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Transcribed by Lila Kakar

02.06.14

[Neuroscience] [Lecture number] Orofacial Sensation I by Dr. David Sirois [Slide 0] Pre-lecture introduction Dr. Jean-Pierre Saint-Jeannet Alright so lets get started. So the next couple of lectures will be given by Dr. David Sirois who is an associate professor in the Department of Oral medicine here at NYUCD short introduction, Dr Sirois got his D.M.D at University of Pennsylvania and also got a Ph.D. from University of Pennsylvania and was recruited here NYUCD in 2000 as chair of the department of oral medicine. Dr Sirois is a specialist in oral medicine, um, for oral pain in general, it has been one of the topics of his research, I believe. So hes very well suited to give you those two lecture on orofacial sensation, so and I would like to thank Dr Sirois for participating in the course hes been associated with the course for a number of years before I was in charge which was very recently so thank you very much for your participation. [Slide 1] Title slide Dr. David Sirois-My pleasure. First time Ive ever had such a kind introduction thank you. Nice to see you all. Well get to know each other more and more as the years go on. Well have time together again in the second and, uh, third years as you get increasingly sophisticated in your training in medicine and, uh, so forth so. So theres a single PowerPoint that I present and it covers both hours of lecture and feel free to interrupt me Ill try and keep an eye on the clock so that we get through the material and Ill try. And youll notice a lot of slides but in the end in reality if you can walk away from a message, uh from a lecture, with 7 or 8 messages that stick that would be great. Ill try and make sure you know what those messages are. [Slide 2] Educational Goals 1 Dr. David Sirois-So just to set the stage were going to talk about somatosensory physiology and I want to make it relevant to the patient situation so Ill try to make it a practical discussion of the physiology and how it helps you understand what a patient is experiencing in health and in disease. So well talk about the major components of somatosensation and somatosensation means sensory experience from your mucocutaneous your sensory surfaces on the skin and on the mucosa and that in contrast to say your ear or your eye or taste sensation. Alright so well talk about the major components that contribute to that and the major differences between touch and pressure and these different what we call modalities of somatosensation. Modalities and the pathways that um send those messages along then of course when youre talking about neuroscience youre not just talking about anatomy, connectivity youre talking about function. And as you get increasingly sophisticated in your understanding of neuroscience and neurology as it relates to dentistry, youll understand that the nervous system is unique, I think, and that its not just the static anatomy of the nervous system that you have to know something about but the function. Because the function of the system can change dramatically depending upon the activity its involved in and there is a term we use called plasticity and that is the ability the capacity of the nervous system to create memories as an example or to recover from injury. How does the nervous system 1

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do that? Its because its pliable its plastic the whole fact that I can remember where Im supposed to be today is because Ive modified synaptic relationships in my brain and Ive established a memory. I didnt change anatomy to do that I changed function. And Ill emphasize that point more as we go along. So well talk about the pathways but also how do these pathways function so that you have a human experience. And then of course well focus this on the trigeminal and oral systems. [Slide 3] Educational Goals 2 Dr. David Sirois-Alright so you should be able to describe not only somatosensation but the unique experience of nociception and nociception is the physiological process of detecting a painful stimulus and a painful stimulus is usually one that is injurious, harmful to tissue, okay. And well talk about the physiological basis for that and the interactions even between when we talk about pain admittedly most times that people certainly experience acute pain its because theres been tissue injury and inflammation. And the chemistry of inflammation, the immune system, interacts with the nervous system. So youve all, if youve ever hurt yourself, youve all experienced that light touch to injured skin or a body part, wherever it is, hurts. The exact same stimulus energy is perceived entirely differently. Now its not because youve changed the anatomy its because youve changed the function. And the nervous system has become sensitized as a result of that inflammation. So thats going to be a very key point, you talk about 7 points to remember, that will be one. And Ill remind you as we go through the notion of primary hyperalgesia, that is the pain experience that occurs at the site of tissue injury and how does that happen. And youll learn youll get introduced now and over the next two years to the notion you could have neuropathic pain, pain that originates from a misbehaving nervous system in the absence of tissue injury. So the nervous system has the capability to misbehave and if it creates electrical activity associated with that misbehavior youll have a perception that goes along with it that physiologically is real but may not be physically real. The clearest example, its an extreme one, youve probably, weve all heard of people with phantom limb sensations. There is an undeniable yet unorthodox fact that a patient, and theyre not imagining that missing body part, thats a real physiological experience thats based entirely on neural processes not transduction of a physical stimulus from a body part because thats in the trashcan but its a real process the patient is having and likewise the can experience pain in that missing body part. So thats neuropathic pain that originates from a misbehaving nervous system and doesnt require tissue injury and thats something called secondary hyperalgesia as opposed to primary hyperalgesia in the context of or instance of tissue injury. Well cover it more as we go on. [Slide 4] Orofacial Sensation Dr. David Sirois-Okay so what are the kinds of things we can detect? Well not only can we detect when a stimulus contacts our somatosensory surfaces, somatic sensation, we can also detect position of body parts in space. And I want you to understand the complexity, and Ill emphasize it as we go along, of the orofacial region. Im sitting here talking to you moving my mandible, using my masticatory muscles. Also Im using the hypoglossal muscle to move my tongue. Um Im doing all 2

