| 00:02 | Lecture 20 of cellular neuroscientist talked about strategies for controlling seizures. And so |
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| 00:12 | looked at them a number of mechanisms I said, I don't necessarily want |
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| 00:18 | to remember the names of the trucks what they buy. Why? As |
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| 00:25 | matter of principle, what is very is if you look and how many |
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| 00:33 | are targeting, we sign out the sodium check inhibiting the blockers of |
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| 00:46 | Now look at how many drugs target receptor or gamma oric signaling to just |
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| 00:55 | a turn over or Gaba receptor agonist both cases, stimulating the influx of |
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| 01:07 | and hyper polarization. So there are challenges as I discussed. If you're |
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| 01:17 | a drug that you want to control circular release, you have to take |
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| 01:22 | consideration that there is this protein podium . And then if you make a |
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| 01:30 | that targets the secular protein partum it has to be looking at soluble |
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| 01:36 | the neuronal membrane. It crosses neuronal will cross the aar membrane too. |
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| 01:45 | maybe that's not a good way to to to, to control the |
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| 01:50 | release. One, maybe it So it's a bit of more of |
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| 01:53 | challenge to control the secular. Let's a little bit about the endocannabinoid system |
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| 02:03 | you have essentially control of synoptic calcium , multigated calcium channels. But if |
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| 02:13 | look at this mechanism here, here have epileptic drugs, anti seizure drugs |
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| 02:20 | control synoptic multi counseling channel. Here sign up the multi counseling channel. |
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| 02:31 | . Oh illustrated here. OK. it's a, it's a target. |
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| 02:37 | same target is through metabotropic signaling by B one receptor activation where you have |
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| 02:44 | of two major end of cannabinoids that more A E A and two, |
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| 02:51 | two major cannabinoids they're produced on the there is heightened levels of signaling in |
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| 02:56 | synapses. Let's imagine this is excitatory . If there's too much of CALS |
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| 03:01 | too much equalization, too much of being released, it leads to |
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| 03:09 | So, uh controlling calcium and controlling release can prevent that excitement toxicity |
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| 03:18 | and the cannabinoid signal through CV it is very well equipped to control |
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| 03:23 | circular release and it controls both excited inhibit the release. So a lot |
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| 03:28 | problem with just stimulating that the cannabinoid or cannabinoid receptors. Again, C |
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| 03:35 | one receptors will be expressed on both during excitatory neurons and will be controlling |
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| 03:41 | inhibited or an excitatory signal. And most of the drugs that we're talking |
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| 03:47 | . If they're targeting some channel, they're targeting Gaba receptor, they'll find |
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| 03:52 | Gaba receptor and inhibitory cells on excitatory . So another challenge in a lot |
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| 03:59 | these drugs is that across the board affect both sodium channel gaba but may |
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| 04:05 | be a specific to specific inhibitory exci our population of cells. So they |
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| 04:10 | that future drug design really has to carefully address how you can target specific |
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| 04:17 | , excises inhibitor and maybe even specific of cells. Let's say the ones |
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| 04:24 | release dopamine or produced dopamine, the that produce serotonin and so on. |
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| 04:29 | that would be very, very important take into consideration the future drug |
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| 04:34 | We talked about cannabinoids, whether they , we distinguish between industrial hemp or |
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| 04:41 | high T C cannabis synthetic cannabinoids which very different. Talk about delta eight |
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| 04:47 | delta Tanin. Uh H H C semisynthetic cannabinoids. Uh Story of Charlotte |
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| 04:55 | , I think we ended here last and Charlotte's Figgy had a syndrome or |
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| 05:06 | I remember when we looked at the of the voltage gated sodium channel, |
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| 05:10 | said that if you have any one those mutations and S C M one |
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| 05:14 | gene which codes for the voltage gated channel. And if you have any |
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| 05:18 | of those mutations along those amino acid in the channel protein structure, you |
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| 05:26 | end up having Dr Syndrome or SME . We also talked about generalized epilepsy |
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| 05:31 | feb seizures plus. So Charlotte Figgy Dravet syndrome and like a lot of |
