| 00:08 | This is lecture 20. For cellular we talked about migraines. Last lecture |
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| 00:15 | talked about uh Professor Aristides the hour the traveling wave of leah low or |
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| 00:24 | critical spreading depression as a mechanism that the pain perception. So we talked |
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| 00:32 | this whole cycle of trigeminal and trigeminal thalamus activation, singular cortex activation and |
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| 00:42 | perception of pain and that perception of is coming from this of mechanisms that |
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| 00:49 | discussed. Um no susceptible information from meninges, transient global amnesia and the |
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| 01:00 | and the pathways that are involved in we think is initiating cortical spreading depression |
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| 01:07 | and also the perception of pain that have during migrants that are defined by |
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| 01:17 | headaches. And so there are cellular and glutamate levels in particular and potassium |
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| 01:25 | to sell you really grow up and a cellular level you have this deep |
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| 01:32 | with a few action potentials. We the differences between pre excel it'll postdoctoral |
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| 01:40 | and seizures. We discussed how there intellectual phases and seizures and that helps |
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| 01:48 | with diagnostics uh Sometimes even with E . G. Diagnosis of seizure activity |
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| 01:54 | picking up the intellectual bursts. And talked about how there's a difference in |
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| 01:59 | spreading depression network produces a few action but overall it is silent and this |
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| 02:05 | polarization kind of a potential that is prolonged and it's a very slowly traveling |
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| 02:15 | The two hypothesis. But csD is sally with lighter made extra cellular |
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| 02:23 | We talked about how you can recreate spreading depression using different models such as |
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| 02:31 | potassium chloride glutamate application. Anything that increase glutamate levels of blocking glutamate |
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| 02:39 | potentially manipulation of certain potassium pump, stimulation, hypothermia, local injury, |
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| 02:48 | frequency pulse stimulation. There are more metric changes with severe migrant nurses in |
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| 02:58 | . And there are functional imaging changes severe migrant nurse and what I discussed |
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| 03:05 | I pointed out several areas, mostly areas, no matter of sensor |
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| 03:09 | One but also the auditory areas in visual areas uh in the occipital lobe |
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| 03:17 | same for functional imaging. There are and glutamate increase in gabba decrease which |
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| 03:25 | be similar to the chemical imbalance we in seizures and there are also changes |
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| 03:31 | signaling, increased signaling and functional imaging primary visual so matter sensory s warm |
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| 03:41 | temporal paul areas here in the temporal . Um medication for relief because we |
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| 03:49 | about various from pain relievers and all juices. Adam said it's energetic prescription |
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| 03:58 | over the counter pain relievers, prescription medications are allergic calcitonin, opioid |
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| 04:06 | nausea drugs and preventative medications that we about, I have to share on |
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| 04:18 | level. Sorry with this. So if you're searching for some general information |
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| 04:28 | neurological diseases, a place like National of neurological disorders and stroke can be |
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| 04:38 | good resource for finding general information for yourself some definitions for example, but |
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| 04:47 | you read about what migraine is fundamental abnormalities caused by genetic mutations that's worked |
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| 04:58 | the brain. New models are aiding and studying the basic science involved in |
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| 05:04 | biological cascade genetic components and mechanisms of . So we really focused on the |
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| 05:11 | and the cellular mechanisms of migraine and a little bit about the therapies and |
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| 05:16 | similarities and differences with epilepsy and seizures particular, or cortical spreading depression. |
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| 05:23 | cellular mechanism of migraines with seizure seizure activity mechanisms for epilepsy. I have |
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| 05:32 | components. Understanding of the causes of as well in advance that the fact |
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| 05:36 | will give researchers the opportunity development as could be more targeted to preventing or |
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| 05:42 | attacks entirely. And so it mentions treating migraine magnesium, why would you |
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| 05:50 | magnesium treatment? Magnesium walks in NBA after? So you're reducing this glue |
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| 05:56 | signal and it comes on cue I don't know the cellular mechanisms, |
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| 06:01 | B 12. There's a lot of . So there's things that you can |
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| 06:04 | on your own information from National medicine channel, I am potassium channel |
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| 06:16 | So, for example, if you talking about one of the mechanisms that |
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| 06:21 | us abnormality and there's two hypothesis potassium glutamate. So if you have potassium |
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| 06:30 | , how can you get to abnormal state? Well genetically you may have |
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| 06:36 | channel empathy and potassium channels and that channel, for example would stay open |
