okay let's get started with some neurologic pathology the first thing that we're going to talk about is the me mea mechanism of brain injury so at the root of most brain injuries there's going to be an inter ition or blockage of blood flow to the cells resulting in some dysfunction so the mechanisms so they can happen in a number of ways we can have mechanical trauma we can have a schem and often one leads to the other some problem with the ability of a cell to produce energy so a Cell Energy failure in injury induced apoptosis reperfusion injuries so that's where we've had sisia and then we reintroduce a a blood flow with oxygen so these are all factors that will contribute to brain injury uh and we can sort of subcategorize these injuries as describing them as either primary injury so another way to think of that is that it's acute so this is an injury that occurs immediately after um whatever the triggering factor was so there's no time for intervention until it's already presented presented itself so this would be an example of a an es schic stroke where there's a blockage in a blood vessel and there's an immediate response um it might be the result of a trauma um like what might happen if there was some kind of a sheer tearing of tissues in the brain maybe with a a severe Whiplash or concussion type scenario but basically in in any of these situations there's a sudden stoppage in blood flow now a little abbreviation symbol for blood flow is a q often with a little dot over it like that so I'm going to use that going forward when we talk about blood flow because it's EAS than trying to always read my writing hopefully it is anyways um so our concern here is that if the esea is for any significant length of time and it in the neur neurons it doesn't have to be very long seconds typically uh then it could be result in some irreversible damage to the cells um so we get the possibility of ear irreversible esia and that might lead us to cytotoxic we're going to explain all of this cytotoxic edema and that's mainly because the cells uh lose their integrity the cell membranes lose their integrity so they lose their ability to selectively be permeable uh and as a result contents from inside the cell are able to escape and contents from outside the cell are able to enter uh and as a and and so we get a complete loss of Integrity within that group of cells that's affected by all of this if we describe it as a secondary injury secondary injuries are are subsequent to some sort of challenge subsequent to the onset or damage that we experienced and it may take uh anywhere from as long as days to weeks maybe even months in some cases to present themselves so since it's slow gradual it may lend itself to apoptosis but remember hopefully from your previous pathology course uh you'll remember that apoptosis is a is a process that's NE and tidy and organized cell death sometimes nicknamed as a cell suicide but it requires energy we need to have energy so if there was a sudden stoppage like we were describing in our primary injury there would no wouldn't be any availability of of ATP or energy sources so the the process of cell death in the primary injury would be necrosis and it's messy and inflammatory and and um that that kind of thing separates the two so basically necrosis is the result of of severe or sudden whereas apoptosis is the result of moderate type of injuries and it's all basically based on ATP availability so let's take a closer look at esia with respect to its effect on neurons primarily or let's actually call it an es schic injury so basically any any reduced blood any reduced oxygen delivery to the neurons would be described as a type of potential es schic injury it could be because there is reduced uh blood flow to the tissues that we're talking about neurons or it could be that the content of oxygen within the blood that's being delivered to those neurons has been reduced so basically when we have a when oxygen demand is not met by blood flow so either because the content of the of the blood is reduced in oxygen or the total blood flow to the cells are reduced either way the cell is going to respond the same way there's not enough oxygen being delivered to that cell so typically this is going to contribute to in one way or or another to most types of brain injuries um and that's either because the primary injury or the secondary injury results in reduced uh oxygen delivery so we're going to end up with abnormal neuron function and there's often going to be some loss of Auto regulation so one of the ways that we can regulate blood flow in all over the body is referred to as Auto regulation if there's reduced flow uh reduced oxygen being delivered to a group of cells chemicals are released from those cells that promote vasod dilation and vice versa if there's plenty of delivery of oxygen and nutrients to a cell then chemicals can be released that would result in local vasil constriction that's what we're talking about when we talk about um Auto regulation so typically if oxygen delivery is altered is is not being the demand is not being met then there's going to be either depending on on the onset either it's going to result in a primary injury or secondary injury and that likely somewhere along the line will result also in a in an abnormal Auto regulatory response either the abnormal Auto regulation could be part of the cause or part of the response