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| 05:39 | with Dr syndrome and with what we intractable epilepsies are hard to treat or |
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| 05:46 | epilepsies. They are untreatable because uh are no pharmaceutical drugs or pops of |
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| 05:53 | that help sufficiently these Children to stop . About 30% of them still go |
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| 06:01 | having seizures and them having cocktails of , which can then if you're talking |
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| 06:07 | Gava agonous ethanol binds to Gaba So agony of Gava that increase inhibitory |
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| 06:14 | mimic a little bit of a drunk . And it happens in Children, |
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| 06:18 | , you know, sway and they their heads and chairs and tables and |
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| 06:23 | also a heavy burden, not only the brain but also on the body |
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| 06:28 | the organs of the body. And at the forefront of a change in |
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| 06:34 | cannabis laws were really the mothers of epileptic Children that approached the regulators and |
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| 06:40 | lawmakers with bags full of cocktails of that are still insufficient at controlling the |
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| 06:49 | . And this is just one example Charlotte figgy was a girl that had |
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| 06:55 | conservative parents military ex-military and they could treat Charlotte figgy with uh antiepileptic |
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| 07:05 | When she was being treated with anti medications. She was having very high |
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| 07:10 | of some of these GIC agonists and was having about 50 convulsions a day |
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| 07:18 | being drug all, all day long all night long. And so my |
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| 07:26 | moved to Colorado and worked with a that is in this article from epilepsy |
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| 07:33 | 2014, Edward Mob. It was attending neurologist. She had a confirmed |
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| 07:40 | C N one A mutation syndrome. Diy. And he gave her a |
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| 07:47 | of Delta nine T H C and CBD. And it reduced her seizures |
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| 07:56 | 23 nocturnal or n convulsions per The Charlotte figgy story later, there |
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| 08:07 | a whole business of Charlotte's Web, brand brand that was developed and the |
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| 08:13 | of it was developed around this competition C A DH C uh Charlotte. |
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| 08:18 | think it really brought this kind of new movement of medical cannabis for treatment |
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| 08:25 | epilepsy, which actually has been around thousands of years but just have really |
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| 08:32 | regulations in each country and at each in in our history, uh human |
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| 08:40 | . And since, since then, has passed last year. Unfortunately, |
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| 08:47 | Children with Dr Syndrome pass 20% of loss as we discussed last time, |
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| 08:52 | from so unexpected death of blood. for a lot of Children, cannabis |
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| 09:00 | an alternative, becomes an option and medical only if it is supervised |
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| 09:06 | If it is just used, it just used. But if it is |
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| 09:12 | medically, there are medical benefits and are clear medical benefits especially for and |
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| 09:19 | with CBD. Although for many CBD alone is not enough, this |
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| 09:25 | would they use on trial with CBD T H C or other combinations of |
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| 09:31 | cannabinoids. These are not endo these a vito cannas interact in part |
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| 09:37 | cannabinoid receptors. So there's some examples how it came about. It came |
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| 09:44 | from survey studies. 2013, Charlotte's and Charlotte Fi's case. 2014, |
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| 09:54 | was followed by another study of which extracts for treatment of pediatric have |
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| 10:02 | And there was a whole market development strains that had certain ratios of T |
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| 10:09 | C and CBD. When people have that these ratios are important pharmaceutical |
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| 10:15 | people have known this for a long but in the market world so to |
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| 10:20 | , people started developing new strains of is one of them catatonic. They |
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| 10:25 | helped out of that industrial health strains all had higher levels of CBD, |
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| 10:32 | levels of T H C or certain of CBD to T H C. |
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| 10:38 | , when I say it's ancient you know, I'm not gonna give |
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| 10:41 | a whole uh lecture which I could the history of medicinal cannabis. Uh |
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| 10:48 | , written history started in about 2500 with uh with uh if I recall |
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| 10:57 | with the emperor, she mentioning mentioning as as medicine because medicine, there's |