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| 06:42 | for for for for for too long or too short. There's many different |
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| 06:52 | that happened. So you can actually for some of these things on your |
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| 06:59 | . The basics living with genetics So if you look at the genetics |
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| 07:08 | , the vomiting. Familial hemiplegic that's what show us. Familial hemiplegic |
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| 07:15 | is a form of migraine that runs families. So this is genetic migrants |
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| 07:21 | cause intense throbbing pain in one area the head off from the company and |
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| 07:26 | , vomiting extreme sensitivity to light The current headaches typically began in childhood |
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| 07:32 | adolescence. So the onset is typically or adolescence um uh teenage years and |
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| 07:40 | be triggered by certain foods. Emotional minor have trauma. Each headache may |
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| 07:44 | a few hours a few days and types of migraine including the familiar at |
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| 07:50 | pattern of neurological symptoms follows or precedes migrants. So these are great resources |
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| 07:56 | you have to see where are you this resources from MedlinePlus? Do you |
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| 08:03 | MedlinePlus? While it's a part of National Library of Medicine. So I |
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| 08:06 | say that this is probably good reasons the neurological disorders and stroke and |
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| 08:11 | M. D. S. Is good resource. Where else can you |
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| 08:17 | ? The resources? You know? of course and a lot of you |
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| 08:22 | how to use that. And so I did is um but please review |
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| 08:38 | figures, I just forgot to record . So this talks about the parasympathetic |
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| 08:46 | to the brain stem as a son increased parasympathetic tone activation of my |
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| 08:53 | epicenter general vascular pathway. Then you a bison dilation and releases inflammatory molecules |
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| 09:00 | then you have activation of this tree complex and the brainstem during the wave |
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| 09:09 | precedes the cortical spreading depression. You're rises in potassium, a lot of |
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| 09:14 | recorded in E. G. But necessarily very clearly synchronized during this prolonged |
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| 09:20 | polarization that has sustained the decreased deep on this wave of cortical spreading |
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| 09:26 | moving slowly through the brain. Not will come to this image which basically |
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| 09:32 | us that now we have this vessel . We have peripheral to germinal after |
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| 09:38 | that are innovating the identities of cerebral or communicating that bastard violation and inflammatory |
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| 09:47 | going on input from areas supplied by trigeminal nerve including peri orbital scans. |
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| 09:54 | there are three trigeminal, there are aspects of this V one V two |
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| 09:59 | three that formed the trigeminal nerve. is not a digital system, he |
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| 10:05 | . Three components at turns from skins muscles of neck and virgin neurons and |
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| 10:11 | TCC. Okay, they converge into TCC which is trigeminal cervical complex right |
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| 10:21 | in the in the brain stem together the appearance arriving from the meninges from |
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| 10:30 | vascular so there's a convergence of inputs all over trigeminal Merck and his visor |
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| 10:39 | colliding here from TCC ascending connections from DCC transmit signals to multiple brain stem |
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| 10:48 | . Hypothalamic, basal ganglion nuclear, and multiple cortical areas process the inputs |
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| 10:54 | the DCC, leading to the phenotype a typical expression of migrant pain and |
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| 11:00 | associated symptoms. So this is how perceive the pain and migraine pain and |
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| 11:10 | a headache pain. Of course that a lot of migraines maybe in |
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| 11:15 | had a similar mechanisms to migrants, the perception of pain even in headaches |
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| 11:21 | be singular to migraines. And so important to understand there is no pain |
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| 11:26 | in the brain. So this is whole cascade signaling cascade of events that |
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| 11:33 | to the perception of page and then gets into this neuronal neuronal and you |
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| 11:42 | , we all signaling release of gene related peptide that I won't burden |
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| 11:49 | with. But this is an article is uploaded on your lecture supporting reading |
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| 11:56 | . Uh and I recommend for you read it because I'm a place a |
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| 12:00 | for more detailed question on this exam from this particular. Mhm. So |
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| 12:13 | lecture, the second half of this , probably the last new material that |
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| 12:19 | going to cover is an Alzheimer's The first slide says epilepsy and |
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| 12:25 | Why is that? Because there's something on. And of course as as |
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| 12:32 | know this is figure one on the shows seizure disorders of all the |
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| 12:41 | So it doesn't mind of usa. python ah and all types of seizures |
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| 12:48 | in the second half of life Beginning the age of 50. So first |
