, the effect of light on melatonin secretion was examined. Melatonin is a hormone produced at night that influences arousal and is secreted in a cyclic fashion. Just like sighted individuals, the blind patient exhibited acute suppression of melatonin in response to light and was most sensitive to blue-light exposure.

Furthermore, blue light also shifted the timing of the circadian pacemaker and improved alertness, as measured by subjective scales, auditory reaction time, and changes in brain activity. While a few rods and/or cones may remain, Zaidi and colleagues have strong evidence to show that they contribute little, if at all, to these effects. Thus the authors were able to show that the effects were maximal in response to wavelengths of light that the retinal ganglion cells respond best to, and not the wavelength that the visual system detects best.

In the second patient, a different a set of tests was administered to assess the effects of light. First, the pupil-constriction response to various wavelengths and intensities of light was examined. Consistent with the major role of the pRGCs in mediating this response, pupillary contriction was stimulated most by blue light (

480 nm), the wavelength that pRGCs are most stimulated by.

Given that the non-visual responses to light appeared to be intact in this patient, the researchers were prompted to ask whether some minimal awareness of light might still be retained despite the inability to detect any response to light by conventional measures and the patient's inability to see light. Remarkably, the patient was able to tell that the blue light, but not any other color, was switched on, demonstrating that the pRGCs also contribute to our ability to "see" light.

These results have a number of important implications for human vision and vision-related diseases. First, they suggest humans possess light-sensitive cells, apart from rods and cones, that are important for non-visual light responses such as the entrainment of circadian rhythms and elevating arousal and brain activity. Second, this information may change how injuries to the eye are treated.

For example, surgeons might want to think twice about removing a damaged eye that still possesses functioning pRGCs, given the important physiological role that these cells play in maintaining normally timed sleep. We will now need to begin to think about these additional functions of the human eye, and consider not just vision, but also how light affects sleep, alertness, performance, and human health. The remarkable discovery of a novel photoreceptor in the mammalian eye has shed new light on an organ that has been studied for thousands of years.

The researchers include Farhan H. Zaidi, Division of Neuroscience and Mental Health Faculty of Medicine, Imperial College London, London, UK Joseph T. Hull, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA Stuart N. Peirson, Nuffield Laboratory of Ophthalmology, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK Katharina Wulff, Nuffield Laboratory of Ophthalmology, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK Daniel Aeschbach, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA Joshua J. Gooley, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA George C. Brainard, Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA Kevin Gregory-Evans, Division of Neuroscience and Mental Health Faculty of Medicine, Imperial College London, London, UK Joseph F. Rizzo III, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Charles A. Czeisler, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA Russell G. Foster, Nuffield Laboratory of Ophthalmology, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK Merrick J. Moseley, Department of Optometry and Visual Science, City University, London, UK and Steven W. Lockley, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


There’s more to vision than meets the eye

For years, science teachers have explained to their students that the eye is like a camera: The lens allows light to enter the eye, and the retina — like film — processes images and allows us to see.

In spite of how well that metaphor works, it’s probably time for an update. For one thing, as we plunge deeper into the digital age, fewer children will know what film is (c.f. record albums, eight-track tapes and black rotary phones). There’s also a key piece missing in the comparison. Most cameras also have light meters, and recent research suggests that the eye’s “light meter” is involved in more than just vision.

Some blind patients, as well as some blind animals, still show pupil constriction in response to light (see Figure). Recent work by the Van Gelder lab, in close collaboration with researchers at Novartis Gene Research Foundation, has shown the protein melanopsin is critical to these non-visual light responses.

A light meter cannot form images, but it can determine how bright the environment is. In a camera, that information helps the photographer determine how to set the shutter speed and whether to use a flash. In the eye, that information is used for a lot more.

“Brightness information is used in brain systems below the level of consciousness,” says Russell N. Van Gelder, M.D., Ph.D., assistant professor of ophthalmology and visual sciences and of molecular biology and pharmacology at Washington University School of Medicine in St. Louis. “These systems help synchronize your sleep/wake cycle, reset your internal body clock to jet lag if you travel across time zones, control the pupil of your eye and how it responds to light, and regulate the release of hormones such as melatonin.”

Van Gelder and others have been studying the “light meter” system in the eye, and they have learned that this non-visual system continues to gather and use information about light even in animals that otherwise are visually blind.

“The non-visual system has a job to do whether or not the animal can see,” he says. “The eye is still capable of controlling certain non-visual functions, and research conducted over the years leads us to believe that’s also true in humans.”

