 He's written one of the best review articles available. His lab focuses on AMD and photoreceptor transduction pathways, and the residents have noted that even on Saturdays and Sundays, he's usually here long before we are, so he's considered one of the hardest working faculty that we've come across. So, and Dr. DeGree would like to just do a quick introduction to the talk as well. It's called Melanopsin, but I think the importance of this talk is that it's actually what has Melanopsin got to do with your life. And I think I hope by the end of this talk that you'll understand how Melanopsin is really changing the way we think about certain conditions in ophthalmology, but also how it affects our lives. And you can't imagine my absolute delight when Ng Ben Fu joined the faculty because we had been interested in Melanopsin as a transducer of information to the brainstem and participating in photophobia, and here he came with one of the very best reviews ever written on this topic. And so I went, we have got to do grand rounds sometime, but it's taken us about three years to get our act together to get us both in the same place. So Ng Ben, we're thrilled that you could join us today. My voice okay? So I think this is my first grand round presentation, and also most of the time I'm talking with the KTE, but I can hear you, I am excited to present in front of more of the MDs following me on a strong line, trying to with high dosage. So what I'm going to do today is to give you a review of the current understanding about the sensitivity of the red nail, the gut nail cells. And Cassin is going to talk about some really fascinating work about the function of the individual cells, especially the kind of part of the photophobia in migraines. So our legal system performs two essential functions. And one is to perform imaging functions, the other is to perform not imaging functions. The imaging function is created by laws and the code. And it has a high spatial and physical resolution. And if we allow our imaging objects to come to us, the non-mutiform vision will provide a measurement of anti-immuminance, but now the system to control a host of important visual functions. So the question is, are these two functions performed by the team? I'm going to search for the novel arcana for the receiver when it starts in the field of imaging now in a field that is internal for shooting. And this is very important to control your lot of visual and logical functions. And it has a lot of your 24-hour cycle. And in order for the internal force to do the donor day, it also comes out. And it also knows that the most important visual tool to set the internal force is the daily change of dose, amount of night, or irradiance at dawn and dusk. So you can already immediately see the performance function very different from the traditional and the dual function of the unit. So the eye are also being used as an interface between the environment of the donor day and the state unit because there's lots of evidence that this involves animal model implementation after removal of the dog's eye. You know the opportunity to perform the activity as the end of the circle as the end of the circle because so far the master is making a completely internal force. So it's very difficult to perform the activity as the form of the animal and the irradiance that relates to the eating from the dog. There are a few ways to perform the activity. So I think everybody in the field assumes, I think it's over actually over a hundred years, I assume that the dog and the home have told me that the dog is there in the red eye. However, there's more and more evidence, better than I think the dog is there. So the challenge is the dog and the home problem. For example, patients with severe dog and animal models in the R-D-I-D mouth who are very severe photoreseparate degenerates are pretty low and vulnerable by home. People are still reluctant to accept that there's additional costs for the receptors beside the dog in the home. They may come to argument that for this there is severe degeneracy. But what is the remaining field photoreseparates are capable of leading the response? And especially in the R-D-I-D mice, they still have some symptoms. In 1999, Dr. Foster showed that he believed that what he did was particularly R-D-I-D mice, which is another string of mice that has essentially been needed all the time for the receptors. So for R-D-I-D, there might be, for the Lord this is only my evidence, that I'm just going to leave it for you to follow. There's still a total disruption for the receptors of the R-D-I-D mice. But the R-D-I-D mice are still in the home. You may understand that animals are active in the dark space. They sleep in a light space. You believe there are costs of mice, they are just in your face. Also, these measurements are for another kind of non-minimum concrete. Pupillary light is in there. In the different areas, if you look at the cells, you can see why they are open in the dark. So the R-D-I-D mice also come in, although they have much higher light in the home. Pretty well. And the same group went ahead and measured spectrums in the region. This is what we need. We might have to consider whether to use it, to use it is a pupillary light reflect. And we found a P-489 in the penulonite ring. And it's very different from what we know in the rock. This is in the mouth of