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| 12:54 | all, if you look at Apple Sandstone owns and seizure different ideology. |
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| 13:02 | is, you have a lot of at the early developmental years and into |
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| 13:11 | teenage years and drops significantly and then starts speaking again in the population of |
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| 13:19 | and over What's really interesting that if look at that population of 50-59 years |
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| 13:31 | , the incidents ratio Of epilepsy and diagnosed with Alzheimer's disease is elevated nearly |
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| 13:44 | fold at this age. Now, disease is an aging Population disease and |
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| 13:53 | incidence and prevalence of Alzheimer's increases after years old. And if you have |
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| 14:00 | disease in this 50-59 year period, have 87 times more likely to have |
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| 14:10 | and seizures from that likelihood and increase . It's about 20 times. This |
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| 14:18 | 87 times. This is about 20 in the group 60 to 69 in |
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| 14:24 | group 70 to 79 it's still three more widely to have this co occurrence |
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| 14:36 | . And so a lot of times is referred to as co morbidity. |
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| 14:41 | with Alzheimer's may have seizures in epilepsy that means that it's not only Alzheimer's |
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| 14:47 | is killing them, It's also the morbidity, it's making them die faster |
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| 14:53 | and seizures. So the department from diseases is now, uh, the |
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| 14:58 | of the farm, they give them Alzheimer's disease. And and it's interesting |
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| 15:06 | we talked about for example, we talked about glutamate and gaba and |
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| 15:12 | of the therapeutic mechanisms and controlling glutamate gaba. What we talked about |
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| 15:20 | we talked about analgesics and we also serotonin the law. Um and there |
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| 15:29 | opioids in there as well. When talk about Alzheimer's disease, we typically |
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| 15:36 | about the seed locally and chemicals and single colony in is produced. And |
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| 15:46 | if you nuclei in the brain that that the selma's that produces pseudo |
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| 15:55 | they're rising. Okay, these modular systems, it's referred to as modular |
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| 16:01 | system because it's a select group of , the medial septal nuclei and the |
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| 16:07 | nucleus of main art. That's where are cells that produce versatile colony. |
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| 16:16 | they project the civil code name through are called diffused projections into the sub |
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| 16:24 | and into the new york protocol that's lot of making areas and into the |
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| 16:31 | of course then tom to mesons seppala towel complex projects to the Thailand with |
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| 16:45 | parts of before. Right. That's cool. So you have this Ponta |
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| 16:54 | follow technical complex. It's obviously it's to foulness parts of the forebrain. |
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| 17:07 | have the medial septal and Maynard that onto the hippocampus and onto the |
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| 17:17 | So there is sort of a little of division of where these different nuclear |
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| 17:21 | what parts of the brain they're But the fact of the matter is |
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| 17:26 | is the main neurotransmitter and it's going have a real modular Torrey effect is |
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| 17:31 | projections onto the brain. Alzheimer's If you look on a cellular |
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| 17:38 | it has two distinct features. It amyloid plaques also called beta amyloid plaques |
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| 17:47 | senile plaques and they are located extra intracellular literally neuro february tangles. So |
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| 17:56 | are neurofibromatosis side of skeletal elements and have entanglement with the side of skeletal |
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| 18:03 | that impact the transport inside the south the very ambivalent plaques impact the outside |
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| 18:14 | we're following in the function of neurons glial cells. Because they aggregate these |
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| 18:21 | normal um polytech tides and cause engage cells and cause a normal accumulation of |
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| 18:34 | . So they become these calcified plaques the wheel cells form the we also |
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| 18:41 | surround them and these plaques start impacting this neurons nearby. And it turns |
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| 18:50 | that the axons of these neurons are sensitive. And once the axons started |
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| 18:55 | affected by the amyloid plaques they can longer produce the action potentials. Therefore |
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| 19:01 | isn't enough synaptic transmission and communication synaptic which can then lead the neuro |
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| 19:09 | depression of the synopsis the death of synopsis, death of the neurons and |
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| 19:15 | confined in with inflammatory processes that are when there is such abnormal formation of |
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| 19:22 | analog flax. Then we'll have engaged inflammatory processes by the glial cells and |
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| 19:31 | become uncontrollable, becoming sustained. This causing too much inflammation in the brain |
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| 19:38 | one is called brain on flames. , if you look on the gross |
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| 19:44 | level on the left, you have healthy brain and on the right you |
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| 19:50 | a brain that has been affected by out some of those disease. And |