because of the reduced oxygen availability everything starts to break down so when we have es schia one of two things is going to happen we can have immediate neuron pathology because those neurons can't produce enough ATP so we're going to talk about the mechanism that results from that in just one second the other possibility is that it sets up secondary and that's basically what happens when there's reduced oxygen delivery that more gradual onset that we talked about but it allows for an increase in free radical what are more completely referred to as free R radical oxygen species those free radical accumulations that we've mentioned before so the other possibility is that we get this accumulation of free R radicals let's call that an a the other uh thing that can happen is we can get an accumulation of what are referred to as excitatory um proteins amino acids we'll talk about those a little bit later and inflammatory reactions so normally oxygen is going to be required in order for molecules to accept electrons within the electron transport chain in the mitochondria that's what one of the reasons why oxygen is so important in the production of ATP within the mitoch condure remember if you don't have oxygen you can't get the products from glycolysis to enter the mitochondria if you can't get uh the pyate to enter the mitochondria to become a SLE coenzyme a you can't activate the KB cycle and then the electron transport chain so that's why oxygen becomes so important so if the mitochondria can't produce ATP because of the lack of oxygen available for pyruvate entry then what's going to happen is we're going to have to depend on Alternate Pathways if oxygen isn't available then anerobic pathways are initiated or become dominant and in anerobic Pathways what we're talking about is that the pyu levels increase and as pyruvate levels increase the liver is going to convert a percentage of that pyruvate to lactate so that's happening in the liver and lactate is otherwise known as lactic acid so that's going to lead us to acet dois and acidosis of course is a Dr is is a decrease in the ph and a decrease in pH is toxic to neurons so this sets up an environment that's very dangerous for the uh the environment of the neuron and and we have of course a decreased ATP in the [Music] neurons causes ion gradient pathology so remember for a neuron a neuron was described as being excitable and that meant that when you depolarize that neuron it could generate an action potential to deliver an electrical signal to the next cell in the pathway whether that's another neuron or an effector like skeletal muscle or smooth muscle or cardiac muscle so in either case that transmission is going to become abnormal not enough ATP in neurons causes abnormal ion Behavior so for example we're going to have an abnormally functioning sodium potassium pump remember it's described as being an active pump it requires ATP so if we have an abnormal sodium pottassium pump then we can't adequately set up the polarized membrane effectively potassium typically is going to leave from inside the cell and not be adequately uh return not adequately returned sodium and chloride and calcium ions are going to enter so that's going to change the uh polarity of the cell it's going to actually promote a depolarization but it's a it's referred to because so let's let's make sure we so pottassium leaves and sodium chloride they typically go hand in hand and calcium they can all enter calcium leaves and I'm going to have to move that to another slide because we've lost with no O2 we get no ATP we become anerobic that's a quick summary of what we were talking about on the previous slide okay with anerobic [Music] um me mechanisms we lose and our sodium potassium pump becomes abnormal we said that pottassium can leave the cells so normally it's the number one positive ion inside the cell it's going to leave the cell and sodium chloride and calcium can enter the result of those primarily those positive ions entering into the uh cell is that we get what's called an anoxic lack of oxygen depolarization so the neuron is going to become excitable so what this means is with with no at P we end up with an abnormal calcium balance abnormal neuro transmitter production or synthesis because we've lost ATP now the cell's losing its function one of the function of these neurons is to produce neurotransmitters for the electrochemical transmission of signaling within the nervous system if you reviewed those those recordings on the nervous system you'd recall all that okay and the other thing that's going to happen is that the neurotransmitter mechanism for uptake is going to be reduced so we're we're going to talk about an example of that in just a couple of minutes but basically what that's going to result in is more exposure of the subsequent cells in the nerve pathway in the neuron Pathway to that neurotransmitter if that neurotransmitter happens to be excitatory it makes the cell more depolarized or more excited and maintains that excitability that becomes a neurotoxicity and the that can't be sustained all of that can't be sustained so the result is going to be necrosis or apoptosis depending on whether it's a primary or secondary circumstance so let's take a look at a couple of these things let's take a look at what happens with respect to abnormal calcium so if we said that we had abnormal calcium metabolism