 Welcome back to the lecture series on animal physiology in the NPTEL. So, today we will be talking about some of the diseases of the spinal cord, especially the lower motor neurons. So, let us just start off with. So, we are into the section 5 nervous system and this one is your lecture 8. So, we have talked about the problems of the higher brain functioning how it is being compromised in Alzheimer's disease in epilepsy, especially in all the Alzheimer's when the pyramidal neurons of the hippocampus starts to die because of trafficking along the axons starts dying. Then we have talked about the Parkinson's disease and how the neurons in the substantia nigra lose their contact with the lower motor neurons which are present in the spinal cord. And we talked about the aldopa therapy, today we will be talking about the lower motor neurons. Now, the word we will be dealing with if this is the brain and this is the brain stem and this is the spinal cord and along the spinal cord you have the ventral horn which is this central blue line what I am drawing in the center and which is basically the zone where all the motor neurons are sitting. These are the motor neurons which are getting signals from the upper motor neurons or the cortical motor neurons and based on that they execute their functions they could be either called as. So, this is the ventral horn or descending pathway because they are bringing the signals from the brain to the target tissue. These harbors all the they are sometime also called somatic motor neurons or there are several terminologies somatic motor neurons or spinal motor neurons or sometime they are also called the lower motor neurons they are also anonymous to each other. And depending on their position say for example, so they have been numbered as l 1 l 2 likewise there are different numbering scheme based on the position they are having. So, say for example, if I just put likewise like you know which one is coming out from where likewise you know the processes of the motor neurons are coming out depending on some of them go and in a way the eyes then the ears like some of them are taking care of the other body parts likewise. So, depending on the damage depending on the problem at what zone it is. So, for example, if there is a problem out here. So, automatically the eyes will get affected if the problem is here may be the hearing may get affected or if the problem is somewhere here may be the in a movement of the hands may get affected depending on the zone where the injury takes place or the problem takes place that leads to the necessary the subsequent problem. So, what exactly happens? So, we have already talked about from the motor cortex you have the higher motor neurons which are synapsing here and we have already talked about the different circuits like you know these are the muscles and within the muscles and you have the innervations and these innervations are being you know some of the innervations going all the way to the brain and there are reflex circuits which are coming back bringing the signal and based on that the neuromuscular junction functions. So, whenever there is a problem out here. So, these signals which are supposed to come from these somatic motor neuron spinal motor neuron or lower motor neuron will not reach the target and if they do not reach the target. So, basically what happens this muscle of yours is paralyzed it would not be able to function the way it should function. So, now in this situation what will happen you have two options either some way or other you bypass this route and whatsoever the signals which are coming all the way from the from the brain is directly transmitted to the muscle or you have something else which could which could repair this circuit. So, first of all let us talk about the diseases of the spinal cord motor or the pathologies of spinal cord motor neurons pathologies of I am putting a short from that spinal cord motor neuron or lower motor neuron or sometime S M N somatic motor neuron this could be the somatic or spinal cord standing for motor neuron and with the motor neurons people sometime write as two separate words motor and neurons or sometime they write like this. So, these are all just you know depending on which country and where it is being used. Now, coming back to the pathologies there are two ways one is when there is a injury in the ventral horn these injury could take place either due to trauma during road accidents or any other form of accidents you know mostly the spinal cord injuries are from road accidents or some other you know some other physical trauma due to some other act. So, what exactly happens is this if you look at the circuit this is how it happens. Now, I am going to blow up the ventral horn this is the spinal cord and a blow up zone I am talking about and this is where the ventral horn. So, the ventral horn this is something very interesting to note. So, for each one of these muscles there are different routes. So, when paralysis happens say for example, still the complete paralysis takes a lot of time still some part of the muscles will still kind of you know move there are always redundant pathways which help us to kind of regain some of the functions. So, let us look at the pathways how these motor neurons are kind of arranged here. So, these are the bodies of the motor neurons which are coming out going to their target tissues all over like this we are sitting at different level it is just like at different staircase kind of situation and in between you have the different astrocytes glial cells which are present here all these astrocytes