so our lecture today will be about cortical spreading depression now what is cortical spreading depression really we hear a lot about it when it comes to the pathophysiology of migraine but we just accept it and move on but let's talk about it more than a headache it's a neurological storm phases that shift and change form Ora to pain it's a complex disease migraine is a journey not just a squeeze cortical spreading depression is a phenomenon in migraine that is usually associated with the aura phase of migraine when it comes to Aura we have our typical Aura and we have our nontypical Aura symptoms now what's typical and what's non-typical well let's follow along with unraveling migraine so our typical Aura symptoms are visual sensory speech and or language those are our three typical Aura symptoms and they generally move in this order as well not always but usually then we have our non-typical Aura symptoms this is motor we see this in hemiplegic migraine all our non-typical Aura symptoms have their own diagnosis it's not just simply migraine brain stem we see this in Migraine with brain Samora and retinol and we see this in retinal migraine not only does cortical spreading depression result in aura or is the mechanism behind behind Ora symptoms but it also results in pain involved in migraine and we can see this again in unraveling migraine under migraine pathophysiology we see trigeminovascular system activation cortical spreading depression activates trial nerve afference innervating menial blood vessels and according to new research it also leads to changes in CSF composition now these changes include elevated proteins or elevation in certain proteins and one of the most common ones we know that is involved with migraine pain is cgrp so cortical spreading depression actually causes changes in CSF composition increasing proteins like cgrp that then find its way into the trigeminal ganglion thereby causing the pain now to understand cortical spreading depression let's break it down word by word so let's start with cortical let's just get this erased here so what does cortical mean cortical means the cerebral cortex the outermost layer of the brain now if this were a 3D image it would be the entire outermost layer of the brain but if we look at it as more of a sagittal cut we see that it's this outermost layer right here gray matter now this is important for a few reason and one of the reasons is location so cortical spreading depression usually but not always starts at the occipital lobe okay so let's actually label this end of the brain as the posterior end and this as the anterior leg just do a for anterior cortical spreading depression usually starts at the posterior end of the brain where the visual cortex is It's always important to ask ourselves why we know that migraine Aura almost always starts with a visual Aura and it may also be the only Aura present and it's also the most common type of Aura in migraine with aura but why does this occur why can't it start with a language Aura like we talked about albeit sometimes it does but not usually so why the occipital lobe well it's because the occipital lobe has the highest neuronal density in the cortex it makes it more susceptible to cortical spreading depression higher neuronal density means more tightly packed neurons which is the perfect environment for the spread of electrical and chemical changes that are characteristic of cortical spreading depression because cortical spreading depression is a self-propagating wave of neuronal and gal depolarization that spreads across the cerebral cortex at a rate of 2 to six or 2: 5 depending on which source you read millimeters per minute so it's a wave of neuronal and gal depolarization I understand you don't know what depolarization is yet but we will get to it you will understand by the end of this lecture so like we talked about this wave generally starts from the posterior end of the brain and moves anteriorly from the posterior to the anterior again occipital lobe has the highest neuronal density and we will get to this but cortical spreading depression can also be started due to the increase of neuronal activity another reason why it makes sense why higher neuronal density will result in cortical spreading depression and therefore a visual Aura is most likely the first symptom of aura and possibly the only symptom now as it progresses from posterior to anterior with migraine with aura we see different symptoms occurring so for example again in the occipital lobe let's just label this occipital we see changes in visual processing why because the occipital lobe is in charge of visual processing so when we see migraine with aura we see visual Aura now as it moves posterior to anterior we're going let's actually draw the uh Central sulcus here so we don't get confused there you go and then we have our parietal lobe so this would be our parietal lobe and when it goes posterior to anterior what was the next aura that we usually see we see a sensory aura so this would be things like paresthesia again we'll get to this in more detail a little bit later so prioloe and the prial lobe is in charge of sensory processing so this will be sensory Aura now as it continues to progress we have the temporal lobe here and we have the frontal as well now the frontal lobe is in charge of motor control however there's also a location in the frontal lobe that's in charge of language so as it progresses from posterior to anterior there are locations in the frontal lobe and in the temporal lobe that are in charge of language so temporal language or Aura and frontal also is the language Aura but also with hemiplegic migraine we have a non-typical aura so when it goes to the frontal lob and the primary motor cortex we have motor Aura okay this is non-typical the rest are typical Aura symptoms so visual Aura we start with visual Aura then sensory usually and then language third so again as CSD cortical spreading depression progresses from posterior to anterior there are an array of symptoms that can occur now not only is the location the cortical part of cortical spreading depression not only is that important but also the structure of the