Transcribed by Lila Kakar

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of that and Im using my facial nerve to articulate and phonate by my facial muscles, right? And Im doing all of that without thinking about it and Im not biting my tongue or biting my lip in the process. Those are highly complex sensory motor integrations that occur between nerves that you dont even think about. You have to think about speech when youre learning just like you have to think about walking when youre learning to walk but after a while its happening at a subconscious level and what are the systems that support that and what happens when they are disturbed? So patients dont think about chewing they just do it. You put a high restoration in a patients mouth and all of a sudden they bite down and hit one high spot theyre gonna invoke a jaw opening protective reflex. How do they detect that? And what can they do to contribute to their clinical problem? And how can you identify and resolve it? Theres a simple example. Okay so knowing where you are in space. Now to give you a sense of the complexity look at the fidelity. Nowhere, if you were to try and determine the sensory resolution of your different body parts. So for instance you can detect two points as being independent or separate and if you move the as close together as you can you find a threshold where you lose the ability to discriminate them as two points. You know that there are areas of your body that are more sensitive for that like your fingertips or your lips than other areas of your body like your ass, right? Now I can guarantee you thats a fact now whats the neurological organization that supports that and why is that important and Ill tell you now that the resolution-this is phenomenal. Have you all used articulating paper yet? So articulating paper is essentially carbon paper when youre creating an occlusal surface in a restoration and the teeth have to come together there has to be normal contact if its abnormal it wont work right or youll break a tooth or youll break a restoration. Youre ability to detect something between your teeth is on the order of 50 microns thats one twentieth of a millimeter thats a sheet of paper. Thats a piece of articulating paper that we put between your teeth or a skin of a popcorn kernel when you bite down. You can detect that. And nowhere on your body-the closest you can get to two point discrimination anywhere else on your body on your lips or your fingertips where its the most sensitive, the best you could do is maybe 8 mm. An order of magnitude larger than that. So thats highly sensitive in the trigeminal system and thats phenomenal, it really is its a challenge. What are the sources of detecting those stimuli and whats the process by which it happens? Thats important to understand so you can directly understand disturbances when they occur. And of course other important oral experiences or peri-oral are taste and smell but those are being covered in other lectures so well stick to somatosensation okay. And then well talk about craniofacial integration and the kind of complex behaviors like speech and swallowing that I just mentioned that are integrated and subconscious. Okay. [Slide 5] Sensory Neuraxis vs Motor Neuraxis (image) Dr. David Sirois-Just to remind you, youve probably already had this, and if you havent and Im making an inappropriate assumption interrupt me and say we dont weve never heard that before. But I would imagine at this point you understand the simple principles of an ascending sensory projection or a neuraxis that goes from out here in a skin receptor somewhere out here or if your detecting proprioception, 3