the P-489. The other part of the point is the u-ray component. The green in the u-ray region. So already from this kind of experiment in theory, it shows there's really indeed a cost for the receptors in the inner retina. So here it's really interesting because after this discovery, people become very careful because you cannot really call the mice a limitation or a result of a non-loader ring to nine for the cost. They have for the receptors in the ganglion cell. They perform many functions as a result of this. Another important thing that I think in the early days is what's uncommon for clinicians to re-involve the eyes of people with very severe photoreceptic generations because they seem to act as a source of infections. But they don't know, by doing so, they are really a very important part of photoreceptic. And I'm really more of an important person than I think I would have based on that in the years now. So then companies do it for a very important year. There's a series of elegant studies. Finally, they are down to identify those so-called intrinsic disorders in the retina ganglion cell. So this was one of the top 10 discoveries until the first experiment was done by a diverse person at Brown University. It's straightforward. You already know I need to be clear that there's about one person in the retina ganglion cell in the late at night, including an FDA. So what we did is we took the retina gene into that thing and then we took a transport into the ganglion cell. In doing so, for now, I think we find the ganglion cell. Then I can record the ganglion cell. So fortunately, I really put a sensitivity with our daughter. You can see, there's a recording on the whole cell. You can only read my ganglion cell. And even after a complete recording of your retina gene, we assume the first demonstration that there's sub-population ganglion cell actually to respond to that. On the other hand, some of these papers of science, the science editor, he made the publication for a whole year because they still don't believe this. So they worry this is something, this is something too new and evidence-less. Until another paper I will introduce it in the next few slides. But can we do a wide-out map at Hopkins with a genetic method, a low-calorie map of things and also looking at how many things. You can map the external projection of the cell into that thing. And the two paper published finally after one year struggle, slide by slide. And then the other thing is very interesting. Those cells are very different from the ones where life is cornered by the cells. There's a few digital machines on your planet and they are very similar with the whole research. And they are insulated for no life. It's just exactly what you expect as a security for the research. And there's MNA recording on the ganglion cell. The MNA basically marks the natural rays or the chip or the simultaneous record of hundreds of ganglion cells. This is important because those cells are very sparse. It's very difficult to find them in the ganglion cell. And this shows the total sparse in a wide-out map. It's really, really good as an encoder on that irradiance. On that, because they are also very similar to the internal light for non-time, it's really something very different because it's better than the regular irradiance So, the other thing very interesting is that they actually function much earlier than the other ones in memory. So, in the mouse, you have MNA, they will learn how to become medics. They function actually, their eyes are more open on the chip chip cell. But you feel apparently, eyes over, eyes over, they don't have more than the ganglion cells. So, that's very interesting indication of people that suggest actually doing pregnancy basically using the same strategy of laser, those ganglion cells to synchronize with outside sonar days, one before they go on and on. And also, those non-uniformifications actually are more easy in the immediate formulations. The other really important kind of layer down is the pigment in the system because in order for the detection of the eye on the retina, you really realize that in the food market, then you have the membrane structure and then you believe in the core. Then you have the base, and then you have the retinal. And then the strongest candidate is the menopause. So, it is for the first time from the general dilemma on the retina, the other surprising finding is that menopause is actually more similar to the menopause than menopause. And this is really important to express in as in projecting retina ganglion cells. So, in the last couple of months, we have impact in the non-uniformifications, for example, on the retinal, or to have impact in the treatment. So, this is a recording found by the other person. It will be the menopause that comes so high, but the menopause is more common in the retina. Unless, by using this real geometric measure, we need to map out the axonal projection. So, when it is looking at how the green market is the menopause, the axon fibers in the retina are too high in projection as in actually we see it by never in the region. And if you look at the retina, you can see the cells actually truly spark, about 1% of the ganglion cells. And finally, through the entire retina, and the people in the retina, this is very important. Remember, the light has passed through the ganglion cells first before