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| 19:56 | can see that there's a tremendous shrinkage the overall brain tissue. There's a |
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| 20:03 | on the shrinkage on the gray but also on the white matter. |
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| 20:09 | these are the severe or advanced stages Alzheimer's disease. This is an artist's |
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| 20:17 | surely amyloid plaques that are dispersed there neurons. These aggregations of misfolded programs |
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| 20:23 | them. Kill brain cells and are of Alzheimer's disease. This is from |
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| 20:29 | National institute on aging. Alzheimer's Jeans. And what we know about |
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| 20:38 | concept of Alzheimer's disease. There's late of Alzheimer's disease which has been 60s |
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| 20:44 | later or early onset of Alzheimer's which is this earlier group 50 and |
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| 20:50 | some 1000 to late 40s. Typically the variant of the liberal protein E |
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| 20:57 | police region on chromosome 19. Uh if you have a variant uh |
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| 21:06 | you have an increased personal risk for disease. It's involved in principle lipid |
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| 21:15 | in the brain A poorly comes in different forms or alleles. Each person |
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| 21:20 | two April. We alloy wheels, from each biological terror so early |
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| 21:28 | So the Alzheimer's disease is typically due the A. P. P. |
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| 21:33 | precursor protein on chromosome 91 20 promise mine and I invented 1 21 and |
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| 21:45 | on chromosome 14 3 single and two chromosome one. Each of these mutations |
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| 21:50 | a role in the breakdown of a protein whose precise function is not the |
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| 21:57 | will be understood. But this is P P will accumulate. The breakdown |
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| 22:06 | part of the process that generates harmful of amyloid plaques. A hallmark of |
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| 22:14 | disease, jesus dr Yeah, let's a quick question for the Alzheimer's |
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| 22:24 | You know how one of the methods treatment that we have mentioned, I |
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| 22:28 | in neuroscience and and in this class well was administering acetylcholine but within the |
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| 22:36 | Kolding encounter the same problem. If is these plaques that are not That |
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| 22:43 | blocking the communication between the two synopses not. Yeah, no, that |
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| 22:47 | an excellent question. And I think of answering you here, I'm gonna |
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| 22:51 | it in a few slides. Actually don't want. So, so let's |
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| 22:56 | at this mechanism here. So you apple. We perform amyloid bayed eyes |
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| 23:07 | primarily by neurons in the brain. number one, this is how you |
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| 23:15 | this diagram. I don't know if can see it. Maybe I can |
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| 23:19 | the marketing world and let's see if can. So where it's basically amyloid |
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| 23:41 | producing neurons in the brain. It's or lipid dated april re secreted by |
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| 23:49 | and astra sites. Okay so this A B. But today it is |
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| 23:59 | then you have and the subsequent deposition relax in the diva. So you |
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| 24:06 | this admiral data aggregation and you have plaque deposition. What's interesting is the |
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| 24:15 | is very prone to seizures and hippocampus neocortex are also the sides with some |
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| 24:21 | these plaques will start forming. Another fact is that these flax can migrate |
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| 24:27 | the brain so they move there seems be almost like an invasion that starts |
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| 24:31 | one part of the brain and then continues very slowly into the other parts |
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| 24:36 | the ground. Mhm. So so then we get into more details on |
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| 24:47 | amyloid beta uptake. Um So this a cell surface low density heparin sulfate |
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| 24:58 | media under psychosis of amyloid beta by my career there's an endo psychosis going |
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| 25:07 | In addition to promoting a production and of a beta april reform paris. |
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| 25:13 | clearance by reducing solid little uptake and across the blood brain barrier. So |
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| 25:19 | that is what this mutation also does . So you have basically the whole |
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| 25:28 | circuit and it gets down to the the you know to the neuro toxicity |
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| 25:36 | we fragmentation becomes neurotoxic have a beta outside and I'm alive. Beta formation |
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| 25:45 | retrieve fragments in europe toxicity. It neurotoxic, it impacts the blood brain |
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| 25:52 | and makes bloodrayne very leaky. It inflammation and turns on Rios is and |
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| 25:59 | have no permanent inflammatory cytokine secretion by microbial cells leading to chronic neuro information |
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| 26:06 | neuro degeneration. And you have obviously neuro degeneration in vivo. You can |
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| 26:19 | the sin absence here following apartment number and now you have the chronic generation |
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| 26:25 | these pro inflammatory processes that can become that can start breaking down my eliminated |
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| 26:33 | and the synaptic connectivity and Sinatra So that one part answers the question |