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a muscle or joint. And theres a primary afferent that connects and that primary afferent has a synaptic connection either at the segmental local level like the spinal cord if youre a spinal nerve or the trigeminal brainstem complex if youre a trigeminal nerve and then it has a second order projection that might go up to the thalamus and then a third order neuron that goes on up to the cortex to where our awareness or consciousness is. So thats an ascending typically three neuron relay for detecting sensory information. And likewise we have a motor neuraxis which is a descending projection, when the cell bodies of the upper motor neuron live up in the cerebral cortex the precentral gyrus. Um and they project downward and will synapse either in the trigeminal motor nucleus or somewhere in the ventral gray horn in the spinal cord and give rise to a motor neuron that goes out to your extra fusal muscle fibers, is that familiar? Thats basic anatomy. [Slide 6] Neuron (image) Dr. David Sirois-Ok. Um and of course what makes nerves so interesting is that their excitable tissue. Um and you know that nerves store energy because they have selectively permeable membranes and by blocking the conductance of an ion across that membrane-whoops, keep hitting the wrong button- we block what would be the natural downhill electrochemical gradient of an ion because weve blocked a channel we create a store of energy. Its like having a racing car in a pinewood derby or something held high up at a point by a gate and gravity is the force. Thats your potential energy, release the gate the car rolls down the track. Similarly here open up the channel, the ion flows and there is a depolarization of the membrane and thats what makes it excitable and you know that a neuron has literally tens of thousands of synaptic of- excuse me- of receptors connected to it and I want you to understand that the complexity is phenomenal. Its nowhere so simple that you touch, stimulate a single nerve, and get a simple perception. Its always more complex than that. Youre instantaneously integrating thousands of inputs that are both excitatory and inhibitory and youre creating a sort of population response, hundreds or thousands of neurons responding to a stimulus ultimately to lead to some sort of perception. But on an individual neuronal basis which is what we are looking at down here, this one neuron has to decide as it takes all of these inputs and integrates them instantaneously its going to ask one question: am I going to what? What does a neuron do? It has an on or off phenomenon. On or off whats happening? Student-Action potential Dr. David Sirois-An action potential or not! So neurons encode all of our experiences and signals to muscles as a series of action potentials. And the only thing, you know a single action potential is stereotypical. It looks the same. But what makes a unique message is the population response of thousands of action potentials so what youre really creating is a spatial and temporal message a population code where you have action potentials that vary in frequency how fast is a neuron firing and how many neurons are doing that and you create a message that way. So at the simple neuronal level yeah its just on or off but its thousands of neurons that are creating a message. Alright and so you know that over here on the right hand panel we hold essentially a neuronal membrane at a resting potential with a resting neuronal 4

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membrane and if we allow that to depolarized by hitting a critical depolarizing threshold youll get an action potential. And the way that happens is by sodium crossing the membrane down its electrochemical gradient and depolarizing or making the neuron more positive. Likewise we could increase chloride conductance and chloride conductance would hyperpolarize the neuron moving it further away from the threshold potential and therefore make the neuron less excitable, right? So you can create inhibitory situations or excitatory situations. So that adds more complexity. Imagine this single neuron here on the left receiving thousands of inputs and each of those receptor potentials is contributing a small part of energy excitement to that neuron that help it decide: Am I going to have an action potential? So you have thousands of additive inputs so if right here you inject a single inhibitory current you can shunt that entire neuron and shut it down. So even though its welling up with excitement you can throw some water on the fire so to speak, and hyperpolarize that neuron and its no longer excitable. And thats important because youre going to do that pharmacologically every day of the week, unless youre and orthodontist but even orthodontists use local anesthesia sometimes. Because local anesthesia blocks sodium conductance, and if you block that from happening you dont depolarize. But we also prescribe them medications that can be analgesics or antidepressants or anti-anxiety drugs and thats because they reduce neuronal excitability as do some analgesics and morphine as an example, so we can hyperpolarize a neuron using drugs, increased chlorine conductance for example, or we can use drugs like local anesthetics or wht class of drugs do you think is the most common class for blocking sodium conductance other than local anesthetics? What other class of drugs do you think is primarily designed to depress neuronal activity? Think about a clinical disorder thats characterized by almost uncontrollable electrical activity. What? Say it. Student-Seizures Dr. David Sirois- Seizures, seizure medication. Anti-convulsant anti-seizure drugs commonly block sodium or calcium conductance or the both of them. And therefore make a neuron less excitable. Okay so thats really important to consider and its worth [Slide 7] Synaptic transmission (video) Dr. David Sirois- even for a moment. Okay so lets just take a look two neurons talking with one another a presynaptic neuron is gonna get depolarized and release a neurotransmitter and that neurotransmitter binds no crosses the synaptic cleft and will bind to a postsynaptic neuron and- for some reason I cant see whoops I know what Ill do hold on, okay- so just again to cover this briefly ill use a few movies to illustrate some points so again here we are not talking about sensory transduction where stimulus is being transferred or translated from a stimulus energy such as touch, heat, cold into a stimulus, well talk about that shortly. Here we are talking about two neurons along a relay exciting one another and they do that by releasing a neurotransmitter across a synaptic cleft and that neurotransmitter will bind to its unique receptors. And if it binds and adds up enough, again, local depolarizing currents itll cause that postsynaptic current to add up in time and space and depolarize the second order neuron and pass along an 5

