 already introduce you to the basic structure of the ear and eyes. So, in this lecture what I will try to do is that I will just go do a recap in the form like you know initially when I showed you I will just drew all the figures of the hair cells or the rods and the cones. So, in this lecture I will give you the actual picture like I have collected all these from different journals and I will give you all the references please go through them and eventually we will be talking about how this actually this hearing prosthesis or the cochlear implants or the camera in front of the eyes are being fit ok. So, to start off with so, there are there will be two classes which I will be taking consecutively this is this will be the section of the implants man machine interface and the implants and all those things ok. So, the title of this class is biology of hearing and the cochlear implant this is part one there will be then eventually we will move on to the vision and then we will move on to the brain. So, this is the reference I wish all of you to kind of consult the cell biology of hearing by martin Schwendler and kashir and muller this was published in journal of cell biology in the volume 190 part one rather issue one from page 90 20 kindly go through this is available online. So, this will be a big help to understand. So, this following paper the cell biology of hearing by martin Schwendler and kashir and muller which is published in journal of cell biology in the volume 190 issue number one in the year 2010 will be a big aid to understand some of the structures which I have already discussed with you in one of the classes. So, here I want you to go through it. So, coming back to the structure of the auditory sense organ ok. So, if you look at this structure you will find that this is where what I have already showed you that the outer ear you could see the outer ear out here and then you see the inner ear. So, the middle ear and all the three bones and here is the inner ear and I told you that there are a hair cells which are present. So, these two micrographs what you see out here underneath there are four pictures out in this picture these two pictures this one and this one you could see these are the arrangement of the hair cells which is shown like once again let me. So, they are in array and they are actually sitting out here inside the cochlea what I have drawn. Now if you look at this picture at a further resolution they are if you kind of see the dimensions of the individual cells that will give you an idea how small these structures are which are sensing your different frequencies and this reference again this is another reference which I want you to be able to go through is by furnace D N furnace in journal physiology in the year 2010 which was in the issue 588 ok please go through these things where you have a scanning electron microscopic image of hair cell bundles with the inner hair IHC inner hair cells here from the part of the rat post metal day 10 ok. Please go through this and that will kind of give you an idea at these are the nanomachines of the body which helps us to decipher wide range of signal from sound, light, smell, taste so on and so forth touch. So, likewise so these are those specialized destruction that is that is the reason why I am taking this a special lecture where I wanted to you guys to expose to those specialized structure which are translating the physical signal of nature into electrical signals these are really some of the profound machines which has evolved over the course of evolution of thousands and thousands of years ok. So, now look at this one if it moves in one direction then it will pull all of them in one direction and I will show you that. So, if you look at it they are arranged in a height as if like in a staircase they are arranged in a staircase if you look at the slide now with this. So, look at this they are almost arranged like a staircase model out here. So, they are all so now if you look at this cartoon what has been drawn out of those pictures. So, it is as if you are sitting in a photo session look at this picture as if these cells are sitting in a photo session and the cameraman is sitting here it is almost like that. So, this bigger one which is called the kinosilia and all these are the stereosilia they are connected with a connector linking the tip link you could read that tip link out there and the tip links and here you have another set of links and these are all eventually connected to this cell. So, if this kinosilia moves on the left then the rest of all the connectors will move to the left if the kinosilia move to the right and everything will move to the right depending on now if you look at this image depending on in which direction they are moving it decides that what kind of current it is going to conduct whether it will be inhibitory or excitatory. So, from here so this is the molecular architecture. So, this is all consists of different kind of myosins if you could see and please I request you go through this reference. So, they are these myosins are basically the they are also called the myosin motors these are the molecular motors or the protein motors what is involved and they are actin. So, they if you those of you have please go through the basics of actin myosin integration in order to you know results in the movement of the sliding movement. So, you are having this actins and the myosins you have the adipter proteins and like and so forth. So, this is how the molecular architecture looks like it is a very complex and beautifully knit structure if you look at it. So, you see this wonderful super coiled proteins which are forming the base or the framework they are connected with each other and they have a whole range of sub types and this is the schematics again for this schematics you have to refer to that this journal that journal physiology D N furnaces article. So, if you look at this this is where the channels are setting. So, if they pull in one direction the gate opens and the calcium enters. So, if you look at this this micrograph and look at it look at this micrograph very carefully. So, this is how the calcium entry is taking place. So, there is a pull it is almost like a hinge of the door there is a pull on the left it pulls on the left like this and the channel