reaching the rods and the cones. So, this is really spark, or not the light getting through the ganglion cells without interfering with the rods and the cone, the so-called image formulation. Because even if there are two dens, there are too much light, then the cone function will be affected. It is very smart and never designed. With the same technology or the genetic in the map of projection lucid, even number of women in the region and has a very important functional implication. These are the main and the major sites of prediction. That's in IGL, in the 60s and 20s, only were technically very important for preliminary construction. This is very interesting for the area of the 90s business. So, this is important for many sections I think has been talked about later. That's on my side, but what I wanted to think out is the actual critique is also a matter of making it financially important for the region. So, it's very interesting. And then also the real QO for the region. We have major innovation for the SIN, the dominant role for the security for the internet. The other thing, very important for preliminary nightly business in the non-continental and the very bright night the wire has come to this area when they have some trouble to come to it all the way anymore. So, they have been incomplete. They need many barriers so they seem to have a scene for the conflict in mechanism. And also it's about SIN recognition but this is pretty new finding. Let's see, that really comes to the back, three mechanisms one is about how much that means if you give me a wine, you change down the course. I mean, change the course in 24 hours, right? The other is course in the internet and let's talk about the life and in the malevolent non-continental where you can explore how much we are functional and they actually search the planet in the response to life so there's three. The epilogic word scrub is pretty bad. And after discovery of those we know how much we are self which is natural for children. So, okay, maybe there's another additional for the research that we read. This is addressed again, with a genetic approach by putting all three systems at a Y. So let's look for the triple non-continental life. There's a malevolent non-continental that is disabled. There's a malevolent non-continental that is disabled for something and there's a female non-continental that is disabled for something. So in triple non-continental you can say in the country that people with a wide open and really mouth-like that people with non-continental life, they don't respond to children. So that is real for 90 months. Now, what you see is a conflict against the active one. The conflict seems like very well to be dark like that in the United States. We don't want dark things that are active, but we don't want them. We are hungry very much. We don't care about dark and night things. So they lose the opportunity to synchronize to the outside. So, only such is that the new original photoreceptic system and this is actually reported on monkeys. So it's very similar to what happened to them. They just let out the included range of the three systems. The dark death of the three systems are abnormal. Light of death is in that normal photoreceptic system and the the kind of response. So that was the most interesting to do these things. There's only two items, and there's an overlap in that. I just briefly mentioned it's very interesting. I already mentioned that the non-continental were actually more similar to invertebrate pygmal. And when people start to work on the political conducting mechanism, they still under very active research that's more convenient on the field. But there are two major conducting mechanisms. One is to forget the marriage, which may be denied, but it's open now. And the other is very early in the world, on the phone. So the fly-wise, both use this for the treatment, but the fly-wise, the buy-stay treatment, of the CQM, of the PLC, of the M6 channel. A lot of things, the food treatment, of the CQM, that is the main couple for the CGMP, the Canon channel. So all the evidence so far suggests that those skills actually mean very great both in the mechanism. It's very, very fascinating. And then, I just read a very recent article, is the title is, may not be as good as in high-tech technology in human readiness. It's pretty interesting. And this, I just mentioned once, that it will come out very new. So I talk about immunity from the vision, non-immunity from the vision, the rodent point was IPRGC, but you know, I don't want to give you the idea that there will be rodent point for immunity from the vision, IPRGC for non-immunity from the vision, because they have certain overlaps. One example is here is that, you can see here, all the test samples of the immunity from the vision, that's also on the axon of the vision SCN, or you know, the non-immunity from the vision, the sensors are also in the vision, IPG, because you have to be able to see that everything is, you know, not really important sensors for immunity from the vision. So there's a, there's a water part in the bottom of the line, the physical and emotional part is there, only you can be self-accompanied. So the mind will now assume toward people's headphones that the two people are the managers of the team should succeed. You can perform pretty well without rodent point. So this, my tip