Transcribed by Lila Kakar

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action potential signal. So again here the pre synaptic neuron on your left has an action potential thats coming down and once again gets to the end will cause a release from these vesicles of neurotransmitter and theyll bind to the post synaptic receptor and create what are called post synaptic excitatory potentials thatll add up in space and time that will cause depolarization of the resting membrane. Okay. So these excitatory post synaptic potentials add up. I just want to wait for one moment to show you something and then well move on. Okay so the presynaptic current, they release it, and youll see here these small excitatory post synaptic potentials here and the amplitude of that small potential. If enough of them are delivered theyll add up and the height of this will get larger and larger and cause a depolarization. Similarly we could as I mentioned earlier now look at this complex relationship between two neurons were releasing here a neurotransmitter called GABA and when GABA binds it causes an inhibitory potential to occur and hyperpolarizes the cell and makes it less reactive like we spoke about a moment ago. here we get inhibitory potentials and theyll add up and the reason thats important well come back a little bit later before the end of our time together to understand and here you can see the negative amplitude of the inhibitory potential but whats occurring is just imagine this single neuron right here literally with tens of thousands of connections coming in and at any point in time this one neuron is simply integrating all of those inputs and so its receiving all of these excitatory inputs and yet you could hyperpolarize that cell by some simple strong inhibitory potentials down here near the axon hillock and that would prevent this cell from depolarizing. So here this cell is adding in space and time and these inputs are coming in and if enough of them add up youll fire an action potential down here and as you can see theyre just adding in space and time and all of a sudden you get an action potential but we can easily shut that down by simply hyperpolarizing that cell so these excitatory potentials can be shut down and the cell becomes unresponsive. So just a general introduction of this excitable tissue-And its important [Slide 8] Sensory receptors Dr. David Sirois-were gonna talk about some anatomy, but always layered in the background of that anatomy is some function. Alright let me put it back in presentation, so how does all this begin, of course, you remember that out in the periphery youve got receptors and those receptors are intended to detect things happening in your environment, and we have mechanical receptors that detect touch, and we have low threshold mechanoreceptors that detect light touch and we have high threshold mechanoreceptors that acquire more activation and they are encoding maybe painful touch stronger magnitude, youve got thermal receptors, that detect changes hot and cold nociceptors that vary widely in what they are detecting, both mechanical and thermal and even chemical injury to the tissues and so forth. So these receptors are very unique so a mechanical does not care as an example about a thermal stimulus, you can heat up a mechano-receptor all you want, its not going to fire. So a very important part of how we can tell that this is a touch stimulus versus a warm stimulus is something called the modality specificity of a receptor. Modality specificity, that is receptors are tuned to specific energies, 6

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and they only respond to those energies, and they encode them with receptor potentials and well look at them in a moment. [Slide 9] MR MOV 04 (image) Dr. David Sirois- You may have remembered youve studied in histology and even microanatomy this wide variety of different kinds of receptors that are in the skin and mucosal surfaces and they detect variably vibrations, high threshold, low threshold, and even proprioceptive signals. And the way that a mechanical just to remind you [Slide 10] Mechanical Senses (video) Dr. David Sirois- the simple mechanical receptor works is, as a stimulus comes along so keep in mind that anywhere in your skin or mucosal surfaces, anywhere that you look youre gonna have a wide variety of these different kinds of receptors. So they have to be distributed in your skin, in a manner that allows any area of the skin to be able to detect both thermal, mechanical, and chemical stimuli. So youll have a variety of different kinds of receptor types in your skin or mucosa and along comes a stimulus and by the way there is also free nerve endings for detecting pain signals, but when a simple thermo, excuse me mechanoreceptor stimulus comes along, as in this example and you know that these mechanoreceptors are sort of arranged in this onion skin, like this onion skin approach, or design, and when mechanical forces delivered to that receptor as youll see in a moment it deforms the receptor and the deformed receptor allows the flow locally of a small receptor current. So each receptor generates a small receptor current you can see right here, and these will add up in space and time, so if youre getting touched, let me ask you a question? How do you know Im touching you with one pound of pressure or 10 pounds of pressure? How do you know that? How do you tell the difference? So imagine the heavier stimulus is going to deform a greater area of skin as an example its gonna recruit and involve a larger number of receptors, those receptors are either gonna be low or high threshold depending on their tuning properties. So youre gonna get a larger population of neurons and receptors responding so you essentially encode the stimulus based on a population signal, hundreds or thousands of neurons and the way they encode that is exactly as you suggested, the more pressure the more receptors and so we integrate and add those in both space and time to create a signal. Ok? So were gonna talk a little bit about some important organizational properties like receptor fields theyre very important to understanding how the patient is experiencing their sensory world, but enough to say for now that those sensory receptors detect things in the simple ways that I just showed you and they create the important message here, is that they create receptor potentials, and receptor potentials are linear. The more force the greater the potential period, so it is literally almost a linear curve up until the point where they become saturated, thats very different from an action potential. An action potential is on or off there is no difference between action potentials, the only difference is the frequency and populations of neurons that generate a spike train or an action potential train, so receptor potentials are linear and they correspond to the intensity of the stimulus so