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| 11:05 | other facts that illustrate use of cannabis use of T H C, not |
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| 11:11 | CBD or health but T H C different medical conditions throughout the ages. |
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| 11:19 | now. Yeah. Ok. Maybe stupid question. But like so |
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| 11:25 | for instance, with uh Charlotte like when these patients have like super |
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| 11:30 | like seizure disorders, when, when get the T H C, is |
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| 11:34 | still like, do they still get high or is it like the way |
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| 11:39 | is a the range is like, a great question and yes, they |
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| 11:45 | may get high. And then the and the family have to evaluate is |
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| 11:50 | high better and different from my child the hide that my child is getting |
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| 11:55 | benzodiazepines and other things. And it's the liver and kidney and body functions |
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| 12:03 | than this, that can be more metabolized. I would argue. So |
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| 12:11 | a case by case basis. But the way that they started the therapy |
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| 12:17 | her, it was adjunct. She already on so much of anti anti |
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| 12:23 | drugs and she was literally swaying during day like drunk. And so they |
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| 12:29 | , which means that they added, is called adjunct therapy. You add |
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| 12:34 | , you add new therapy, which the C CPD. It helped. |
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| 12:38 | what they did then they took her the pharmaceuticals and left her just or |
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| 12:44 | know, and this is taking It's called weaning. When you |
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| 12:49 | if you have one drug with two and you see one drug is working |
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| 12:52 | , you take the other one off then you adjust the concentrations so that |
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| 12:58 | is called titration. This is this is how this is how this |
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| 13:03 | this child to be too high. should go lower but maybe more |
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| 13:08 | So this is all regimented and uh physician will work out because these preparations |
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| 13:15 | plants, from extracts we'll talk about a second. They're not your typical |
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| 13:20 | va approved pharmaceuticals, the typical FDA pharmaceutical to each drug, even the |
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| 13:26 | that are so. So in over the counter called O T C |
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| 13:31 | over the counter, it means you grab it, you know, |
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| 13:34 | just buy it right. Uh They come with drug monograms. You've probably |
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| 13:44 | it, you bought something, you something AC DS, maybe a, |
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| 13:48 | cream, maybe a cooling or anything menthol. And inside that cardboard |
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| 13:55 | , there's usually a piece of you just throw out the box and |
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| 13:58 | little paper. But if you take little paper out and you unfold |
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| 14:02 | that little paper like unfolds into what typically 12 pages of information that's called |
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| 14:09 | drug. And this is what physicians can use as a reference point. |
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| 14:16 | a lot of times it will state this is the starting dose. You |
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| 14:20 | , these are the being used in clinical trials being shown, this is |
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| 14:24 | top dose. These are the side . It doesn't really exist for cannabinoid |
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| 14:32 | that are made from plants of This is a big hole that I |
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| 14:38 | the, the, the, the and the marketplace, the industry and |
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| 14:44 | government have to address together. because a lot of people are seeing |
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| 14:49 | from these preparations, but there's no for, do I need three times |
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| 14:56 | T H C and CBD for this driving syndrome versus, you know, |
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| 15:02 | to 1 T H C to CBD uh partial, simple partial seizures. |
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| 15:12 | , it's, it's, it's wide , it's wide open for investigation. |
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| 15:16 | , despite that, I blame actually big part of cannabis industry because they |
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| 15:21 | already publicly traded companies that make some of them in revenue and they |
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| 15:27 | not be that profitable, but they a lot of money going back and |
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| 15:32 | and they still do zilch of real pre clinical and clinical research. But |
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| 15:39 | see that, you know, they called medical cannabis companies, medical cannabis |
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| 15:45 | such, you know, different states Texas, Texas still has that, |
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| 15:49 | , that loophole too that I'm interested uh the development of that research |