on it is that it doesn't mean you can walk around without rodent point. That's not what it suggests. Well, it suggests those cells have some needs to go in moderate immunity from the vision, but rodent point is really a dominant one. So, this is also very new, but I don't want to mention to it, it has pretty important in the vision of the immunity. For example, for the recognition, my team had a IPG, and also the vision study is very interesting. In the RC patients, those cells are actually very resistant to degeneration, but in the coma patients, so in all human patients, in any coma that they found, they actually see that they have flaws. They actually are in this. I mean, of course they have serious disorders, children are in their next problem. Also, that the patient might not be seen, but they do not affect his orders. Most of them are here in early stages of the coma. In all the people, they have trouble to sleep, and one theory not emerging. This may be the main role in this marathon. I would go here. So, I think Nguyen has really brought us to a point here to understand that these cells are really different. They respond to blue light, to that superior chiasmatic nucleus, which really takes on an importance in our understanding of sleep and our circadian rhythms. I'm going to cover two aspects, because I won't have time to cover more, but I'm going to talk a little bit about light sensitivity and this finding of how melanopsin may actually interfere with pain and migraine. The supra-chiasmatic nucleus really affects our circadian rhythms. We've got photic and nonphotic or image and non-image clues. I'm going to briefly talk about the pupillary light reflex, and then I'm going to talk about how this pathway may actually interfere with pain and migraine. The first thing I want to talk about is photophobia. Brad Katz did a wonderful talk on photophobia and on blepharospasm and FL-41 tint, but I'm going to use this as light sensitivity with a sense of pain, because that's what our patients report when light hits their eyes, there is a sense of pain. It's been relegated into the functional diseases of the eye category and all the people that come in with sunglasses, they're told, oh boy, they're crazy in their clinic. Well, I'm going to hopefully by the end of this talk, at the end of this, you'll see that they're not completely crazy. We're very tuned into anterior causes of light sensitivity. I mean, today we heard about this corneal problem and his problem was photophobia, and we're cloning to the posterior causes when people have inflammation of the eye or if they have pain with eye movements of photophobia with optic neuritis. And there's certainly our brain causes of photophobia like meningitis and blepharospasm. And there's psychiatric causes of photophobia like agoraphobia and depression and then a host of other things can be with photophobia. We actually looked at all the cases of photophobia in our clinic here at Moran and migraine and dry eyes were the two most frequent. Migraine more in women, dry eyes both in men and women, and then a whole host of other conditions, trauma progressive super nuclear palsy which actually is a symptom of that disease. That's a Perkinsonian symptom depression. And we looked at children and children by and large did not get diagnosed for the cause of photophobia although migraine and dry eyes were still the most common. So the most common cause of photophobia in general is migraine and migraine has photophobia as one of its key features. So any of you who's had a migraine knows that light sensitivity with pain and it can accentuate your pain is key to the migraine experience. And almost and light can trigger people's migraine attacks and people with migraine are more light sensitive just in general than the normal population. We've shown that bluffer spasm patients have a similar light sensitivity and they have very poor light tolerance that's very similar to migraine headaches as well. So the question is why might melanopsin be involved in photophobia? And one of the things is that people who have very poor form vision actually can be severely light sensitive. Think about your patients with retinitis or ultrasound or cone dystrophy. Another line of evidence is that the melanopsin wavelength, as Ingebin has told us is 484 nanometers which is blue light. And if you do a spectrum of light for human beings blue light is the least comfortable light that people experience. And interestingly blue light activates different types of the brain and in this thing you can see that it's activating into the brainstem into the hippocampus, amygdala and thalamus. So there's something about this blue light that actually is very, very important. Now for years people thought in order to be light sensitive you had that vision. But in 1920 Sigward reported that in 46 patients he had three patients who had light sensitivity despite being blind. Then there was another series of light sensitivity and blind, painful eyes. And then the article that I'm going to spend a lot of time on by Rosetta and Mommy Burstein and Boston we were able to participate and actually have patients from my practice that had migraine were legally visually blind but had severe light sensitivity and we found that the people who had either their eyes were missing or they had absolutely no light perception they had no light sensitivity to