Transcribed by Lila Kakar

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the way that we encode stimulus intensity is the addition in space or time of all of those receptors. [Slide 11] Action Potential movie Dr. David Sirois -so a stimulus with that much energy will create a receptor potential that looks like that and it may or may not be enough to generate some action potentials, if I deliver a larger stimulus it will create a larger receptor potential and that will create a different action potential train that differs in frequency as you see here, and of course it will involve more neurons, and so locally whats happening in this excitable tissue is youre creating larger degrees of a local capacitive current thats going to travel down the neuron or along the dendritic tree and add together with other currents and if its enough it will create action potential. And you know that along the neuron itself some neurons are myelinated and some are not. And that myelin is insulated protein that makes the conduct at a faster rate because the stimulus of the potential can jump from one node to the other. We will review that in a moment that its at a much faster rate than just spreading along a neuron thats unmyelinated. So this local current that you see right here is just gonna spread down the neuron depending on whether its myelinated or not then itll happen at a different rate. [Slide 12] Ionic Basis of the action potential Dr. David Sirois-Um ok let me skip by this in the interest of time. [Slide 13] Mechanoreceptors: skin, mucosa, teeth, pdl, tmj Dr. David Sirois -So now lets talk about the unique kinds of receptors that are in the oral cavity that youre going to be dealing with for the rest of your life. So, we certainly have plenty of free nerve endings, in fact if you look at the pulp of teeth alone, the pulp most of us dont have sensory experiences with our teeth. The only sensory experiences you have with your teeth are usually unpleasant ones you dont feel warmth in your tooth or cold in your tooth unless its uncomfortable so the pulp is largely filled with free nerve endings and other kinds of receptors that detect noxious stimuli so the pulp is highly, leans highly towards nociception. Alright, thats unlike the skins surfaces or the mucosal surfaces and your ligament your periodontal ligament around the root of a tooth where we have the full spectrum of receptors that allow you to detect sensory pleasurable experiences as well as noxious ones. Alright so free nerve endings are very prevalent throughout the skin and mucosa and almost exclusively present in the pulp and you have a variety of other kinds of mechanoreceptors that youve learned about elsewhere distributed in the rest of the muco-cutaneous surfaces. [Slide 13] Mechanoreceptors: deep tissues Dr. David Sirois - And you also saw, so thats it the superficial layer of the mucosa and skin, you also have them in deeper layers like ligaments and joints, temperomandibular joints, and muscles, mastication is an example. So all of these things are receiving inputs and encoding those in the trigeminal system and you know the trigeminal system is not your exclusive nerve for sensory information in 8