when we don't have enough ATP what does that mean so the thing to keep in mind is that calcium is a really important signaling molecule and lots of molecules including hormones and neurotransmitters are examples of signaling molecules calcium is an ion that's an important signaling molecule in a lot of cases accumulated levels of intracellular calcium for example within the the cytoplasm of the cell indicates a pathology and might signal a proptosis so um what we're concerned about is that if the calcium is accumulating in the cell it may indicate a signal for apoptosis cell suicide so the mitocondria normally mitochondria play an important role in the regulation of intercellular calcium so they're going to sequester or take up calcium if it is accumulating in the cytool but if the at but it requires ATP in order to do that that's a it's an active transport so it requires ATP if ATP isn't available this mechanism is going to fail and intracellular calcium will accumulate so an important role for mitochondria is that as calcium levels begin to rise intracellularly they will be taken up by active Transporters into the mitochondria and removed from the cytool in that mechanism but basically if the ATP isn't available then calcium is going to be uh accumulating within the intracellular fluids and the result of those that calcium level rising is it's going to Signal the production or activation of some uh enzymes that are going to ultimately promote um uh irreversible damage to the membranes of the cell so basically this increases the category of enzymes phosph lipid Li lipases enzymes that act on the cell membrane remember about 85 90% of a cell membrane is made up of the phospholipid bilayer so these enzymes are going to attack or break down phospholipids just like the the enzyme name is phospholipase so it's going to break down uh the cell membranes irreversibly damage so if you have irreversible cell membrane damage you've lost the Integrity of that selective permeability mechanism so things can get out and things can get in now another component to what happens with with a lack of ATP available for cell metabolism is that you get the activation of these excitatory amino acids so in this situation um some of our some of our most abundant neurotransmitters are proteins made from amino acids so for example the the most common um excitatory neurotransmitter we have in the nervous system is glutamate glutamate is an amino acid that acts as a neurotransmitter so it's our primary excitatory neurotransmitter okay abbreviation for neurotransmitter and T so basically this this this uh excitatory neurotransmitter under normal conditions is going to promote normal growth and development and the maintenance of brain function so we like to have this glutamate available because it's kind of like what we talked about when we talked about um you know promoting growth and development with some of those protooncogenes when they work healthy they help regulate normal uh growth development mitosis although we don't have too many neurons that can undergo mitosis but the idea is with the uh availability of glutamate then the central nervous system is able to develop and mature and be maintained in a healthy way over stimulation however results in damage so that's that's when the so we'll say normal for growth and maintenance but overstimulation causes damage and that's otherwise known as ayto so the glutamate would be the exotoxin in this case if it's excessive so basically to give you an idea of what's going on there glutamate remember with neurotransmitters they've got a match with a receptor that's specific for that neurotransmitter so when we talk about glutamate the typical um receptor for glutamate is described as uh as a an am the abbreviation is PA so that's going to be on the target cell if we're in the central nervous system it's another neuron and when the glutamate binds with the ampa receptors it allows sodium channels to open so just the typical neurotransmitter uh electrochemical set of steps that we've always talked about when we talk about neurotransmitter activation in a cell we're going to try to introduce positively charged ions to the inside of the target cell to depolarize that Target cell and generate a new action potential so so far are exactly what we expect so these receptors open up sodium channels that's going to give us depolarization now in addition to activating these ampa receptors um the depolarization is going to make a available to the glutamate molecule a secondary receptor and the secondary receptor is described as an M NM da NM da receptor and the nmda receptor is a receptor that will um bind to glutamate on the target cell okay and that's going to promote sodium and calcium influx so in other words we now we've added calcium into the intracellular environment positively charge ion it's going to promote depolarization but when we introduce the calcium uh water's going to follow and when water follows we can get we're in at risk of what's called cytotoxic edem edema and again you talked about that when you talked about the breakdown of the sodium potassium pump and cell injury generally in uh your previous ppy of course or you should have talked about it at least so so our a am Let's uh let's fix this so when we have glutamate binding to itsa receptors sodium influx gives us depolarization but the mechanism with glutamate and the glutamate