and then you have the oligodendrocytes which are you know covering myelinating the axonal terminal these are the oligos which are around the axonal terminal. So, now think of a situation when there is a huge impact falling because of some kind of a road accident or something whenever such impact happens what happens immediately is these cells some of these cells because of the impact starts to die there is a physical injury which it leads to. So, as soon as there is a physical injury. So, we are now talking about the spinal cord injuries just for spinal cord injury and sometime in the literature you will see it is being represented as S C I spinal cord injury the short from a spinal cord injury and this is the high impact very high impact this leads to a physical injury to the motor neurons. And as I have already mentioned this motor neurons are the ones which are formed very early in the development. So, these are extremely susceptible to injuries so when in the way there is a physical injury the next thing what happens is very interesting at the site of injury there is a rushing of micro glial cells soon post injury. So, let us see let us go to the next slide. So, here is an say for example this is the motor neuron which kind of got because of the impact gets damaged. So, as soon as there is a damage. So, this is damage physical damage followed by physical damage the next thing happens all the micro glial cells which are small cells they start rushing to the site. So, these are the micro glial cells, cells rushing to the injury site. So, what the micro glial cells does after reaching to the injury site is that. So, this cell soon after the damage this leads to the second step is this. So, followed by the damage there is a lot of cellular debris is just like you know there is a car crash and there is a lot of debris of the car crash. So, the micro glial what it does it goes there and eats away all this cellular debris that is the function of the micro glial. We have eats away or cleans away you can call it eats away or cleans away all the cellular debris. This is the first step what happens and micro glial acts on all kind of cellular debris at the site of injury it could be a neuron it could be a oligos it could be the astro sites whatsoever. So, then it forms. So, for example, the way the shape looks like is say for example, this is the ventral horn and these are the flanking dorsal horns. So, dorsal horn dorsal horn and here you have the ventral horn and here is the site of injury this is the site of injury because of heavy impact. So, the site of injury soon after the micro glial cells do their cleaning up act this site is now filled with a specific kind of fluid. Likewise and some connective tissue. So, it forms a fluid filled cavity newly synthesized connective tissue this fluid filled cavity is called is a specific term for this is called sirens. So, the formation of sirens is an is a immune reaction in order to ensure that the debris which are present at the site of injury does not affect the metabolism of the cells in and around it. But, because of the formation of the sirens and the presence of the newly formed connective tissue which I have indicated out here notes this does not this acts as a sirens does not allow sirens acts as a block. For regenerating cells to grow what does that mean regenerating I will just diagrammatically show you cells to extend their process. This means again I will just use a diagram to explain this what does that mean this means that say for example, here you have the again I am using this diagram repeatedly. So, here you have the ventral horn and say for example, let me redraw this because flanking zone and here you have the. So, say for example, this is the site of injury let us put it like this as a red color and this is the sirens and here the ventral horn neurons which are still going out likewise processes are going out and some of the processes which were kind of was suppose to move like this have died out because of the injury. Now, yet in this zone there are another set of neurons which are much more smaller which are called the inter neurons and it is believe that some of these inter neurons which are present here have the ability inter neurons to transform into motor neurons because their functions are very similar to motor neurons or their functions are very similar their electrical activities are some of them are very similar to the motor neurons. But at least electrically they have a very similar signature to the motor neurons. So, pardon me because I just if it is a functionality. So, that is wrong electrical signatures are very similar, but these inter neurons or any other neurons say for example, these neurons decide to send out a process to you know make up for this say for example, this start sending out a new process, but this process cannot pass through this cavity because this cavity which is formed here will not allow anything to pass. So, you have to bypass it like this. So, some way or other for the therapy to take place the biggest challenge is how to remove the sirens it is not an easy job because the very moment you have to approach the central nervous system. So, another thing of a real life situation. So, for example, for an individual if I had to remove say small sirens kind of a structure from the spinal cord. So, basically I have to first of all do a surgery the first surgery is a neurosurgery which will be a very tricky surgery you have to open the spinal cord you have to really poke all the way to remove the sirens and then only some form of neuronal regeneration may take place