A study conducted at Harvard Medical School in the 1990s demonstrated one of those non-visual functions in humans. The researchers studied patients who were so blind that they could not tell when a bright light was shining into their eyes. The researchers measured the blood for levels of the hormone melatonin, which normally peak at night, but drop quickly if lights are turned on.

Melatonin levels decreased in some of the blind patients when they were exposed to light, even though they couldn’t see that light. But when the researchers blindfolded these patients and then turned on the lights, melatonin levels did not drop. Those findings suggest that although their eyes could not sense light in the normal way, they still were somehow regulating the release of melatonin, providing evidence that the eyes are involved in functions other than vision.

The retina’s primary visual system consists of photoreceptor cells in the retina called rods and cones, which convert light signals into nerve impulses processed in the brain. The non-visual system relies on different kinds of cells called intrinsically photosensitive retinal ganglion cells (ipRG cells). These cells don’t appear to be involved in vision, but they are directly light sensitive and play a crucial role in other functions.

Photoreception in the retina begins with light striking a photopigment molecule. Light induces a chemical change in the photopigment, which then is amplified into a signal the photoreceptor cell uses to communicate. Van Gelder is one of several scientists working to identify the photopigments that ipRG cells use.

In a study published earlier this year in the journal Science, his team reported that a family of proteins called cyptochromes are important in the pupil’s response to light in blind mice.

“First, we showed that blind mice lacking cryptochrome lost about 99 percent of their light sensitivity compared to mice that could see and about 90 percent of their light sensitivity compared to blind mice that still could make cryptochrome,” Van Gelder says.

They demonstrated the importance of cryptochrome by exposing blind mice to light. Although the mice could not see, their pupils of their eyes changed size in response to light. It took about 10 times more light to make pupils constrict in blind mice with cryptochrome than in mice that could see. In mice without cryptochrome, it took 100 times more light.

In the months following that discovery, Van Gelder and colleagues from the Novartis Gene Research Institute, the Uniformed Services University and other centers demonstrated that mice lacking a second protein called melanopsin were even worse off than those without cryptochrome. They reported in a subsequent issue of Science that visually blind mice without melanopsin lost all pupillary responses and had other problems, too.

“These mice not only are blind, they also are circadianly blind, meaning they can’t synchronize their behavior to the day/night transition,” Van Gelder says. “It appears melanopsin is absolutely required for the regulation of that function.”

The work supports the notion that the eye is responsible for more than just vision, that it regulates functions such as circadian rhythms, pupillary responses and hormone secretion. Those functions are very important in animals. For example in sheep, levels of the hormone vary with the season and help the animals breed at the appropriate time of year.

At present, melatonin is the only hormone linked directly to this system, but Van Gelder believes others also may interact with the eye’s light meter. The stress hormone cortisol, for example, is released by the adrenal glands every morning. The regulation of this hormone can be disrupted in mice that carry mutations in so-called clock genes, and Van Gelder is investigating whether mice without melanopsin or cryptochrome experience similar disruptions.

“If you’re blind, you probably think that although you have no vision, everything else should be fine,” Van Gelder says. “But if you lose this second system, you might be at risk for other serious problems.”

One of those problems might be a heart attack. For reasons not well understood, most heart attacks occur between 4 and 6 o’clock in the morning. Van Gelder says the body’s circadian clock somehow interacts with other systems to influence risk. It’s possible, he says, that by controlling the release of hormones, this non-visual system in the eye plays a role.

Another group at risk for loss of the non-visual system is patients with the eye disease glaucoma, which affects at least two million Americans and is the leading cause of blindness in African Americans. Glaucoma targets retinal ganglion cells like the ones that make melanopsin and cryptochrome. In severe cases, patients can lose 90 to 95 percent of their retinal ganglion cells. That could affect their ability to sense light with the non-visual system that Van Gelder and colleagues have been studying.

“We need to determine whether patients in the early stages of glaucoma show signs that they’re losing this second system,” he says. “If so, it’s possible they should be treated more aggressively.”

Panda S, Provencio I, Tu DC, Pires SS, Rollagg MD, Castrucci AM, Pletcher, MT, Sato TK, Wiltshire T, Andahazy M, Kay SA, Van Gelder RN, Hogenesch JB. Melanopsin is required for non-image-forming photic responses in blind mice. Science, 301: 525-527: published online June 26, 2003 10.1126/science 1086179.

Van Gelder RN, Wee R, Lee JA, Tu DC. Reduced pupillary light responses in mice lacking cryptochromes. Science, p. 222, Jan. 10, 2003.