migraine. But if they had any type of light perception they all had light sensitivity with their attacks. And interesting also the people who lost their eyes had these problems with their circadian rhythm the people who still had their eyes were able to continue to have circadian rhythm. So the answer is you don't need vision to be light sensitive. How would the discomfort occur? Well it has to come from the pain system that serves the brain and the eye which is the trigeminal system. And while we all learn in medical school that the trigeminal system I can't walk around and be too active. But as the trigeminal system this free branches the endemic division the maxillary division, the mandibular division but actually the trigeminal system also the first division supplies all the meninges of the brain and so that this system, this trigeminal system which goes also into the brainstem is really the pain forming pathway for the eye and for light sensitivity. Our current understanding of migraine is this that people inherit brains that are sensitive to light that there is this connection with the meninges that set off the use of neural tissues that affect blood vessels that then have afterments that go into the trigeminal system, go into the brainstem and the reason I'm telling you this is because this is going to be very reminiscent of what you're going to see in the melanopsin system and that we experience pain partly because of this meningeal dural afferent input into the trigeminal systems that then affect the trigeminal systems that then are, this is part of the trigeminal lupus caedale actually into the brainstem. So this paper which came out this spring was the first paper to demonstrate that these intrinsically photo sensitive ganglion cells actually connect to the trigeminal system in the brainstem and that there is this retinal phylamic pathway that goes to the pre-tectal region where these trigeminal afferents occur. Now this diagram looks a little bit confusing but it really isn't. So here what Dr. Burstein and his laboratory did was stimulate the dura and find the pain-sensitive areas of the dura. Then he put light in the eye of these laboratory animals and found there were certain cells that lit up just to light not to mechanical stimulation chemical stimulation or anything else just light. And then he was able to record in the brainstem, especially in this posterior phylamic area these areas that were both dural sensitive, meaning coming from the dura, the trigeminal system into the brainstem and light sensitive at the same time. And then he found some that were just dural sensitive and then he found some places that were insensitive to both light and sound. So these recordings showed us that these cells then connect in the and thalamus in this posterior thalamic region in these anesthetized animals. What was even more exciting is that the latency and the way these spikes occur are very characteristic of melanopsin firing. So look at this. Here comes the light on and it took a while for the spikes to start being generated but even after the light goes off the spikes keep coming and that's very typical of these melanopsin game-winning cells. It takes them a lot to get going but once they get going they do not do not. And so this really kind of correlates with our patients who get horribly light sensitive for whatever region they're firing and it's impossible to turn that light sensitivity off. Then anatomically he was able to show that the trigeminal nerve cells within this posterior thalamic area actually connected anatomically with the intrinsically light sensitive retinal ganglion cells so that there was actually axodendritic and axosomatic connections in this region so that there's actually an anatomic connection to the pain. Then he traced these cells to both the somatosensory parts of the brain and the visual parts of the brain. And then there were other cells that had some connections as well. And he put together this diagram where the intrinsically photosensitive retinal ganglion cells project via the optic nerve to this posterior thalamic region which also receives input from the trigeminal system and that these two can connect and then go to the cortex where people could actually experience pain, experience light sensitivity. And in this editorial that accompanied this article this is a very nice diagram that light goes in, that diagram I showed you of migraine. You can see how similar this is that these trigeminal this light sensitivity pathway is connecting with our trigeminal afference from the dura and shows a pathway whereby in migraine people can have their light sensitivity and pain actually worsened by light and that this is one of the keys to understanding migraine. So I would just say for photophobia this is a common symptom I think that it may not be the only pathway to the development of photophobia but it's certainly part of it and especially in these patients who have no form vision we know this has to be part of it and I'm sure that the rod and cone pathway is also connecting in some way to these trigeminal afference as well and Brad had a nice talk about using the FL-41 tint as a blue blocking lens to assist these people with photophobia. For the last couple of minutes I just want to mention and Ben also mentioned this about the pupillary constriction and some studies that have just come out this