some of these neurons or something can move through and regain the path say for example, this one is taking care of one set of muscle this is second set of the third set of muscle this muscle is no more functional because the connectivity is lost. So, this muscle becomes paralyzed. So, this is exactly what happens. So, what are our options are we really helpless here. So, one therapy with people are trying repeatedly is some way dissolving the sirens by using molecules dissolving sirens because sirens sirens is this does not remember this does not promote regeneration sirens. Is negative impact towards regeneration one way that you have some molecules some x y z molecules which will dissolve the sirens and this may promote there is another situation which may happen think of it another situation may be say for example, here is a motor neuron and here is the original process it has and this may be the original the first the muscle which it was inner rating. Now, because of the impact it loses this contact. So, now the motor neuron is sitting like this it has a small process coming out and rest of this process dies out because it is no more getting any supply from the cell body this dies out. Now, what this could this. So, automatically if there is an injury here. So, there is a formation of sirens out here. So, this would not allow this neuron really to you know penetrate through this, but if we have some mode that we have some some kind of molecule which could dissolve this fluid field cavity dissolving this fluid field cavity and there is a possibility then this neuron may starts to send out again sends out its process, but that is a very debatable issue could there be a motor neuron regeneration or there is another option which is if by some chance some of the surrounding intern neurons which are much much smaller may transform. So, one of the next theories is some of the intern neurons becoming motor neurons. These are very debatable topics and there is enormous amount of research going on across the world for those people who are working on the cellular side of a spinal cord injury. They are working a lot to figure out if there are some intern neurons which may transform. So, in other word what will happen if there is a very close by intern neuron and it can get transform into a motor neuron. So, this is I represent I n and this is I represent by m n as a motor neuron and the intern neuron then there is another possibility it may, but of course no one can guarantee that it is going to follow the same path. There is no guarantee neither you nor I or no one else can give a guarantee. So, there is another way that you put some form of a conduit tube I will come to that the next level of therapy which is feasible. So, this is another option the intern neurons concentrate on the motor neurons. So, the other option is that you have a source of stem cells. These stem cells you are transforming them into motor neurons and then what you do is you take these motor neurons. So, this is all happening outside. So, this falls under the regime of regenerative medicine regenerative medicine. And you take these in vitro motor neurons and you put them back out into the ventral horn which is out here and you have the dorsal horn. So, you take your motor neuron and go, but again mind it there is a sirens which is waiting. So, you implant your motor neuron here and of course, you have to put those kind of molecules which will ensure that you dissolve the sirens with a hope that this motor neurons eventually goes back to its original target. If this is the original target which is lost it goes there and forms a connectivity. This is all a guess work this is one option or the other option is you take your motor neuron stem cells and you directly implant the stem cells out here. If you implant the stem cells out here and then you have some kind of drug some kind of growth factor releasing pills or growth factor releasing aspect chemicals which transform these stem cells here itself to motor neuron and it goes and inner weight direct stem cell implantation. So, either you could implant the motor neurons directly which are form through the process or you can implant the stem cells directly at the site. So, both these approaches are being tried out, but then there is another side of the game which is even more tricky. So, realize the original situation before the injury taking place. So, here you have the dorsal horn and here I just drawing it wrong. So, here you have the ventral horn V H and dorsal horn D H D H. So, originally even much before the injury the pathway is like this is coming to its original and here is the target tissue. Now whenever you are implanting anything out here. So, for example, I implant something out here. So, in other what you are essentially doing is this you realize that you know these are also under the control of the higher motor neurons which are coming from the brain from somewhere from the upper motor neuron. So, whenever this particular connectivity goes off say for example, this one goes off in other word what is happening the fuse is gone or the connectivity is gone. So, what you do in a real situation you put the fuse back in our case the fuse is your stem cells or the motor neurons. So, these are either you may have the stem cells or the motor neuron you are implanting here. So, now while we are doing. So, you have to ensure when you are putting the stem cells you have to ensure that they follow the same route by which it could go to the exact target organ in order to do. So, some people across the world are working on developing conduit