This research was funded by the Novartis Research Foundation, the National Institute of Mental Health, Research to Prevent Blindness, the Association of University Professors of Ophthalmology, the Culpepper Medical Scientist Award, the National Eye Institute, the American Cancer Society and the Fundacáo de Amparo à Pesquisa do Estado de São Paulo.


Blind Humans Lacking Rods And Cones Retain Normal Responses To Non-visual Effects Of Light

In addition to allowing us to see, the mammalian eye also detects light for a number of "non-visual" phenomena. A prime example of this is the timing of the sleep/wake cycle, which is synchronized by the effects of light on the circadian pacemaker in the hypothalamus.

Researchers have identified two totally blind humans whose non-visual responses to light remain intact, suggesting that visual and non-visual responses to light are functionally distinct. Indeed, this separation was suggested by earlier studies in mice that demonstrated that circadian rhythms and other non-visual responses remain sensitive to light in the absence of rods and cones, the two photoreceptor types that are responsible for vision.

It turns out that mammals have an additional light-sensitive photoreceptor in the retinal ganglion cell layer (pRGCs) that is directly sensitive to light and is primarily responsible for mediating these responses. These cells are most sensitive to short-wavelength light with a peak sensitivity at

480 nm, in the visible blue light range. While these studies and others in sighted subjects suggested that this non-rod, non-cone photoreceptor might play an important role in human photoreception, this had yet to demonstrated unequivocally until now.

To address whether the cells identified in rodents and primates also exist in humans, Zaidi and colleagues first had to find patients who lacked functional rods and cones, but retained pRGCs--a formidable task, given that fewer than 5% of totally blind people are thought to retain this response.

This group of researchers was able to identify two such rare patients, allowing them to perform a series of complementary experiments to address whether non-visual responses are possible in the absence of rods and cones and to determine the most effective wavelength, or color, of light that induced a response. In the first patient, the effect of light on melatonin secretion was examined. Melatonin is a hormone produced at night that influences arousal and is secreted in a cyclic fashion. Just like sighted individuals, the blind patient exhibited acute suppression of melatonin in response to light and was most sensitive to blue-light exposure.

Furthermore, blue light also shifted the timing of the circadian pacemaker and improved alertness, as measured by subjective scales, auditory reaction time, and changes in brain activity. While a few rods and/or cones may remain, Zaidi and colleagues have strong evidence to show that they contribute little, if at all, to these effects. Thus the authors were able to show that the effects were maximal in response to wavelengths of light that the retinal ganglion cells respond best to, and not the wavelength that the visual system detects best.

In the second patient, a different a set of tests was administered to assess the effects of light. First, the pupil-constriction response to various wavelengths and intensities of light was examined. Consistent with the major role of the pRGCs in mediating this response, pupillary contriction was stimulated most by blue light (

480 nm), the wavelength that pRGCs are most stimulated by.

Given that the non-visual responses to light appeared to be intact in this patient, the researchers were prompted to ask whether some minimal awareness of light might still be retained despite the inability to detect any response to light by conventional measures and the patient's inability to see light. Remarkably, the patient was able to tell that the blue light, but not any other color, was switched on, demonstrating that the pRGCs also contribute to our ability to "see" light.

These results have a number of important implications for human vision and vision-related diseases. First, they suggest humans possess light-sensitive cells, apart from rods and cones, that are important for non-visual light responses such as the entrainment of circadian rhythms and elevating arousal and brain activity. Second, this information may change how injuries to the eye are treated.

For example, surgeons might want to think twice about removing a damaged eye that still possesses functioning pRGCs, given the important physiological role that these cells play in maintaining normally timed sleep. We will now need to begin to think about these additional functions of the human eye, and consider not just vision, but also how light affects sleep, alertness, performance, and human health. The remarkable discovery of a novel photoreceptor in the mammalian eye has shed new light on an organ that has been studied for thousands of years.

This study was published online on December 13th in Current Biology.

The researchers include Farhan H. Zaidi, Division of Neuroscience and Mental Health Faculty of Medicine, Imperial College London, London, UK Joseph T. Hull, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA Stuart N. Peirson, Nuffield Laboratory of Ophthalmology, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK Katharina Wulff, Nuffield Laboratory of Ophthalmology, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK Daniel Aeschbach, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA Joshua J. Gooley, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA George C. Brainard, Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA Kevin Gregory-Evans, Division of Neuroscience and Mental Health Faculty of Medicine, Imperial College London, London, UK Joseph F. Rizzo III, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Charles A. Czeisler, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA Russell G. Foster, Nuffield Laboratory of Ophthalmology, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK Merrick J. Moseley, Department of Optometry and Visual Science, City University, London, UK and Steven W. Lockley, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.