nmda promotes sodium influx and calcium influx which increases the depolarization and sustains the polarization but water is going to follow the calcium and that could put us at risk for what's called cytotoxic edema and in this situation basically if there is reduced uh oxygen delivery to the cell because of poor blood flow or poor oxygen content the reuptake of glutamate is also going to be impaired so not only do we have the actions of glutamate being excitatory and being compounded by the activation of the secondary receptor there then you also have a problem with reuptake of glutamate so it's binding to The receptors for a longer period of time and the effects then are going to be sustained so what we're going to get is the increased glutamate promoting an increase in the intracellular calcium that um becomes a vicious cycle so we already had es schea reduced ATP production now we also have a problem with reuptake of glutamate so we we we become it becomes a vicious cycle so if you remember our pathway would look something like this Let's uh put our cell two so if we had glutamate as our neurotransmitter so we'll make our glutamate green when our action potential arrives at the end of the axon and stimulates the opening up or the release through exocytosis of glutamate into the synaptic space we're going to have receptors okay now I'm going to draw them in two different colors I don't know how well this is showing up but let's uh let's put them in so we're going to call the nmda uh we'll highlight it that way and we'll make the AA look like that so then when the glutamate binds to Thea that's going to open up a channel for sodium and sodium is higher in the extracellular fluid than it is in the intracellular fluid so sodium rushes in if enough sodium rushes in we get depolarization that's all standard now the nmda receptor it is selective for both sodium and calcium so now we would have sodium rushing in and we're going to put our calcium here like this so our calcium rushes in our sodium rushes in and as a result water is going to follow the calcium in particular but basically because it's a salt or a solute it's it's going to encourage water in in the interest of trying to maintain an equilibrium and we're going to get our cytotoxic edema so those are the steps that we're talking about so our first step was the the activation of our our a MPA receptor so sodium depolarizes uh the that post synaptic cell and we and we get our action potential that but that what that does is make available the second receptor the nmda receptor and the glutamate can now bind to that secondary receptor as a second step calcium channels open up water follows there's our cytotoxic edema the other thing that's going to happen then is that there's going to be increase in total uh let's see therefore we're going to have an increase in intracellular calcium and we already know that if we increase intracellular calcium and there's not enough uh ATP available then we're going to impair mitochondrial function and that's going to increase and if we if we can't access the electron transport chain we can't get extra electrons so that's going to increase free radical accumulations so this is this this is this vicious cycle that's going to occur in the that started with reduced oxygen availability therefore reduced ATP production these are processes that require uh ATP and and in order to maintain the intracellular environment in an ideal way in the in the way that's going to allow normal transmission throughout the nervous system so logic would say that all we need to do here is fix the oxygen problem the issue is that if uh oxygen um deprivation or oxygen loss has occurred for even um you know as much as a minute within the neurons the these mechanisms have already gotten started neurons have a require a constant blood supply we mentioned this in our review of the nervous system require a constant blood supply in order to receive oxygen they don't have any ability to store oxygen they don't have any ability to store glucose so they need a constant blood flow in order to be able to make ATP they're not neurons typically are not very effective at utilizing other sources than glucose to make ATP so their their the accumulations intracellular accumulations and dysfunction is very rapid within a neuron so the the logic would say well let's just get some oxygen back in let's reperfuse these neurons the problem is that you that reestablishing a blood flow can cause something called reperfusion injury so reperfusion re perfusion so this occurs uh occurs when oxygen is reintroduced and what happens is it actually will promote inflammation remember white blood cells are presented to the esic tissue es schic cells or tissues then they release inflammatory Messengers otherwise known as cyto kindes that's just a fancy word for a type of cell messenger and the new oxygen promotes or causes oxygen damage to the DNA of these cells as well as to lipids and proteins and carbohydrates that have been depleted up till then so this all of this can lead to apoptosis so you would think that reestablishing oxygen is a good thing but if it's beyond a certain point and in in neurons it's very very short period of time the increased oxygen in the dep depleted cells gives us an increased risk for free more free radical formation that's what we're talking about when we talk about damage to the lipids