opens this is how this structure functions this is while I was drawing it it was really tough for people to visualize exactly what is happening that is why I decided that I will give you a special lecture where I will have all these figures the schematics which will help you to appreciate how this whole process is taking place and followed by this if you come to. So, these are called MIT currents mechanotransductioning current basically. So, if you come back to this one. So, this is where the current is being generated you see there is green green patch. So, that is showing that there is a calcium influx of the calcium current and this is how you are recording those currents in terms of the nanoamperes. And if you go back to the previous notes you will see and these are the different deflections which are taking place delta x is showing in terms of micrometer the deflections which are taking place and these are the currents which are generated with respect to the different kind different level of delta x. So, this is the function. So, x axis is showing you the delta x or which is the deflection and on the other hand the y axis is plotting the current. So, here also you can see the different currents different day at different time points. So, this is how all these nanoamperes currents are being measured and these are very small current, but good enough to code a piece of information what is being processed by the hair cells. So, coming back. So, these are the hair bundles and the mechanotransduction what is taking place. So, if as I was telling you it is pretty much the reputation of it. So, there is an stimulus they move in one direction. So, you see in this situation this is all moving towards the left once they once they move towards the left the calcium channels pulled and calcium channel opened and again there is an adaptation they come back to their original position. So, if you follow this diagram very carefully then the whole mechanotransduction will be very clear to you people and this is how they are attached. This is believed how they are attached. So, there is a spring there is a tip density if you look at it and this is that spring which is pulling this pink color spring attached with a partly green color pink plus green color this thing. So, this is what is pulling. So, if this one moves on the left. So, automatically this will make the whole structure move to the left from after giving you this overall outline I will move on to the cochlear implant. So, how the cochlear implant really looks like as a matter of fact it was the cochlear implant as I have mentioned earlier it was the first one which was the success story of mankind in terms of neural engineering on neural prosthesis. So, this is how the cochlear implant works you have a microphone there is a sound processor there is a transmitter and there is a receiver and from here this signal is fed into the cochlear. In the cochlear there are these are these are connected this whole thing is connected to the cochlear nerves and this cochlear nerves carries the signal to the auditory cortex. So, essentially what you are doing you are ruling out say for example, if these cells of yours these hair cells of yours are all damaged. So, what you do you fed the direct information the sound information directly to the cochlear nerves and the cochlear nerves and take the whole information through the cochlear nucleus to the auditory cortex of the brain and where it is being processed. So, you are bypassing the whole cochlear and this is what I wanted to highlight in one of the previous lecture. So, this is how it looks like the cochlear implant the auditory system is composed of outer ear this is the summary of it and the middle ear and the comprising the tympanic membrane and the auditory occipals and the inner ear composed of the signal like cochlear containing sensory hair cells bathed in a fluid. So, this was what we discussed these sensory hair cells activate the fiber of the cochlear nerves which emanate from the spiral ganglion cells and project to the cochlear nucleus of the auditory brain stem. The neural pathway that leads to the higher auditory processing center of the brain the inferior colliculus medial geniculate nucleus and the primary auditory cortex. So, if you go through this then this will give you an idea about how these signal serving process and if you read through here. So, what is happening is that a C I consist of an the cochlear implant C I stands. So, the cochlear implant consist of an external microphone which collects the sound waves. So, look at it which collects the sound waves and. So, this is what is collecting the sound waves and a speech processor which converts the sound waves into electrical impulse. So, here is the speech processor sound processor. Then next come which converts the sound wave into electrical impulse and then transmitted to a receiver implanted under the skin here is the receiver which is underneath the skin. So, after the receiver implant the receiver sends the electrical impulse to the microelectrode array implanted within the cochlear. So, here within the cochlear the microelectrode array which are. So, all these EMEA what we have studied from the beginning. So, this is where they are finding their applications why the EMEA has to be studied in order to understand how this whole cell electrode interfacing is. So, very important criteria before all these kind of implants will be successful. Now, coming back to the slide. So, this is where microelectrode array implanted within the cochlear the electrodes directly stimulate the correct population of auditor in a. So, that electrical signals are propagated to the appropriate tonotopic regions of the cochlear nucleus of the brain stem and then on to the higher auditory cortex. So, from here this is going to the specific part and from here it is moving to the auditory cortex. So, this is the overall summary of the cochlear implant what I wanted to show you people. From here this is another cartoon which is showing the same thing the microphone the amplifier in the sound processor the sound signal are converted in the electrical signal and then through the cochlear. So, this is where the cochlear nerves to the medial geniculate fiber or the thalamic fiber thalamic region from the brain stem from