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| 26:40 | was just passed before amyloid plaques disrupt initial signals. So actually it's one |
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| 26:50 | these interesting things that happen in your that you come up with a great |
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| 26:58 | and you start doing the work. as you're doing that work and you |
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| 27:03 | up with a great idea, you that great idea with your colleague and |
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| 27:10 | neighboring institution Baylor College of Medicine and it happens and it's a really cool |
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| 27:17 | and so he he pursues dr Matthew Baylor. This idea from our discussions |
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| 27:27 | I've generated and he includes me in research that he's capable of doing in |
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| 27:33 | way much better in a different way I was able to do it at |
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| 27:38 | time. And the idea that I was to follow the idea was that |
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| 27:48 | beta plaques are going to start impacting communication and they're gonna start impacting external |
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| 27:57 | external signaling and they're gonna start impacting they'll drive from neurons. So I |
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| 28:07 | there's this method here that's shown circle you have the exact distance the rings |
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| 28:15 | come out of the stuff. So said you know what we have these |
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| 28:22 | that have the plaques. And so can look at this E. P |
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| 28:27 | T T. A. It's a mouse model so that you're looking at |
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| 28:34 | from the top right hand green our flame and S stain which will stain |
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| 28:41 | the beta amyloid plaques. And you see that at 11 months you can |
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| 28:49 | a lot of these very bright dots light up everywhere dominating in the cortex |
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| 28:55 | also in Hippocampus and support it fully well. So now I said we |
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| 29:02 | where those blacks are. Said why we use this method? And by |
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| 29:06 | way this method of the rings was used to he described morphology ah and |
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| 29:17 | extent of the processes such as dendrites axles coming off the stained neurons. |
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| 29:25 | I said we could apply the same and analyze the location of these plaques |
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| 29:31 | how close they are located to the and to the axons into the bend |
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| 29:37 | and would damage. Are they causing ? And we can look at that |
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| 29:43 | a morphological perspective and we can look it from a physiological perspective. So |
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| 29:51 | rassmann's group was well equipped to do for morphological perspective. and we demonstrate |
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| 29:58 | from a physiological perspective where we showed this beta amyloid plaque build up in |
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| 30:07 | mouse model and a similar transgenic mouse was causing failures in action potentials. |
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| 30:14 | causing failures in producing the action So we morphological e when dr raz |
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| 30:24 | , looked and did the calculations what saw is that there was a significant |
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| 30:32 | . T. G. S. transgenic tita is one mutation, A |
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| 30:37 | . P. And T. To two mutations. Okay. And so |
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| 30:42 | you have two mutations CPP and Ta and you haven't had to load |
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| 30:47 | beta amyloid plaques. We saw a reduction A significant reduction from about 20 |
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| 30:57 | m to about 12 micrometers in the initial segment. This is A. |
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| 31:05 | . S. Stands for the actual segment. So this is the axon |
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| 31:09 | segment that will be generating the action . And we saw that if these |
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| 31:17 | are in the vicinity of the the first thing that happens is they |
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| 31:23 | impacting the length of the axon initial and by making this accident initial segment |
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| 31:30 | renders the cell not being able to as many action potentials. We can |
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| 31:36 | them as reliably because this is the accident initial segment where the cells will |
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| 31:41 | producing the action potential which is eventually neural transmission. So this is what |
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| 31:48 | rassmann's group demonstrated that if we the actually the closer these flax, the |
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| 31:59 | you are located, if you're the that are located in the first |
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| 32:03 | the damage on the action initial segment be greater. If you're in the |
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| 32:09 | ring there is still going to be but it's going to be less. |
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| 32:13 | so this was a real way and can see these white squiggly things adjust |
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| 32:18 | accident initial segments and showing the length these acts of initial segments and showing |
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| 32:23 | the closer you come to these the shorter these actual initial segments |
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| 32:31 | So this was quantified and that this significant. Um I was happy that |
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| 32:36 | contributed with this methodological application of this had been bent in this idea and |
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| 32:44 | location of the flax and acts and segments and how they could be shortened |
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| 32:49 | in the lab at the same time my life were reporting failure of action |
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| 32:55 | . And so I have a Alzheimer's disease. I didn't upload for |