tubes likewise these are nano scale tubes which ensures that the process the newly implanted cells the processes send out by the newly implanted cells follow that tube and reaches to the target organ. So, there are specialized materials which are being used very strong biocompatible material which could be used as a implanting agent for taking care of this in your patients. So, these are some of the ways by which you can at least we dream of that we can hope that some of these spinal cord injury patients could be cured. There is another way which is a purely neuroelectric way that is you are we believe and some of these therapies are being done. We believe that you develop you implant some kind of a neuroelectric chip out there in these sites which will regulate the motion of these target tissue neuroelectric chip implant. So, these are all the futuristic technologies what we are talking about the regenerative medicine neuroelectrics and some of the there is another theory which I kind of missed out while talking about Parkinson and all those things all those disease that there are different deep brain stimulation using electrodes. So, that is another way of approaching. So, that falls under the regime of neural engineering where basically deep brain stimulation by implantable electrode neural engineering. So, this is where this whole domain falls where you implant different kind of you know neuroelectric devices or chips or like you know electrodes which will stimulate that specific circuit just like an electric circuit you replace it with another electronic component which will stimulate the specific target organ. So, if I had to summarize what are the different things you have just now talked about is one of the option is that in the circuit. So, talking about what all we have just now talked about as you could have the stem cell therapy which falls under the regenerative medicine you could have directly stem cell transform into motor neurons which could be implanted you could have electrodes which could be implanted at both at this level as well as the higher brain regions you could have neuroelectric chips to ensure that this circuit works and neuroelectric chips. So, no one thing therapy and above all we have to ensure that there are the sirens could be dissolved first of all and then you have different conduit tubes which I was mentioning which will allow these molecules this stem cell processes and motor neuron processes to move to their target organ. So, essentially what it mean is this there cannot be a single modus operandi by which we can take care of spinal cord injury patients there has to be multiple routes multiple approach and a very interdisciplinary approach which takes into account expertise from material science biomaterials nervous system development biology cell biology electronics and then only we can approach such tricky problems of nervous system damage. So, there is this is one of the pathologies we talked about which takes into account the injury to the motor neurons, but think of it how the myelination and all these things will proceed in these neurons. So, those are even much more challenging thing or think of situation like multiple sclerosis. So, what happens in multiple sclerosis is m s your glial cells starts dying and when the glial cells starts dying. So, in other word what is happening if these are your neurons and which are myelinated. So, there are two kinds of neuron either they will be myelinated or they will be non myelinated in case there are myelinated neuron and say for example these are myelinated neuron likewise these are all the myelination you see. So, say for example this myelination are lost the very moment this myelination is lost. So, what is happening is that electrical impulses which are getting generated here start getting short from the electrical impulses which are generated here. So, in other word the signals does not reach to a target properly there is a improper transmission of signal and this is very terrible situation which happens in multiple sclerosis because of the death of the glial cells and as of now there is no such cure for multiple sclerosis. The third form of pathology is something called ALS which full form is amyotropic lateral sclerosis or this is also called Lou Gehring disease what these disease is all about. So, this is again a spinal cord disease. So, again I will go back to the ventral horn here are the dorsal horns and the ventral horn here is the huge cell body of the motor neuron setting. So, what happens in Lou Gehring disease is very similar to what happens in Alzheimer's that these cells started to die and the reasons are not known except and a very small cases where there is an enzyme which is called SOD super oxide dismutase. This is a very small portion of super oxide dismutase this is an dismutase. So, just to tell you what where the origin of this SOD there are the body has three specific enzymes which helps us to safeguard ourselves from oxidative damage one is glutathione peroxidase the another one is catalase and third one is SOD super oxide dismutase. So, any compromise with these enzymes can lead to oxidative damage in our body. So, super oxide dismutase is one such important enzyme in our body. So, a very small say for example, out of 101 or 2 patients of may be 3 are being seen with a mutation in this particular gene of super oxide dismutase. So, in other word they are unable to produce proper super oxide dismutase. So, under that situation these neurons are in continuous stress from continuous oxidative stress, but this is a very small proportion of it I am