here it is moving to the enlarge field potential amplitude in the auditory cortex and enhance synaptic currents. So, this is the situation when your hair cells or what I showed you those wonderful mechanosensing cells are getting degenerated and you have no other option, but to resort to neural engineering techniques in order to restore your vision. These are the extreme situation, but this is one of the big success story of mankind a of last hundred hundred fifty years of man's quest to interface machine with its body parts. So, from here the stimulating hearing auditory neural pathway from the cochlear of the inner ear to the auditory cortex of the brain. So, hearing can be restored in the congenitally deaf kittens. So, this is where it was done with an electrode that stimulate the auditory nerves in response to environmental sound related by a microphone and sound processor it is pretty much the same thing what we just went through. So, electrical discharges of the neuron in the auditory pathway results in a strengthening of intra cortical synapses that was the synapse strengthening if you look at it enhance synaptic currents this is what it meant. From the results in a strengthening of the intra cortical synapses and an enhancement of the neuronal response to sound the area of the auditory cortex which over which electrically evoked field potential can be registered is enlarged in cat with early implant red and yellow compared to the deaf cat which is in blue. So, this is how it looks like. So, here is a blue showing you the deaf cat the red and yellow are showing in the implanted cat. So, this is what I wish you people go through bit carefully from here I move on to the next one which is the eye or the retinal or visual or retinal prosthesis. So, this is I have already discussed with you people the structure of the eye and give you a part of the idea about how you place the camera in front of the eye. So, here I decided I will show you some of the real time pictures which will help you to appreciate this subject much better as compared to just me drawing out here on the on the screen. So, just the same way as we have walked through with the hearing or the ear prosthesis I will walk you through with some wonderful pictures out here that will help you to understand it better. So, this is the overall this I have already discussed with you people. So, the structure of the eye the cornea the lens and here you have the retina and you have the vitreous humor. So, the light travels all the way through and I have already told you that there could be either a corneal blindness where basically we say that if somebody has donated eye basically it is the cornea which is being taken out from an deceased individual and implanted into another individual and the cochlea has very little blood supply. So, the compatibility of the tissue my compatibility or immune reaction is very least then comes the blindness of the lens which is essentially the cataract. So, you replace this lens with a synthetic lens and now comes the retina where if there is a damage in the retina then we need something will be more than cornea or lens implants what is that and that is what we are going to discuss. So, this is the overall a structure of the layout the pigment epithelial cell the rods and the cones layer any of the horizontal cells the amacrine cells the bipolar cells and the ganglionic cells. So, this is the complete layer which is dealing with the whole eye prosthesis the whole structure of the eye and this is in a much more kind of you know blown up picture where you have the pigment epithelial cell sitting at the base on top of that you have these violet and black shade rods and the cones and then you have the horizontal cells then you have the bipolar cells here you have the amacrine cells out here go through it and here you have the retinal ganglion cells which are carrying the message to the brain and this is how the light falls light falls from this side actually as a matter of fact always remember light is falling. So, essentially here the first layer what you see this red could be divided the first layer is the retinal ganglion cell layer, but since neither of this layer this layer or this layer l 6 l 5 l 4 l 3 has any kind of photoreceptors or any kind of light sensing proteins in them. So, the light is only sense by the photoreceptor layer and beyond that there is an opaque layer of the pigment epithelial cell which is essentially the absolute the back of the eye if these two lines. So, this is the front is retinal ganglion cell and the bottom will be the pigment epithelial cell which is basically helps in having a cushioning effect. So, this is how a physically a rod and a cone looks like these are from the fish retina and the references given here please go through this if any one of you is interested really to see how they look like and how they are being isolated from the fish retina it is a paper in comparative biochemistry and physiology part a in molecular integrative physiology in the year 2008 the month of August this is volume 158 and issue number 4. So, these are the rod cells physically that is how they look like this is where the outer segment of the rod cells this is the inner part inner segment of the rod cells this is where all the light sensitive proteins redoxins are setting and this is from where the impulse is being sent. So, all the dark current which are measured it is measured here similarly here is the cone. So, this is the outer segment where the specific redoxin are sensing RGB red green and blue color they are sitting here and then out here from here the signal moves and look at the dimension they are in even their thickness is less than 10, 10 micron. So, this is the kind of dimensions we are talking about and then they will be hardly 30 microns. So, the rod system has low spatial resolution but is extremely sensitive to light. So, it is a specialized for sensitivity at the expense of resolution rods do not discriminate different wavelengths of light. Conversely the cone system has very high resolution but is relatively insensitive to light that thus it is a specialized for visual acuity at the expense of sensitivity cones can discriminate different wavelengths always remember this. Now, this is even a much more well kind of you know almost