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| 33:00 | as additional data. I have a that shows that inhibitor inter neurons are |
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| 33:09 | to fire and Alzheimer's disease and that's because that relates to the imbalance of |
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| 33:17 | condition of the citation and that goes the argument that supports the film |
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| 33:24 | uh incidents, path of physiology of disease and epilepsy excitatory inhibitory in |
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| 33:37 | So finally, most of the drugs is still talking about your question to |
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| 33:43 | napoleon is synthesized by themselves and we see with Colin and cocoa way |
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| 33:51 | cold and a single transfers for chat made locally and uploaded into vesicles, |
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| 33:58 | gets released possum optically it can bind the island. Tropical make a tiny |
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| 34:03 | pill and receptors a medical tropic, current acetylcholine receptors once it's released in |
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| 34:11 | not to collapse, it is clear the molecule abbreviated here, A C |
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| 34:16 | E, which stands for esa taco race that is a tropical island |
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| 34:23 | breaks down the single Colin Colin. pathetic acid Coleman gets re transported with |
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| 34:31 | podium co transport and remember and transported the neurons that synthesize. Okay, |
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| 34:38 | released percent applicant we they re synthesize the synoptic terminal and upload this. |
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| 34:45 | don't tell me for this repeated release . So what happens in Alzheimer's disease |
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| 34:52 | that this system of a pseudo colonial and in particular in the frontal areas |
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| 35:00 | , he is most susceptible to damage Alzheimer's disease. So this is the |
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| 35:06 | and cellular expression of that disease and we're seeing is that there is a |
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| 35:15 | of a student Colombian neurons. Most the medications for Alzheimer's disease are common |
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| 35:23 | or a seal of protagonist arrays They basically block or inhibit activity of |
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| 35:29 | C A. G and by blocking activity of a ch even making a |
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| 35:34 | coding a lot more bio available than synapses to buying through synaptic receptors a |
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| 35:41 | of the issue, I always said this medication is that if these pre |
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| 35:47 | terminals killen merger terminals if these cells actually dying because that's what's happening and |
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| 35:53 | disease and there are no socks that making a set of phony and releasing |
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| 35:57 | single called and releasing acetylcholine although diffuse throughout the brain structure but still specifically |
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| 36:05 | the certain synapses which is not understand diffused system but it doesn't mean that |
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| 36:10 | doesn't have its own complex, very but very specific logic as well. |
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| 36:17 | these ending strategical and ergic neurons of for taxes. So there's another strategy |
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| 36:26 | using Normandy as Alzheimer's medication 19 blocks M. D. A receptor is |
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| 36:34 | antagonist and M. D. A but it only blocks active in |
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| 36:38 | D. A receptor. So not of them the receptors but active in |
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| 36:42 | receptors. So if there is basically drugs Colin kahl industries inhibitors, they |
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| 36:51 | a single Coley number 19 targets NMDA and glutamate signal. This is |
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| 37:04 | How do you control potassium? How you make blood brand barrier tighter? |
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| 37:13 | think the answer is in the chat . Oh all about just getting it |
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| 37:22 | there and running, Come on, matters exactly. So what I'm saying |
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| 37:30 | that there is you know other aspects probably future medications. Uh some people |
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| 37:39 | benefits from cannabinoids for migraines. Although hasn't been necessarily studied very well but |
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| 37:46 | not surprising since there is evidence that helps with chronic pain and this is |
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| 37:52 | form of chronic pain and we're not talking about peripheral in this case, |
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| 37:57 | a C. N. S. . So, but there might be |
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| 38:02 | very interesting other medications of precursors. is there a way to specifically target |
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| 38:11 | city of columbus actors with other Ah and again, if we do |
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| 38:19 | as a systemic targeting. So there's little cold antagonists are going to go |
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| 38:24 | . But as I said, there's diffused system that we call a diffused |
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| 38:28 | like system. By the means that like system probably has its own |
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| 38:34 | That's a very complex and probably in quite specific mm hmm, targeting pfosten |
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| 38:43 | all of this. You know. results could be to benefit or it |
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| 38:47 | not because as I mentioned, there some of the division of labor and |
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| 38:52 | projections of these nuclei, the koala nuclei and deal with different parts of |
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| 38:57 | brain. Alright, so this actually our lecture and concludes the new material |
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| 39:13 | I will cover in this |
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