repeatedly telling this is a very very small proportion of it which are in the SOD compromise situation. And under that situation what happens what is being seen and in both the situation the symptoms are the same. So, these spinal cord motor neuron starts to their processes starts to die out likewise. And eventually they are not getting their target tissue and once they do not get their target tissue eventually these cells starts dying. So, there are still the causes are not known, but what is believed is something very similar to what is being believed in or what is currently the literature is indicating is that there is a traffic wing problem. In other words if this is the highway through which if I had to blow this up and if this is the highway or the axonal highway call this as axonal highway. The molecules which are travelling along this axonal highway represent the molecules by say black the one which are moving towards the end and the towards the end of the axon to and the one which are moving towards the cell body. This transmission is being obstructed by formation of abnormal protein along it. So, the transmission process is all over is being obstructed and that leads to improper transport of molecules which helps this long process or the conduit tube or the axonal highway to communicate with it is target organ. So, this is one possible one of the situations what is happening. So, as of now there is no cure and like those of you are aware of stiffen hawking on of the very one of the genius of our time. He suffers from Lou Gehring disease and this disease is more prominent among the Japanese and few other places it is slightly higher as compared to places like India where it is slightly lesser. The cases are not that very prominent. So, what are the possibilities? So, these cells starts dying. So, automatically this person loses all the possible motor controls. Motor control is being completely compromised. So, in this situation the though it can receive the signals from the cortical motor neurons. So, from the cortical motor neurons signals are coming, but at this zone these cells are dying. So, there is no use of this signal because this is the second level at the spinal cord this signal cannot be transmitted. So, in this situation again the options comes back could we have a stem cell therapy or could we know exactly that these cells will be designed and. So, we have or and there is one more interesting feature here this particular disease this ALS does not affect the surrounding inter neurons. It only affects the motor neurons and these are very unsolved mystery, unresolved mysteries, unsolved problems of neuroscience that why is it that at that specific site only a specific cell type kind of gets affected whereas not the other ones. We really do not know we do not have an answer to these very challenging problems. So, what are our options for those kind of patients who suffers from Lou Gehring disease or amyotropic lateral sclerosis. One of the option lies is what I have already discussed with you that we may have a stem cell therapy one option or some way or other we know that we could stop these stop the progress of the disease by some pharmacological intervention which will prevent the further death of the neurons because the way it works is that along the spinal cord if you look at it the way it progresses it starts at one point. So, if this is the spinal cord and if this is the ventral horn. So, it starts progressing from one end and it moves on it moves on there is no way at it could start from here it could move like this which is over way you know it does not matter and eventually this person becomes completely paralyzed and eventually dies out because this person cannot do anything because all the motor controls are completely compromised. So, as of now we do not have any cure for all these things it is just you know it gets diagnosed and then you pretty much live a very very compromised life and it is very sad. So, one of the option is that there could be a pharmacological intervention or in regenerative medicine we may have a stem cell therapies which may be able to take care of we produce motor neurons outside the system and implanted back or we may have some kind of neuroelectronic interfacing so that in other word what will happen that the signals which are being sent from the higher motor neuron they will completely bypass this and will go to the target tissue using some form of you know some neuroelectric amplifier or something or other we really do not know I mean we are all just kind of you know trying out several things across the world that what is the best option or best alternative. But as of now these are the challenges of the future of spinal cord injury or degenerative diseases of the spinal cord or this is like Alzheimer's this is like Parkinson's disease like short term dementia and all these things we really do not know or epilepsy as a matter of fact. So, these are the frontier areas where we are now kind of mankind is now heading towards to understand this very tricky diseases I mean and we hope in a distant future we have therapies for all these different things. So, with this I will close on this lecture and next what we will be moving on will be the sympathetic and parasympathetic system and that is the point I what I promise to you I will come back to the control mechanism of the heart and all those things I told you that I will come back remember this and I will come back to the parasympathetic and sympathetic control of the heart and other tissues will come back to that. So, thanks a lot for your attention.