and proteins and carbohydrates and an infu an inflammatory response with respect to the uh the activ of white blood cells and some of the CH the the cyto that activate the inflammatory response this is all an example really of a secondary uh type of injury right it's not acute it's going to take a little bit of time lemia causes cells to produce substrates for oxidative phosphorilation and especially free radical formation that's just another way of saying the same thing so that when the auction is reintroduced the abnormal electron transfer to oxygen creates free radicals cell membranes are damaged because of the accumulating uh free radicals and apoptosis is most likely going to occur so normally I mentioned this but we'll so normally neurons have to consume lots of oxygen for normal metabolism and have relatively uh low antioxidant enzymes and species so this combination makes the brain susceptible to reperfusion Industry uh injuries so there's a high demand and neurons also have they have a low concentration low concentration or let's a better word is low availability so between one and two the result is going to mean the brain or central nervous system is susceptible to reperfusion injuries and this this this uh accumulation of free radicals that can be accelerated during a reperfusion uh um are implicated in any of the neurological pathologies that we're going to be speaking about in the next couple of weeks like Parkinson's disease and Alzheimer's and multiple sclerosis for example and stroke for that matter as well so all of those become factors as far as uh the risk of rep profusion uh Beyond uh the time frame that that it would be beneficial and and as I've said multiple times now that's a very short period of time if neurons aren't reused within the first minute or so after esea has begun then reperfusion injury is a big risk and and and that's going to result in more uh free radical accumulations and the central nervous system is not equipped to deal with that kind of thing so I mentioned Auto regulation before but we also understand that auto regulation is going to be at least in part an active process so if we're not making enough ATP we can't have an adequate Auto regulatory mechanism so if we're talking about abnormal Auto regulation it's important we understand what it is to begin with so normally blood flow there's our symbol for blood flow again is regulated and that's going to be in response to some local factors so what we mean by that is that we can monitor the carbon dioxide levels the pH the oxygen levels um and the goal there is to make sure that if if CO2 levels are rising we understand that the CO2 levels will rise at the same time that we expect pH levels to drop so we're heading towards acidosis or oxygen levels decrease but those would all be uh signals to match flow to correct flow so we're going to monitor these gases and the effects on ph to match flow with demand so we would expect that if we have busy cells within the nervous system requiring more ATP we would expect the flow to increase and vice versa so with that in mind we can see that if we had somebody with hypotension low blood pressure right low blood pressure that could be represented as a type of esia or result in esia but hypertension high blood pressure could cause blood vessel damage and brain edema so that leads to blood vessel damage and if blood vessels are damaged in the central nervous system it can cause edema in the brain swelling around the brain so that's going to create pressure and that's going to create pathology so both extremes with respect to blood pressure are potentially dangerous to the central nervous system so blood vessels in the brain are going to dilate Andor constrict depending on the circumstances so we would expect so the blood vessels in the central nervous system are going to dilate when blood pressure is low or metabolic demand is high so if we have anything that does allow for that dilation to occur then we've got a breakdown in um we've got a breakdown in Auto regulation and that's going to result in esea so regardless of the mechanism if we can't get that that adaptation that regulation to occur we're not getting enough blood delivered to those cells it's described as being an esea now if vasil constriction is abnormal it could lead to a hyper perfusion right we expect vasil constriction to occur if the blood pressure is high and if metabolic demand is low we would expect a auto regulatory mechanism that could cause vasal constriction and if that's not all if that can't occur if that's broken down then the result could be hyper profusion and that may lead to uh edema because of the high hydrostatic pressure in the capillaries affecting the neurons and their environment so when we look at these factors when we look at the factors that we mentioned this one carbon dioxide typically is one that gets the nervous system very excited very early so changes in the blood levels partial pressures in arteries of CO2 uh lead to very quick responses so they require and they cause rapid responses so the mechanism The receptors we have that measure the partial pressures in the arteries for carbon dioxide oxygen and pH for example are particularly excitable to changes in CO2 so if the CO2 levels are rising that's an indication that the there's metabolic activity within the cells and we would expect to see vasil dilation of blood vessels so