giving a three dimensional look about the rods and the cones and this is the reference from progress in retinal eye research in published in 2009 in the month of July volume 28th and issue number 4 please go through it. I mean these pictures the whole reason to show you these pictures that will give you an overall idea or a bit of an appreciation about how wonderfully all these different kind of structures have evolved over a period of thousands and thousands and thousands years of long drawn evolutionary in the evolutionary time scale. Now, coming back. So, this is how the rods and cones are distributed. So, distribution of auto receptor in the eye. So, please again you should go through this progress in retinal eye research in the year 2009. So, distribution of the photoreceptor in the eye overall rods out number the cones by a ratio of 20s to 1 or greater in the retina. However, in the phobia the cone density is the highest and is correlated with visual acuity. So, this is the phobia region. So, these are the those are the different areas of the retina. So, phobia is rich in your cones. So, now moving on to the different kind of currents which are being measured. So, rods are highly sensitive. So, again this is from the comparative biochemistry and physiology art A of the molecular integrative physiology the year 2008 please go through this. So, rods are highly sensitive like sensitive, but their flash response time course is slow. So, that they can detect a single photon in the dark, but are not good at detecting object moving quickly. Cones are less sensitive less light sensitive and their flash response time course is fast. So, that cones mediate daylight vision and are more suitable to detect moving object than rods. This is a very critical thing which I wish to highlight and this is what is called the flash response time. So, the flash response time of the rod cells. So, something move like this cone can detect it, but something like this cone can figure that out rods would not be able to because they need bit of a time to adjust and understand a flash of light. So, this is something very very interesting for you people to really look at carefully that. So, if you look at the slide again bit carefully you see the time window what is the most important here look at the time window the response time how much time it takes reach one of them to respond. So, after this. So, this is about the cones all the different cones the blue cones the green cones and the red cones and the different wavelengths they could perceive. This is how and there are several species which are different other wavelengths which they can perceive the fishes could perceive another color. So, this is how once they are isolated in the cell culture this is how they look like all these are the rods you could see these rods the rod like and they are bit more purified here you have the rod cells and here you have the cone cells. This is how they look like in a cultured dish. So, that is why I wish you people can should have a very clear idea you know how they kind of you know look in the cultured dish and how they grow from here on. So, what if it for photoreceptor hyper polarized on light stimulation was a great surprise to the neurobiologist because it was an exceptional case that a neuron shows hyper polarization not a depolarization on stimulation this you will be able to read just note it down hyper polarization not a depolarization on stimulation. So, this is where I was trying to show you the dark currents you remember I was telling about the dark currents. So, this is the outer membrane and within the outer membrane this is how all those different proteins which are involved in this phosphodiesterase and cyclic GMP and all those things. So, this is the dismembering and this is the outer membrane this is how they are arranged out here. So, and this is the picture of how the dark current are being measured. So, you have a electrode in the presence of light in the presence of light what you see is the minus 70 millivolt out here and where there is darkness you see minus 40 millivolt. So, essentially it was that whole concept of dark current what I have introduced you and what exactly is happening. So, when the light is binding to this membrane. So, what it does? So, this is the once again let me. So, this is what is happening when light is binding. So, this 11 6 retinal which is present there along with the obscene which is forming the complete redoxane moiety split up into. So, the first thing happen when the photon goes this 11 6 retinal become 11 trans retinal and then 11 trans retinal detaches from the obscene. So, this is the detachment which is also called bleaching. So, then would happen this 11 trans retinal through an enzymatic process transformed into a cis retinal, but in the meantime the obscene does certain few other things that will becoming what obscene is doing in this light obscene activates a protein called transducene and the transducene activates something called phosphodiesterase and this phosphodiesterase remove the cyclic gmp gating of the sodium channel which ensures the entry of the. So, if you look at the slide very carefully you will see the cyclic gmp level declines and the gated sodium channels closes. So, this is step 3 is very important for you to look at this is that is step 3 which is very very important. So, this is where phosphodiesterase is binding and removing this gate. So, if you look at this picture it was a cyclic gmp which is holding this sodium channel up here where I am circling. So, once the light falls would happens is this cyclic gmp out here is being removed from that binding side by phosphodiesterase and the phosphodiesterase removes it does this channel closes and once this channel closes the current flow through the through the sodium channel stops and this is how the signal transduction within the I takes place. Now, this is a much more complex picture what is happening light is falling rhodopsin is photo activated transduce in activated followed by phosphodiesterase activation hydrolysis of cyclic gmp cyclic gmp decrease in the cytosol in the sodium channel close and the signal moves. So, this is what is the light cascade the first is this is the basic overall structure of the rod cells followed by a photo excitation what is