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| 15:56 | So, but let's look at this , this really interesting fellow uh William |
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| 16:04 | , a very interesting case. And is an interesting fellow because he was |
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| 16:10 | physician. He was also like an and not a Matic. He was |
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| 16:16 | the army as a medic and he to India to help build telegraph. |
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| 16:21 | in India, he came across Uh and that is because cannabis plants |
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| 16:34 | to have originated in, in in particular, in the region where |
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| 16:46 | plateaus and China meet and it migrated through land just by spreading, sees |
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| 16:58 | wind and the bees and the pollination the nature. Throughout first Asia, |
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| 17:03 | went into the Malays into India, areas like Afghanistan and, and later |
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| 17:10 | spread by ships by trade and by by carriages and horses into Europe and |
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| 17:20 | transatlantic and so on. But the of the plant is from uh from |
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| 17:25 | and Mongolia regions. No. What's ? Yeah. Yeah, it's one |
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| 17:43 | the, is still one of the crops together with uh with for poppy |
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| 17:50 | tradition. Um They're the leaders in production of, of opium and bobby |
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| 17:55 | . But indie also still produces a of opium too. So he goes |
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| 17:59 | India, he sees people using this and, and in fact, there's |
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| 18:08 | very popular drink in India that people . It's called bang. It's cannabis |
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| 18:15 | is mixed with kind of a fatty slew and it's rubbed and it's uh |
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| 18:23 | smashed together and it terms of green cannabinoids or oil soluble. So it's |
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| 18:30 | during some festivals just for, you , as a tradition has low level |
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| 18:36 | teach, I believe, but gets happy but not everybody. Nobody will |
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| 18:42 | a panic attack here. So, , now let's let's talk about this |
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| 18:46 | . So, Shaun, he sees this and he's a medical doctor. |
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| 18:49 | he goes back and he's a very case private practice which I have the |
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| 18:56 | of the family to insert in this . So he on the seventh, |
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| 19:02 | met Doctor Nicholson in consultation, uh spa of a cure from the hand |
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| 19:08 | was agreed to intermit its use to must have told this to the pedestrian |
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| 19:14 | dose of castor oil, the child rapidly became worse. So the two |
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| 19:21 | of aic spasm which is probably generalized . So then which lasted without intermission |
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| 19:30 | half past six, you know, hour walk, hold back was tried |
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| 19:41 | solution. That solution of. So would they try hold back? We |
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| 19:47 | about hyperthermia and like gaps generalize that to lower the volume of the right |
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| 19:56 | central. The hemp was therefore again to him and the dose of 30 |
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| 20:02 | equal to 1.5 grains of the Given the plan immediately after this dose |
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| 20:07 | given the limps relaxed, the little fell fast asleep. And so it |
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| 20:12 | for 13 hours, knocked out the for 13 hours while the sleep she |
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| 20:17 | evident. Then to the peculiar influence the drug on the eighth of October |
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| 20:23 | four AM, there was a severe and from this hour to 10 at |
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| 20:27 | , 25 bits occurred, 100 30 of the tincture were given and 30 |
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| 20:33 | doses it was now manifestly a struggle the disease and the remedy. But |
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| 20:38 | 10 PM, she was again narcotized from that hour noted returned six year |
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| 20:46 | on the three following days, it considerable gripping and un administering large doses |
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| 20:52 | Ammon and oil. Several small dark lumps of ham present were voided, |
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| 20:57 | gave the factual relief the child was in the enjoyment of robust health and |
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| 21:01 | regained her natural form of happy In this case, very remarkable circumstances |
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| 21:08 | themselves. First, we find three in 1/20 of the grain causing profound |
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| 21:14 | . Subsequently, we find 100 and jobs daily required to produce the same |
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| 21:20 | . The severity of the symptoms doubtless be taken into account and endeavor to |
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| 21:25 | the circumstance. So this resonance what he's doing, the resonance extract |
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| 21:31 | prepared by according to him, by the Richard, he and tops of |