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the orofacial area somatosensory information but its nearly exclusive. There are a few other cranial nerves that provide somatic sensation but theyre in very small areas, the trigeminal is largely the nerve from your neck up that provides somatosensation with a few exceptions. [Slide 14] Thermal Dr. David Sirois-Alright and you know that if you look at say a thermal receptor as an example thermal receptors, just like mechanical receptors, can be low threshold and high threshold and they encode or transduce light stimuli or painful stimuli. Thermal receptors are also in tune to different ranges of thermal stimuli. So you have some thermal receptors that encode comfortable temperatures and you have nociceptive thermal receptors that detect um temperature stimuli that are in an injurious or noxious range. Ok. But again all of the specificity is at the receptor level. Receptors are tuned to only their kind of energy and thats [Slide 15] Stimulus response Dr. David Sirois- how were able to extract the quality of a stimulus. Alright, so if we look at now a stimulus response function in a simple case of say touch, in this simple example you could imagine if I start touching you lightly it doesnt hurt but by the time I get up to 15, 20, 30 pounds, that becomes painful so youve got a spectrum of increasing mechanical stimulus that gets encoded, say the stimulus intensity along this line. And everybody in here has different threshold where all of a sudden that thermal- excuse me, that mechanical stimulus becomes painful. Everybodys line is in a different position and your line today could be different during this one hour could be different from the threshold from an hour from now, cause it also depends on your own state of arousal, excitement, other things that are happening to your nervous system at that moment, so this is highly variable, but what we do know as a principle is that the stimulus intensity as you add increasing stimulus the stimulus intensity gets encoded because your adding up receptor potentials and youll cross this threshold where something becomes painful. And when it becomes painful we use the term hyperalgesia which means increased pain perception but its simply a shift to the left and youve increased the gain of this neuron so now a stimulus intensity that used to be encoded at this level is now encoded at a higher level I want you to understand something very important about this, this is called primary hyperalgesia, but the stimulus response function is based on the added stimuli or the added receptor potentials that add together but it depends on whats happening in your nervous system about how that gets processed so as a simple example whats your name? Student- John Dr. David Sirois- John, im gonna ask you a personal question, its not that personal, what temperature do you like to take a shower at? Were all picturing you naked now *laughter* Student - hot Dr. David Sirois- Hot? Pick a temperature, 100 degrees? a little warmer? Student- 80? Yea 80 9

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Dr. David Sirois- 80?! Student -I dont know the temperature Dr. David Sirois- alright whatever that number is, lets say it feels good at 95, thats where you like it, have you ever had a sunburn? Student-yea Dr. David Sirois- jump in the shower; turn it up to 95 how does that nice warm shower feel? Student- hurts Dr. David Sirois- it hurts, same stimulus why did it change? Why under one situation, does 95 feel good and in another situation 95 feels bad? The stimulus energy is exactly the same, why does light touch on my skin right now feel good but if I do it on top of a burn or ulcer it hurts? What happened? Not just directing this at you now John, but everyone, what happened? Your nervous system changed to contribute to your sensory experience if your nervous system is sensitized itll lower the threshold and increase or amplify the response. So its the nervous system thats changed when the sunburn leads to pain, now a bed sheet or a t-shirt hurts, and now 95 degrees hurts, and now light touch hurts. So the nervous system actively shapes the sensory experience but in the case of primary hyperalgesia its receptors sensitization that occurred out in the tissue at the sight where there was tissue injury you burned yourself what is the process that happens at the sight of injury that causes sensitization? What process occurred there? Huh? What is the sight of injury always look like? What are the cardinal signs of injury? Inflammation, swelling, redness, right? So inflammation the chemistry of inflammation sensitizes the nerve and the reason 95 degrees felt worse is because the chemistry of inflammation sensitized those peripheral receptors and now theyre like receptors on steroids. They are responding at a lower level and with a greater magnitude but its very important to recognize that the stimulus energy did not change and the nervous system interacting with the immune system shaped your perceptual response. And then theres another example of allodynia and allodynia, these are important terms for you to understand, hyperalgesia and allodynia. Allodynia is a perception of pain even at the lowest level any degree of touch hurts, now sometimes you do in fact get mechanical allodynia at the sight of injury even a light touch hurts. But were gonna talk more Ill introduce you to the concept and well talk more about it next year when a nervous system starts misbehaving when you have pathological conditions that change the stimulus response behaviors all of a sudden you can now have a patient that responds to light touch with horrible pain. So, do any of you know of a painful condition unique to the trigeminal nerve that arguably has been described for the history of modern medicine as the worst pain known to human beings? Trigeminal neuralgia, classic example of allodynia and neuropathic pain. Light touch, I just went like this, the wisp of a makeup brush, you know, shaving, intense lightning bolt pain. Now the difference there is that whats missing in trigeminal neuralgia is there is no inflammation there is no pathology out there in the periphery. There is no chemistry of inflammation that sensitized those neurons, thats pure neuropathology, thats the nervous system amplifying your response in a pathological way and its hyperexcitable. So a message here for you, is always think when a patient says, Im in pain, look to see if you can find some 10