increased partial pressures in the of carbon dioxide so that little a refers to artery okay so if the partial pressure of oxygenated blood or blood in the circulatory system is rising then we're going to expect to see blood vessel dilation that's the response we would expect to see and if we have a drop in the partial pressure of CO2 to that's going to give us blood vessel constriction and this is what we're talking about when we talk about Auto regulation so in hyperventilation right what happens in hyperventilation the goal of hyperventilation is is to reduce the CO2 that's accumulating in the blood so it also is going to promote a vasil constriction hyperventilation does so hyperventilation is going to cause a vasil constriction to the cerebral blood vessels and that if we reduce we're going to be talking about Inc cranial pressure next but basically if we can reduce um blood vessel diameters in the central nervous system we reduce inter cranial pressure and if if you think about it in partly what's going to increase interc cranial pressures any kind of mass in the interc cranial space so if blood vessels are dilated they would increase into cranial pressure so when we talk about mechanisms that are responding to changes in so if we have a situation where we have our arterial CO2 is going up that promotes um well vessel dilation in hyperventilation when we hyperventilate the goal of hyperventilation is to decrease the partial pressure of carbon dioxide in the ARs so that becomes a treatment for intra cranial pressure or increased intracranial pressure because that decrease in PC2 is going to cause a constriction so the vice versa what we're talking about here is if we reverse these as we would expect constriction so the idea here is hyperventilation can be a treatment although very short-term treatment for Rising interc cranial pressure uh if if the hyperventilation causes V vasal constriction of the cerebral blood vessels you're going to decrease interc cranial pressure so it's effective treatment but only briefly because what happens is if we continue with hyperventilation it's going to lead to ultimately to decreased blood flow to the brain and if we have decreased blood flow to the brain so we're going to call this temporary relief of ICP but too long results in decreased flow to the central nervous system which leads us to esia so that's not a treatment that's going to be depended on for very long because of our concern for esia so basically if we have abnormal Auto regulation it's a mismatch between um [Music] demand and Metabolism so we're we're trying to regulate blood flow to meet those demands anything that increases metabolism of central nerve system will challenge the auto regulation mechanism so what's going to challenge uh what's going to increase metabolism of central nervous system is going to be any mechanism where we that requires thinking that requires responses to changes in our um our member of the nervous system is all about negative feedback is all about maintaining homeostasis so by definition if we challenge homeostasis we've challenged metabolism of the central nervous system uh and if that's if that mechanism of Auto regulation has broken down uh maybe because of of uh exposure chronic exposure to excitatory amino acids like glutamate or epinephrine norepinephrine remember fight ORF flight sympathetic nervous system um those types of scenarios challenge the neurons increase metabolism uh any sort of situation that's a pathology that maybe creates a bigger demand like seizures leads to worsening of these of the es schic imbalance established because of this breakdown so what our treatment goal has to be in respect to this Auto regulation a correction treatment the goal is ultimately to decrease metabolic demand so we should be basically B Ally familiar with this uh this thought process with respect to treatment goals because it applies in the cases of chronic obstructive disease in the lungs it applies to uh chronic cardiac pathologies in the cardiovascular system but in many of these scenarios an early treatment goal is to reduce metabolic demand and that is going to decrease the challenge of blood flow in this case or Auto regulatory mechanisms that are being challenged because of the lack of ATP so what first thing we want to do ultimately is consider a decrease in metabolic demand so how can we do that one way that we can do that is to introduce hypothermia hypo thermia reduces overall Demand on cells generally that decreases oxygen demand unless you introduce shivering and then that's going to increase ATP production because we understand shivering is contraction and relaxation cycles of skeletal muscles that requires a lot of ATP rest is a pretty straightforward one that would decrease oxygen demand pain control would reduce oxygen demand so these all are going to provide some relief to the auto regulatory mechanisms and less dependence on these Auto regulatory mechanisms decreased seizure uh medications if seizures are part of the underlying issue here uh removal of lesions that apply pressure and irritate or excite and a a decrease decrease in the edema that again challenges cells and creates excitation so these are all mechanisms that are designed to try to reduce the demand of Auto regulation and therefore uh provide relief at least in the short term until the actual source of the of the problem can be addressed