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| 21:35 | dr because that's what it was called India Spirit alcohol until all resin is |
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| 21:44 | . So he was basically taking the , cannabis flowers, boiling them in |
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| 21:50 | or eating them in alcohol and concentrating the rest. And to this |
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| 21:55 | alcohol is the extraction of botanicals, just cans but other botanicals is some |
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| 22:01 | the best ways of extracting uh soluble active ingredients. The other thing |
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| 22:08 | he's talking about here is titration. he gives this amount. He sees |
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| 22:13 | effect, it doesn't stop the He gives a higher amount that stops |
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| 22:18 | seizures but then knocks uh this child too. Now, the other thing |
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| 22:26 | uh first fact, you have five that causes a profound narcotics effect of |
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| 22:35 | . Subsequently, much larger doses are . So there is a little bit |
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| 22:40 | habituation and more drug needs to be . And that happens also with anti |
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| 22:46 | drugs or concentrations of T H C CBD in this case, or either |
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| 22:53 | have to be raised. And when talk about legal medical cannabis programs, |
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| 22:59 | have medical cannabis programs that are international . We'll talk about a pharmaceutical product |
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| 23:05 | health insurance, subsidized national cannabis programs as in Germany and then Canada, |
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| 23:12 | call them international because they receive their from other suppliers like Colombia and uh |
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| 23:20 | are the biggest suppliers of Germany, believe for medical cannabis and state cannabis |
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| 23:26 | such as in the United States. example, is Massachusetts. We also |
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| 23:30 | a program here in Texas tax exemptions 20% or so or sometimes 9%. |
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| 23:36 | new program in New Jersey tax for cannabis uh patients, but there's no |
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| 23:44 | here. So none of these state for medical cannabis have insurance. So |
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| 23:48 | all out of pocket part of expense is a part of the program. |
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| 23:53 | no subsidies, recreational programs, a or national level like California, |
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| 24:00 | national level like Canada and they're all programs. Uh Germany is national level |
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| 24:07 | adult use, school taxation uh and can be province or state specific. |
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| 24:13 | in Canada, it's state run dispensaries Quebec in Germany, it is going |
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| 24:19 | be social clubs and uh individual growth home or cannabis use for adult |
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| 24:26 | But medical cannabis in Germany you'll find pharmacies and they sell cannabis uh buds |
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| 24:33 | flowers that we talked about historically, the first isolated T H C incorrectly |
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| 24:42 | structure by Raph Mash. Just passed year. I wanna say almost like |
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| 24:48 | month and a half a month and half. At the age of |
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| 24:52 | he was in his nineties. So remember we talked about H P L |
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| 24:59 | high performance look with chromatography and how separate different uh different uh active |
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| 25:06 | In this case, active ingredients like H C CBD. So uh in |
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| 25:11 | sixties and seventies H B L C widely used T H C is |
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| 25:16 | 1981 1985 there, a synthetic Delta T H C in uh drugs that |
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| 25:23 | tablets for appetite stimulation anti, which anti vomiting a lot of times for |
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| 25:31 | when patients are having wasting or extreme from chemotherapy or other anti cancer |
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| 25:39 | Uh human radiation as well. Plant medications are produced by this British |
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| 25:46 | One of them is called the Big 2015. It's 1 to 1 delta |
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| 25:52 | DH C to CBD, 2.7% T C to 2.5% CBD. It's not |
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| 25:58 | tablet, it's a buckle spray. anti spastic and an anti pain. |
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| 26:04 | in particular for the use of multiple , which is a degenerative disease that |
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| 26:09 | symptomatic of spasms and pain. cannabidiol comes about in 2016 in the |
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| 26:18 | and 2018 or 19 in the United . It's 10% CPD, which is |
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| 26:25 | solution anti convulsant specifically for syndrome and ges epilepsies and it's on schedule |
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| 26:34 | I believe of the current God at drug schedule. So all this time |
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| 26:40 | we still have a good dialects, these molecules in cannabis plant, all |