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proximate local cause for that, is there evidence in the area of pain, of inflammation. In the absence of that evidence of inflammation that you can either detect or hypothesize like you cannot see inflammation inside a patient with pulpitis yet they have a toothache but you can deduce thats happening because they have decay, as an example. Alright so I want you to understand, hyperalgesia and allodynia, in the stimulus response spectrum of the nervous system. [Slide 16] Chemoreceptors Dr. David Sirois-And chemo receptors Im gonna skip by this because others will be talking to you about chemical senses of detection in the interest of time. [Slide 17] Muco-cutaneous innervation Dr. David Sirois-Now I wanna go back and remind you that Ive already stated that throughout your somatosensory surfaces, skin, and mucosa youve got a full spectrum of mechanoreceptors they are distributed all over the place throughout your body. These different receptor types. And they are each tuned to different mechanical-uh, different stimulus energies, weve already made that point. So that the idea for a patient of modality specificity, your ability to detect touch is touch, temperature is temperature, vibration is vibration, taste is taste, is entirely ground in receptor specificity. Period. Just like when you tune the radio to 94.4 youre only picking up those frequencies and youre not hearing the music thats occurring at 105.9. You have no idea whats happening because you cannot detect it, yo cannot detect it you cannot experience it, alright and we know that the nervous system is organized in such a way that these receptors connect to some primary afferent neurons and youve heard about the A- and A- and C-fibers, and these fibers can be myelinated or unmyelinated and they support different kinds of modality experiences, touch, temperature, proprioception, and pain. [Slide 18] Sensory fiber types in a cutaneous nerve Dr. David Sirois-And you know if we were to take any peripheral nerve and cut it in half and look at the spectrum of thousands of neurons that are in an individual peripheral nerve I just cut your mandibular nerve and look, Im going to see a mixture of sensory neurons depending upon the nerve, I might see a mixture of motor neurons, Ill see maybe a mixture of autonomic neurons in that nerve and so forth. And they have different properties so you know you have C-fibers, A- and A fibers and they have different conduction velocities and different diameters. The larger diameter fibers are the ones that are heavily myelinated and theyre also conducting the fastest, right? And the C-fibers which are unmyelinated have the smallest diameter and they conduct the slowest we also know that in a very simple way we attribute different kinds of modality properties to these, so youve probably heard the idea that C-fibers are generally attributed to detecting pain and temperature, noxious temperature C-fibers. And you know that A- fibers, excuse me, A- fibers, are also pain detecting. So youve got this variety of neurons in a peripheral nerve and you might ask yourself then why do you have if you add up, A and C-fibers? Youve got nearly 3 times as many neurons for detecting pain painful stimuli as you do the pleasant ones like light touch. Why do you think thats the 11

Transcribed by Lila Kakar

02.06.14

case? Why have so many pain detecting neurons? One could be in a Darwinian sense you know the better able you are to detect a threat to your existence the better you are to survive, thats true, but its also true that these neurons are doing more than those simple functions appear so neurons, yea, theyre built to send action potentials, sensory neurons up to consciousness, but they also do other things. [Slide 19] Primary Nociceptive Afferents Dr. David Sirois-So particularly C-fibers, in fact not only are they sending electrical information to the brain they are also detecting the chemical environment in which their neuron ends, their dendrites end, so their detecting the chemical environment, if there is inflammation there that generates slower kinds of process, process that are actually axonal transport, and biochemical and molecular signals, that are transported through the axoplasm slowly, on the order of days it might take for a trigeminal nerve to send something by axonal transport from the periphery to the second order neuron. Imagine how long it might take for one neuron thats going down to my great toe the cell body of that neuron, is up in my lumbar spinal cord and its one cell thats 2 and a half feet long so these neurons are more sophisticated than just transmitting electrical activity theyre detecting stimuli chemically they also can sense stimuli in a retrograde direction, so you think about a sensory nerve as just sending action potentials to the brain but actually it can send electrical signals in the anti-dronic direction that is out towards its dendrites, and it can also send chemical signals that way, so in fact neurons can influence the environment theyre in and in fact if I go in, listen to this very carefully, if I stick a needle into your peripheral nerve and I stimulate it at the right frequency, so I select out c-fibers that are responding to that frequency I can cause by electrical activity alone, inflammation. If I stimulate that C-fiber I can get it to cause inflammation, in the terminal field that it innervates because it releases neuropeptides like substance P and CGRP and these are chemicals that when released in the periphery are pro inflammatory. So neuronal activity can not only just lead to signaling experiences that rise to consciousness they also can contribute to events that happen out of the periphery, thats important to understand. Were gonna talk by the time we end this week about when the nervous system is under the assault of an injury youve often experienced that, all of a sudden it hurts not at the site of injury but radiating out from there theres a larger area that becomes painful, even though there is no pathology in that tissue. Why did It become painful? Theres no inflammation there, how did that happen? Youre gonna have patients who walk in and say doctor, look at me for a minute, they say doctor, I have a toothache, and they point here, well which one of those 16 teeth hurt? I dont know, its here. So their ability to localize a stimulus can become difficult, because of the way the nervous system is organized receptive fields well talk about but also how it changes under situations where things get amped up. Now importantly, there are a group of neurons, called silentnociceptive neurons and these neurons are sitting there quietly, unresponsive under normal circumstances, [Slide 20] Peripheral sensitization and silent nociceptor activation