year and last year about melanopsin in the pupillary pathway. So if you shine light into somebody's eyes we get a constriction of the pupil. Well if you just watch carefully you'll see that this somewhat escapes so that the pupil constricts and then there's a little bit of an escape and then if you hold the light on there there's kind of a sustained pupillary constriction and then if you turn the light off the pupils will dilate. Well what was found was that they were trying to explain why would people have a pupillary light reflex if they had no rods and cones. And so these were some studies done by Randy Cardin that showed that if you just shine a red stimulus in somebody's eyes a normal person and a blue stimulus at different intensities you'll get different pupillary light reflexes. So if you shine a very weak stimulus you'll get a response in both in the pupillary light reflex but as you get to the stronger intensity light it's more sustained especially with the blue light. Now this case however really brought home that this melanopsin pathway must be working. So here's a case of a unilateral retinitis pigmentosa patient who had those different light intensity lights both red and blue stimulus shined into their eyes. In the normal eye they had a normal response just like I showed you on the previous slide. In the eye with the photoceptor regeneration the red light produced no pupillary constriction whatsoever. But the brightest blue light gave a nice sustained response and pupillary constriction. This actually was used by Randy Cardin at Iowa and several others in his group to show that probably you could almost divide up people's light response by colored light. So a light blue response is mainly the rod response high intensity red response is more cone and then this high intensity blue response is more melanopsin. So that we now know that the pupillary light reflex is not just input from rods and cones into the pre-tectal area but the melanopsin pathway is also playing a role. And it may help us understand phenomenon like the Flynn phenomenon where you turn the lights off and the pupil actually is constricted maybe it's this continuous melanopsin firing that can continue to constrict the pupil after you actually turn the lights off. And so we would like to we wanted this to link the basic science with our Flynn phenomenon and we'd like to turn the lights on and let Aynman come up here and answer questions about these intrinsically photoactive ganglion cells. Any questions? I mean I think this is really exciting work and it really is kind of like in the pupil world it sort of blew up all the pupil movements and in the light sensitivity world I think it's done the same, yeah. What is known about another light response path? Okay the photic sneeze response is somewhat it's an interesting when it goes to the brainstem and like photic blink it's part of the brainstem circuitry. I don't know if melanopsin is involved in the photic sneeze response. I mean I haven't seen those little mice in all their melanopsin see if they can sneeze or not. But that's another pathway but just like the phonic blink response which we know is involved with blepharospasm it's probably in that same brainstem area because sneezing comes out of the brainstem. Yeah. Well from a photophobia point of view I don't know yet. How about a molecular point of view? Can you think of a way that you could affect melanopsin on a molecular level if somebody were... But you don't want to wipe out your melanopsin cells you'll wipe out your circadian rhythm and as you get older you lose a lot of that anyway and... That's an interesting point because those ganglion cells are not homogeneous. I don't have time to talk about but they are fairly heterogeneous. They have five subclasses and each one has different sensitivities and even some more sensitivities so it's quite possible to use different sensitivities or monitor them with different kinds of sunglasses. I think it's possible. It's still early in time. But the other thing I want to raise up is that it's very interesting phenomenon I think we can do here in the Moran because every time when it works when eyes are dark or dept from movie theater the open eye is very painful. Every time the open eye in the bright night it's very painful. So I think the melanopsin act as mayor or euro in there. But how to dissect the melanopsin was a very common magnet is not occurred in disease but in everyday life when you work from dark place in a bright night it is painful. Conditional. It's still early what they know is they call M1, M2, M3 maybe an additional one but in both loading and primates so and then people also know each of them have very different sensitivities because M1 has highest sensitivity the sensitivity treatment is very high and then they project different subliminates of that IPL just above Gangnam cell so they have different emotional functions but they just come out maybe not here but it's very interesting. Okay thanks, thanks a lot. Do you know what your talk and my talk about this is about Alicia to get out of the intranet our internet, intranet What am I going to do with that under Is it under neuro or under retina? I will send it under retina but also put it under migraine under migraine and neuro so here is retina so let's see is there like a basic retinal anatomy and then under neuro put it under a chemo