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| 26:46 | these potential ratios that you can but it's only really two conditions, |
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| 26:52 | sclerosis and epilepsy. So, and plant, the interesting thing about cannabis |
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| 27:04 | is cannabis plant does not produce T C. It does not produce |
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| 27:10 | it does not produce C B Instead cannabis plant synthesizes acidic versions in |
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| 27:18 | C B G A, an individual which is a precursor to the C |
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| 27:24 | which is petra and the acid gets from C B G A to T |
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| 27:30 | C A through T H C A . So anything that's natural in the |
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| 27:34 | should have SYN for it. If not, it's not produced in the |
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| 27:39 | . So CBD A s sent then produce CBD A. So there is |
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| 27:44 | neutral cannabinoids like T H C C G or CBD in the plant |
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| 27:49 | there's only a city can and for cannabinoids to be converted to what we |
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| 27:56 | neutral cannabis from T H C into H C CBD A and CBD. |
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| 28:01 | a process of heating and decarboxylate. taking the carboxyl group off which is |
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| 28:07 | A is the oxy group. So decarboxylate, DH C A into T |
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| 28:13 | C. These are the three major , the three major cannabinoids that have |
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| 28:20 | major because they're most predominant in cannabis . There's a lot of T H |
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| 28:26 | that the plant can produce a lot percentage of CBD, a lot of |
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| 28:31 | of CD G although not as but it can. And there are |
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| 28:36 | minor cannabinoids. So those are much cannabinoids and you will find that there's |
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| 28:41 | 100 20 different uh cannabinoids and can , but they uh are very small |
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| 28:54 | of the plant. So when you that there might be 0.1%. So |
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| 28:57 | both minor or rare, can have also T H C and CBD, |
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| 29:05 | approved pharmaceutical corporations. That's what we're about. But let's look at how |
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| 29:12 | three major canon are also major because are the three main cannabinoids on the |
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| 29:19 | in addition to another one that is C PM can, but these are |
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| 29:24 | three major ones. Let's look at interaction with the C flow receptor. |
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| 29:30 | C B one receptor controls excited to inhibitory gabble release through this metabotropic uh |
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| 29:39 | regulation through the vated calcium channel. sees an agonist of C P one |
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| 29:47 | and a lot of these molecules could partial agonous phyto cannabinoids or partial agonous |
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| 29:52 | cannabinoids could be full agonous. So partial agonist regulates this pathway by partially |
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| 30:02 | this pathway. Something that may last to 6 hours upon the consumption of |
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| 30:06 | affected dose of these cannabinoids. Then full agon is combined for weeks, |
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| 30:15 | dissociate. And that's, and that's unknown with semisynthetic because of how they're |
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| 30:21 | and they're binding properties to these receptors CD R. And that's also the |
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| 30:27 | that, that, that we have of the analysis of how they actually |
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| 30:31 | this potential with full agony with and others as well. The V H |
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| 30:37 | C B G and CBD. Here looking at C B one receptor. |
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| 30:41 | will also activate CD two receptor. will also interact with other systems in |
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| 30:48 | body. So CBD actually prefers to to serotonin. It has a higher |
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| 30:54 | affinity to serotonin receptors and regulates serotonin CBD A as well over CD |
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| 31:01 | But this is a part of the and in this case, cannabinoid activation |
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| 31:05 | the endocannabinoid system. So it's a agonist, which means it will activate |
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| 31:10 | metabotropic cascade to stop boated calcium channel stop neuro transmitter release CBD is a |
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| 31:20 | allosteric modulator. You guys remember when talked about glutamate uh receptor channels, |
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| 31:27 | said that these are the uh agonous allosteric modulators, negative allosteric modulators. |
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| 31:36 | means that it's going to reduce the . Uh C B one receptor C |
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| 31:43 | P CV G is an antagonist. it, it, it, it |
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| 31:50 | C P one second. So there have it, you have a plant |
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| 31:55 | plant that will produce these three cannabis , it can produce another 10 and |
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| 32:02 | of them will have different targets in body. And even if they converge |