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Transcribed by Lila Kakar

02.06.14

Dr. David Sirois- So if we look at this very simple experiment, which elegantly illustrates and will end after the next slide or two so here we have recording electrodes, in a cat were not moving the position of those recording electrodes, theyre in the spinal cord and theyre recording from the same group of neurons, were not changing that. But what were doing is and were recording those neurons response to flexion or rotation of the knee, noxious rotation which means youre really rotating it in a painful range, or your just bending the knee so, youre stimulating here a flexion, youre bending the knee, and thats what you can see when youre recording from those neurons, you can see theres really no activity, then inject into the joint that those neurons innervate, inject into the joints something called kaolin, now kaolin is a way to introduce experimental inflammation, arthritis. It causes inflammation in the joint we already discovered that the biochemistry of inflammation sensitizes the neuron and its what causes primary hyperalgesia, pain to non-painful stimuli. Right? I showed you that graph. And as you look emerging now after one hour,2 hours, 4 hours the same neuron that was quiet is now increasingly active. So you get a nervous system that under the influence of a prolonged painful stimulus, inflammation, becomes increasingly excitable, and thats really important to recognize because that increasing excitation accumulates and can trigger process like pathological pain, or the spread or referral of pain. The inability to then localize the pain well so sensitization can recruit to class of silent nociceptive neurons and when they get turned on they cause a lot of what we well call generally, plasticity. [Slide 21] The process of feeling Dr. David Sirois-So let me just end with this last topic and we will accelerate the pace a little bit next time it will be easier to do. But I just want you to part today thinking about if you were just looking at the logical series of events to occur to support the process of feeling so first you have to be able to detect a stimulus, you have to know that somebody touched you if you cant detect a stimulus you cant have an experience, and you have to extract, was that a touch a thermal, a vibration, was it sharp, was it dull, whats the quality of that stimulus, location, intensity, is it one pound? Or ten pounds? How do you extract all that information? Once youve extracted all that information and encoded it it has to get connected or communicated along an anatomical substrate, a cable, thats your neuron, your primary afferent, your nerve, and then now that has to get integrated into your central nervous system, cause whats the first thing that happens after youre walking across the living room and boom you whack your shin across the coffee table and you say shit! After you do that whats the next thing you do? Student says: grab it Dr: grab it and what do you do to that site? You just injured it what do you do? You rub it. Did that make your pain feel better? Yes it did. Did it change when you were rubbing it, did it erase the injury in your tissue? Did it? No. but what did your rubbing do? It provided another stimulus, it provided a non painful stimulus, and now that non painful stimulus is going to compete with that painful stimulus for consciousness. And that in fact is what happens, so the point is that your perception at any moment in time is the instantaneous product of integrating all that sensory 13

Transcribed by Lila Kakar

02.06.14

information, so you can change your perception just by changing the level of neuronal activity, integration, modulation, and eventually you get a perception. And that perception can be modified for instance on even the simple idea of even massaging the non with a comfort stimulus then you have a response. So lets stop there and pick up next time and get a little more exciting about how the system supports that, were gonna change and get a little more clinical.

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