cortex is important too what's in the cortex the cortex is gray matter okay so let's just put fun structure so structure the cortex is gray matter that means there are neurons well specific parts of a neuron and gal cells in this gray matter and both of which are affected by cortical spreading depression so gal cells particularly asites play important roles in maintaining ion balance and neurotransmitter levels in the extracellular space so during cortical spreading depression both of these cell types are impacted neurons and gal cells particularly the asites so that's why the cortical part of cortical spreading depression is important all right let's erase this so we can move on to our next topic so we can better understand cortical spreading depression now to better understand cortical spreading depression I want to compare it to a normal way our body sends electrical signals and it does this via an action potential action potential that's how a neuron is able to propagate an electrical signal it's how I tell my hand to move right now it's a three-order neuron system that communicates with each other in order for me to move my hand now this action potential is an electrical signal this is how a neuron is able to propagate a signal it is with the action potential poal so let's draw a graph here this will be your membrane potential and this will be time now time here will be in milliseconds we'll change that a bit when it comes to cortical spreading depression and you'll know why later and the y- axis of course is the membrane potential now neurons have a resting membrane potential of -70 this is the resting membrane potential of 70 molts and this is maintained so this is the resting membrane potential and this is the neuron okay this is maintained by the sodium potassium atpa pump by doing this it allows two sodium to go in let's say this is the neuron here for every three po iium that comes out so you have more positive coming out than positive going in and therefore you have a negative membrane potential okay also there's leak channels involved but that's let's keep it simple for this lesson on cortical spreading depression now the neuron isn't doing anything here right it's just again it's it's resting it's resting membrane potential there's no signal it has to reach a specific threshold Action potentials require a certain threshold to be reached before depolarization which is that word again that I told you we're going to get to so it has to reach a specific threshold and normally that threshold is about 55 molts so the neuron is stimulated now the way it's stimulated is actually different between cortical spreading depression and the specific specialized ability of a neuron to send a signal via an action potential but we will get to that in a bit so the neuron is stimulated and the cell becomes more positive why because sodium is positive so you have more sodium rushing in the cell is becoming more positive and once it reaches the threshold it's an all or nothing response okay all or nothing so if it doesn't reach the threshold you have nothing there's no there's no small response it goes the entire way and so this is and so this is sodium going in don't think of decreasing sodium rushing in okay and when it reaches the threshold voltage gated sodium channels open let's actually change this so it's not confusing and just let's call it influx we have sodium influx and usually the peak it reaches with depolarization is about plus 40 Ms plus 40 molts okay so this is depolarization this is called depolarization this is what actually moves the signal this is how the neurons communicate and then we have our repolarization with our repolarization sodium channels close potassium channels open so sodium channels close and pottassium channels open causing a potassium e-lux okay potassium is late to the party it opens late the e-lux starts late and that's why we have repolarization however because because they're so slow we actually have a hyperpolarization before it finally goes back to the resting membrane potential so again potassium flows out cell goes back a neuron is a cell okay it's a nerve cell goes back to its eventually goes back to its resting membrane potential again hyperpolarization is just because it's a brief overshoot like it's 70 here probably reaches 75 mols because the pottassium channels take a while to close now let's talk about this recovery how does it recover well the same way it maintains the resting membrane potential via the sodium potassium atpa now this pump is an active pump active meaning it's not passive it requires energy it requires ATP to function and this becomes important with cortical spreading depression so the sodium pottassium pump restores the balance here and that's what we need we need normaly again now let's contrast this process to what happens with cortical spreading depression let's draw another chart here and this will be the membrane potential again but so the Y AIS is the same right it's in molt however the x-axis instead of milliseconds the time will be in minutes this represents how long it takes for cortical spreading depression to move across the brain and it also represents how long an aura lasts so the first thing triggering an action potential is triggered by specific stimulus in a localized part of the neuron usually the Soma or the cell body so let's say let's say this is a neuron and we have dendrites here and then this is the axon and this is the axon terminal so an action potential response to a stimulus in the dendrites receiving the information and then eventually when it's done when the action potential propagates across the axon reaches the axon terminal and neurotransmitters are released at the axon terminal okay part of the synapse now when it comes to cortical spreading depression it can be triggered by various factors with cortical spreading depression it could be triggered by an increase of extracellular potassium now we aren't talking about serum or blood potassium please don't think that when we talk about ion changes here it is referring to changes in the blood these are only local changes that are necessary to send to propagate this electrical signal so