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Blind humans lacking rods and cones retain normal responses to nonvisual effects of light

In addition to allowing us to see, the mammalian eye also detects light for a number of "non-visual" phenomena. A prime example of this is the timing of the sleep/wake cycle, which is synchronized by the effects of light on the circadian pacemaker in the hypothalamus.

In a study published online on December 13th in Current Biology, researchers have identified two totally blind humans whose non-visual responses to light remain intact, suggesting that visual and non-visual responses to light are functionally distinct. Indeed, this separation was suggested by earlier studies in mice that demonstrated that circadian rhythms and other non-visual responses remain sensitive to light in the absence of rods and cones, the two photoreceptor types that are responsible for vision.

It turns out that mammals have an additional light-sensitive photoreceptor in the retinal ganglion cell layer (pRGCs) that is directly sensitive to light and is primarily responsible for mediating these responses. These cells are most sensitive to short-wavelength light with a peak sensitivity at

480 nm, in the visible blue light range. While these studies and others in sighted subjects suggested that this non-rod, non-cone photoreceptor might play an important role in human photoreception, this had yet to demonstrated unequivocally until now.

To address whether the cells identified in rodents and primates also exist in humans, Zaidi and colleagues first had to find patients who lacked functional rods and cones, but retained pRGCs--a formidable task, given that fewer than 5% of totally blind people are thought to retain this response.

This group of researchers was able to identify two such rare patients, allowing them to perform a series of complementary experiments to address whether non-visual responses are possible in the absence of rods and cones and to determine the most effective wavelength, or color, of light that induced a response. In the first patient, the effect of light on melatonin secretion was examined. Melatonin is a hormone produced at night that influences arousal and is secreted in a cyclic fashion. Just like sighted individuals, the blind patient exhibited acute suppression of melatonin in response to light and was most sensitive to blue-light exposure.

Furthermore, blue light also shifted the timing of the circadian pacemaker and improved alertness, as measured by subjective scales, auditory reaction time, and changes in brain activity. While a few rods and/or cones may remain, Zaidi and colleagues have strong evidence to show that they contribute little, if at all, to these effects. Thus the authors were able to show that the effects were maximal in response to wavelengths of light that the retinal ganglion cells respond best to, and not the wavelength that the visual system detects best.

In the second patient, a different a set of tests was administered to assess the effects of light. First, the pupil-constriction response to various wavelengths and intensities of light was examined. Consistent with the major role of the pRGCs in mediating this response, pupillary contriction was stimulated most by blue light (

480 nm), the wavelength that pRGCs are most stimulated by.

Given that the non-visual responses to light appeared to be intact in this patient, the researchers were prompted to ask whether some minimal awareness of light might still be retained despite the inability to detect any response to light by conventional measures and the patient's inability to see light. Remarkably, the patient was able to tell that the blue light, but not any other color, was switched on, demonstrating that the pRGCs also contribute to our ability to "see" light.

These results have a number of important implications for human vision and vision-related diseases. First, they suggest humans possess light-sensitive cells, apart from rods and cones, that are important for non-visual light responses such as the entrainment of circadian rhythms and elevating arousal and brain activity. Second, this information may change how injuries to the eye are treated.

For example, surgeons might want to think twice about removing a damaged eye that still possesses functioning pRGCs, given the important physiological role that these cells play in maintaining normally timed sleep. We will now need to begin to think about these additional functions of the human eye, and consider not just vision, but also how light affects sleep, alertness, performance, and human health. The remarkable discovery of a novel photoreceptor in the mammalian eye has shed new light on an organ that has been studied for thousands of years.

The researchers include Farhan H. Zaidi, Division of Neuroscience and Mental Health Faculty of Medicine, Imperial College London, London, UK Joseph T. Hull, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA Stuart N. Peirson, Nuffield Laboratory of Ophthalmology, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK Katharina Wulff, Nuffield Laboratory of Ophthalmology, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK Daniel Aeschbach, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA Joshua J. Gooley, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA George C. Brainard, Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA Kevin Gregory-Evans, Division of Neuroscience and Mental Health Faculty of Medicine, Imperial College London, London, UK Joseph F. Rizzo III, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Charles A. Czeisler, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA Russell G. Foster, Nuffield Laboratory of Ophthalmology, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK Merrick J. Moseley, Department of Optometry and Visual Science, City University, London, UK and Steven W. Lockley, Division of Sleep Medicine, Brigham and Women's Hospital, Boston, MA, USA, and Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.

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