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| 32:07 | here on the same target, the , what they do to that same |
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| 32:11 | C B one receptor is very different activating it to stopping its activation. |
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| 32:20 | , all right, and this kind a concludes our lecture on uh epilepsy |
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| 32:26 | medical cannabinoids. And I do believe there's a lot of pharma neuro pharmacological |
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| 32:33 | drug development in general for the whole that should stem from these molecules. |
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| 32:38 | have to address it carefully with, I said without, without uh preconceived |
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| 32:45 | that it might be a magic bullet everything or that it is so dangerous |
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| 32:50 | it should be a stay there. know, the truth lies somewhere in |
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| 32:54 | and as a recreational substance. Uh is not as dangerous as other recreational |
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| 33:03 | . It's not as dangerous as nicotine tobacco smoking or alcohol, but there |
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| 33:08 | inherent problems with cannabis use. And some people, it doesn't agree with |
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| 33:13 | people. Uh there's cannabis use disorder low percentages of people that use |
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| 33:20 | But it's more concerning with people that psychosis, have pros psychosis uh elements |
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| 33:30 | that are using it without any And there's also a danger of a |
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| 33:35 | of the market and packaging that looks it's chewing candy where it gets find |
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| 33:41 | on the table. So going to , going to the hospital, they |
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| 33:45 | to school the following day. But know, it's, it's a, |
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| 33:50 | , it's a nightmare actually that the doesn't stand in school on, you |
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| 33:54 | , can't express themselves. So we'll about it some more that there are |
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| 33:59 | , there are also uh dangers, are negative effects, it is not |
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| 34:05 | to kill you. So in many cases, neurologists or the supervising |
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| 34:11 | of this obvious neurologist could be an . They will weigh the benefits to |
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| 34:16 | effects. They will weigh, you , probably big case 200 mg is |
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| 34:21 | much three times a day. You to go to 100 mg four times |
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| 34:26 | day, you know, something like . But we have so all right |
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| 34:32 | we're gonna switch a little bit of gears but not really. And start |
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| 34:38 | about migraines and the reason why I'm really switching the gears. Let's make |
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| 34:42 | a little bit shorter lecture. We'll if we get through the whole lecture |
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| 34:46 | . And it's not really switching gears some of the cellular mechanisms that we |
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| 34:52 | that relate to seizures and epilepsy are . But yeah, distinct when we |
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| 34:59 | about language. So simulated this did you know that migraine is one |
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| 35:07 | the major neurological disorders? Do you that migraine is a disability? |
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| 35:12 | the University of Houston has that as of the uh disabilities that you can |
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| 35:19 | as an employee or um Staph is . So it's a common debilitating brain |
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| 35:28 | . It's characterized by recurring attacks as to severe headache, often accompanied by |
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| 35:35 | neurological symptoms such as enhanced sensitivity to , sound touch, smile, maybe |
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| 35:41 | . Uh A lot of people that migraines, they also will have numbness |
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| 35:46 | their hands, visual effects, uh lose partially their field of view. |
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| 35:57 | I have migraine. So I understand symptomology of migraines. Uh There are |
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| 36:05 | subtypes of migraines with overlapping but also clinical features. One third of patients |
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| 36:12 | chora before they have migraines. So is a commonality of similarity to |
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| 36:18 | Remember we said in person, people have internalized seizures would experience chora before |
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| 36:23 | experience event. Um same with It could be an uneasy feeling. |
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| 36:31 | could be that in my case, start losing uh certain parts of my |
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| 36:38 | of view. Like if I look the number screen of the phone I |
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| 36:43 | be missing three and five and no particular pattern. And it also |
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| 36:49 | generating uh flickering activity if it's a or if it's an auditory or it |
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| 36:58 | start generating a little bit of a little bit of reading the ears |