high extracellular potassium or intense neuronal activity and we talked about this already because that's why the occipital lobe with the highest neuronal density is likely the first to experience cortical spreading depression and it may be the only AA symptom so height in neuronal activity or an increase of extracellular potassium this is very different than the highly specialized way neurons normally communicate with each other now let's erase this here and talk about why by the way this is these are the triggers we know about in regards to what gets cortical spreading Depression started but there are likely many many more but why why these various triggers well the cortex again cuz we know what happens in the cortex right cortex is complex and disruptions in ion balance or excessive neuronal activity will result in creating this Tipping Point so these small changes of increased neuronal activity will make the cerebral cortex reach a Tipping Point where normal regulatory mechanisms are overwhelmed and thus initiating cortical spreading depression so many things more than a highly specialized neuron highly specialized action potential of a neuron can make it reach the threshold in order to result in cortical spreading depression again this is for cortical spreading depression okay Mill volts now let's talk about depolarization let me just fill this in here because got erased and for cortical spreading depression the depolarization is massive over a large area but it doesn't reach plus 40 like a normal neuron what it reaches is 0 m M volts and thankfully because we can't have this wave of depolarization acting like a neuronal signal so there's controlled depolarization reaching 0o molts but it's prolonged prolonged over a wider area but not as intense as an action potential that reaches plus 40 and again action potential travels along a single neuron at a time high speed right and that's why the x-axis is different on both of these time here is in milliseconds here is in minutes huge difference so while this travels let's say at around 100 m/ second depending on the type of neuron cortical spreading depression slowly goes across the cortex from posterior to anterior at a rate of about 2 to 5 or 2 to six depending on the source you read millimeters per minute and while it does this it affects multiple neurons and gal cells so a much much slower process an actual potential lasts a few milliseconds depolarization can last a minute or more and this is followed again don't confuse depolarization with depression the D in cortical spreading depression depolarization just means the the cell is depolarizing or when we talk about neuron or the area that we're referring to in the cerebral cortex is depolarizing so for example let's say like how do we measure depolarization for instance so there's an electrode inside the neuron okay this is not an arrow it's an electrode just assume it's an electrode and it's connected to a voltmeter and we also have the ground here okay now the voltmeter will read the voltage so when the neuron is undergoing depolarization it'll read plus 40 so we can actually objectively measure this now when we come to cortical spreading depression because it happens in the cortex we're not going to stick an electrode intracellularly but there is a strip we can use that has three electrodes put it on the surface of the brain have that connected to a voltmeter same way and then have another ground so don't confuse the depolarization which is the measurement we see here with depression which we didn't talk about yet so this depolarization phase lasts about a minute or more and then it's followed by a long depression you see how it's followed by a long depression let me actually put it on the screen here even though it's long just assume it goes past it so we have depolarization here but depression here now why does it take such a long time well there are massive disturbances in cellular function and it takes time to resolve the brain needs to recover from this massive and lengthy cortical spreading depression disturbance so we see here there's a quick recovery right milliseconds there's a quick recovery to resting membrane potential but with cortical spreading depression we have a prolonged recovery and we see this in the symptoms of migraine there is a prolonged recovery but why does that occur well the sodium pottassium pump is in every cell it's also in the cerebral the neurons in the cerebral cortex right so the way it will get back to the cortex will get back to its resting uh membrane potential is also the sodium potassium pump which requires energy so it requires such a massive energy demand even though it only depolarizes to 0o molts it requires so much more of an energy demand due to the spread of cortical spreading depression due to the massive ionic imbalances that occur in the cortex it requires such a massive amount of energy in order order to reach their resting membrane potential again and this means that you need large amounts of ATP in order for ions to move against their concentration gradients so we can reach the resting membrane potential again now this results in a increase of up to 250% increase in glucose use so this is a massive energy demand that is required so it kind of makes sense this may be part of the reason we're fatigued after a mind migraine attack so much energy has been used very different than normal neuronal firing and here we have controlled localized changes in sodium and potassium concentrations in cortical spreading depression we have these dramatic shifts in ion concentrations across a large area where extracellular potassium can reach 20 times the normal limit and also with an action potential you have this controlled release of neurotransmitters when cortical spreading depression occurs it's a massive WID spread release of neurotransmitters like the neuro the excitatory neurotransmitter glutamate it's massive this it's very controlled very specific very action specific when I tell my hand to move forward it's not moving everywhere it's not spasming there's no fasiculations it's doing what it's supposed to do because it's very controlled cortical spreading depression is