taking place where 11 cis retinal is transformative 11 trans retinal and this leads to the bleaching process and then comes the what is happening in the rhodopsin moiety all the arrangement and the rearrangement within it cyclic gmp as transmitter of visual. So, this is another cartoon showing the photoreceptor and so this is something very interesting which I have not highlighted previously the photoreceptor and bipolar cells have no action potential they do not really should action potential it is only the current which is generated which moves on to the next one hyper polarizing membrane potential generates that current which moves on to depolarize the bipolar cells and then followed by the ganglion cell where the action potentials are being generated. So, this is how the signals are moving if you follow this very carefully. So, please remember photoreceptor and bipolar cells have no action potentials hyper polarizing membrane potential then leading to the depolarization of bipolar cells and then at the ganglion cell layer is all the processing taking place. So, essentially what we meant by that if you look at this picture go back. So, all the action potentials are generated in this layer sorry in this layer at the l 6 layer retinal ganglionic epithelial cell coming back to the and. So, this is another picture where we are showing of the phosphodiester is this sitting which is converting the cyclic gmp into gmp and there by closing the sodium channels and if you look through it this is how the phosphodiester is sitting quite it is unable to act till there is an activation from the transduce in protein and this is how they are arranged along the membrane. So, these are all G protein coupled systems and this is the summary of it the bleaching and the regeneration of the visual pigment where it is again getting regenerated and again the 11-sis retinal which is through an enzymatic process from trans to become cis and the cis again get in gets incorporated into the oxen moiety and again gets back to the membrane. So, now coming to the implant position in the body. So, this I have already discussed now I wanted to show the exact picture. So, this is where you can put the implant either you can put something out here in the front of the eye and this is how it looks like that. So, this is the cornea this is the lens and this is where you can put you can put an implant here either you put something in the front of the eye a camera or you could have a implant here where you see this C. So, this here is the retina is the coradier and the fixation of the cable at the exact point then you have the trans scleral trans cordial entry and the sclera you can do it on the sclera. So, this is how it will work. So, this is the implant actual implant which is sitting out here this is where the light is falling the light sensitive micro photo diodes then they have the amplifiers which are sitting there you have the ds electrodes and from here this signal is being sent all the way to the brain. So, please go through this reference by is runner E you could see this then the proceedings of the Royal Society at B which was published in the year 2020 2010 please go through please mark this reference and go through it. So, now this is how most of those implants look like these are the complete. So, these are the basically the light sensitive micro photo diodes which are sitting there and this is where the image plate is involved and all the electrodes are connected underneath. So, you have the see the photo diode electrodes and the contact holes this is how they look like physically please go through this reference that will give you an idea about how they really look like and these are the different spots where you can really make all the connections and there is a reference which is given expert review in ophthalmology published in the year 2009. So, PS is the power supply R is the receiver S is the stimulator and S is the signal processor. So, this is how these different cameras are being put and different implants are being placed. So, there are different regions where they are being placed. So, and if you look at the summary of it please go through this summary of the different concept of intraocular retinal prosthesis and this is either it could be a epiretinal concept or it could be a sub-retinal concept. So, these are those detail which those who are interested really to understand the different system. So, there is something called a Boston retinal implant system please go through it and they have intelligent medical implant systems and any of the second site Argus system. So, these are the different people who have over the years have kind of you know develop these different prosthesis regime and they are the ones who have come up with different models in order to you know for people to understand that how this different prosthesis takes place. So, what I wanted you people a kind of a take home message from this is though I mean this is a very tricky and a challenging area in terms of the fact that as I am repeatedly telling in this course whenever I am talking about animal electricity that how successfully we can implant an electrode without really disturbing the cellular assembly where we are doing the implant. There will be of course some degree of disturbances, but how we could minimize the immune reaction, how we could ensure over the period of longer period of time the electrode fidelity will be maintained. These are some very very challenging problems which mankind is going to face for in a years and centuries to come because this is the long run thing this is not something like you know it is possible it is how much we can find you how far we could be innovative enough to take it to that level where these became a routine thing. So, it is a journey and please go through these references because after this once I have done these two prosthesis I will be moving on to about the man machine interface where people have tried really to you know implant train monkeys I will be coming to that after this. So, I am closing in on this one. So, please go through these references and try to philosophize it in your system because it is something which you have to think a lot this is not something because we know what could be done, but what are the innovative ways thanks a lot.