not controlled it only affects neurons cortical spreading depression affects neurons and gal cells so we have something that's complet completely essential for normal brain function and communication and something that disrupts normal brain function it leads to migraine Ora symptoms and potentially contributing to pain now this prolonged depolarization again is followed by depression this is when the neurons shut down they're not functioning normally anymore and this also manifests as various symptoms for instance you can have and we'll get to this you can have positive symptoms and then you'll see negative symptoms like blind spots gomas and this moves as as this wave progresses anteriorly so while one area can be depolarizing another area can be be in the depressing or the depression phase again depolarizing is considered active and depression is considered inactive now we talked a lot about cortical and we talked a lot about spreading right we know for instance that it spreads at a rate of 2 to 5 mm per minute again slower than an action potential the entire duration can last up to an hour or more with cortical spreading depression it depends on how far it spreads and how long it takes let's actually erase this so we know as cortical spreading depression moves it affects different areas of the brain so therefore we have different symptoms like we talked about before let's see if it's wet ah it's still a little wet but let's move on so when it starts in the occipital lobe we have visual Aura what does that entail well flickering lights also known as scintillations we can have zigzag lines also known as fortification Spectra or we can have blind spots also known as aoma when it passes through the parial lobe we have sensory symptoms with sensory symptoms we have parasthesias also known as pins and needles sensation tingling anything any sensory symptom when it goes through the temporal or frontal loes we have language Aura and this could include trouble finding words speech problems dysphasia or aasia this is all caused by cortical spreading depression again these are typical Aura symptoms we also have non typical so if it impacts the motor cortex we will have hemiplegic migraine and that is temporary weakness on one side of the body if it happens in the brain s regions it may contribute to vestibular migraine resulting in Vertigo and dizziness or even another type of non-typical Aura called brain stem Aura however we actually don't know if this is due to CSD in the brain stem it's kind of debated right now and when it comes to retinal migraine another non-typical Aura spreading depression of retinal neurons may occur this is one Theory anyway and that's similar to cortical spreading depression in migraine with aura so this is migraine with aura and you would have a different diagnosis if the cortical spreading Depression was in the primary mortal cortex for instance and there are there's weakness on one side and then you would have hemiplegic myin right so it all comes back to cortical spreading depression so the symptoms reflect the functions of the cortical areas affected as this wave propagates moving from posterior to anterior now let's talk a little bit more about depression so after this heightened activity this depolarization right we have depression and this is where the affected areas of the brain can't function and this can also explain the progression from positive symptoms like scintillations and fortification Spectra two symptoms like blind spots that occur sometimes the flashing lights move laterally and the blind spot follows it that is the depression phase and what's interesting about the depression phase it's is likely a protective mechanism to prevent further ecotoxicity and allow for metabolic recovery because we don't want to keep the cerebral cortex firing now there are a few things that are also worth mentioning that cortical spreading depression isn't only about just these symptoms but there are also blood flow changes so hyperemia there's so there's an increase in blood flow and then a decrease in blood flow after so transient increase in cerebral blood flow followed by a prolonged decrease in cerebral blood flow and the cerebral blood flow so increase and then a decrease and this decrease can lasts longer than the depression lasts longer than the electrical activity suppression furthermore there is an increase of reactive oxygen species an increase of oxidative stress so while cortical spreading depression doesn't cause permanent damage in a healthy brain the recovery process is demanding and it can contribute like I said before to the fatigue that one can experience after the headache phase or even during again the brain has to restore normal ion gradients it has to clear excess neurotransmitters it has to repair the cellular damage that occurred and it has to replenish the energy that was taken up from this entire process this requires significant time and significant resources also what's interesting about cortical spreading depression there's also evidence that if it impacts the hypothalamus for instance it can result in yawning where do we see yawning we see yawning we see yawning in the prodrome phase of migraine we we see yawning in the prodrome phase so cortical spreading depression may also result in some of our prodrome symptoms like yawning like food cravings like mood changes the hypothalamus regulates autonomic functions and neuroendocrine processes so disruption here could explain these diverse prome symptoms so cortical spreading depression may actually be happening before the aaase potentially if it reaches the thalamus it could explain the hiend full photophobia which is sensitivity to light it could explain the phonophobia which is the increased sensitivity to sound if it's in the brain stem nausea vomiting dizziness disruptions of other autonomic functions amygdala anxiety or emotional changes so cortical spreading depression can affect the protone phase the aura phase and the headache phase and the post drone phase it's an important part of migraine pathophysiology migraine is a neurological disease because phenomenons like this are the underlying pathophysiology of migraine