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| 37:03 | . So it can be visual tactile or speech disturbances. And I would |
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| 37:10 | that a lot of times these speech are typically not uh when you say |
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| 37:18 | it's the phase before the person feels tremendous headache and and can also be |
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| 37:27 | speech disturbance. So a person who pronounce things cannot say things cannot explain |
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| 37:33 | almost. They be, they have expressive where they can express themselves |
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| 37:40 | That happened to me a few It's really scary. The first time |
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| 37:45 | thought it was funny because all I say was taxi, taxi, |
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| 37:49 | taxi, taxi, and my I was in high school were like |
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| 37:54 | , you know, and you 15 minutes later, I was in |
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| 37:59 | office kicking all over the place and know, laid out and for 34 |
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| 38:05 | , it's, it's headache and it's because if it repeats the following |
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| 38:11 | you feel like your whole body went an attack just like you have a |
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| 38:15 | . When people have generalized seizures that to component, it's not just postal |
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| 38:21 | in the brain and it's postal depression because the emotional temperature is involved. |
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| 38:27 | limbic system is involved, you feel great and physically, it's the same |
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| 38:32 | because you, they have had these contractions. Imagine a 20 minute workout |
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| 38:38 | don't control and your muscles are locking and contract just like you have maybe |
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| 38:43 | in your legs from walking out or like that. But all over the |
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| 38:49 | . So when people come out of , they also have all around |
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| 38:54 | Even in uh in motor functions, muscles, joints can be sore |
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| 39:01 | And the same with, with Uh with the sorry the micros, |
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| 39:06 | feels that your body goes through a a little kickboxing match because you had |
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| 39:12 | it's hurting really bad and then other of your body are hurting, but |
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| 39:16 | don't really understand why in 19 Uh this uh brilliant professor received as |
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| 39:25 | think, I hope I'm saying. another neurologist Milner proposed that the clinical |
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| 39:32 | of migraine aura may be secondary to propagating cortical phenomenon, cortical spreading, |
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| 39:38 | or CS D A slowly spreading cortical of neuronal and glial depolarization followed by |
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| 39:46 | relativity. So this is suggesting something is suggesting already we well we saw |
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| 39:51 | depolarizations and seizures, seizures spread. this is suggesting that migraine waves are |
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| 40:00 | than seizure waves. There's certain certain in the dynamics of this abnormal |
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| 40:08 | abnormal wave. In this case, starting depression and the speed the spatial |
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| 40:14 | pattern. In this case, it's slow vibration So this is a schematic |
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| 40:22 | of this, this CS D wave and the involvement of the structures |
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| 40:29 | And the important structures that we'll be is that trigeminal cervical complex and the |
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| 40:36 | nucleus. Here thous activation C C for Corpus Coloso which interconnects the two |
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| 40:48 | , which means that those waves will between the two hemispheres, pain and |
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| 40:55 | of this cortical spreading depression wave that interactions with the, with the, |
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| 41:01 | the vascular vano vascular pain pathway system . So this is another description of |
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| 41:09 | what we call the headache based. notice that headaches are not migraines, |
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| 41:17 | plus or headaches are not migraines. are different from headaches. That's why |
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| 41:23 | don't confused. I had a headache take, I took Advil, I |
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| 41:26 | home, you have a migraine. had to go to an emergency room |
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| 41:31 | because it's just excruciatingly painful and you capac you can't speak, you can't |
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| 41:37 | properly. So the headache phase is activation of this trio vascular system that |
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| 41:44 | no susceptive information from the meninges A central brain areas of the cortex. |
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| 41:55 | then you have this transient global That's what I'm talking about. |
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| 41:59 | it's, it's transient global amnesia. the expressive part of that amnesia, |
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| 42:03 | amnesia can can, can, can a little bit more than transient. |
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| 42:09 | you say transient, it'll last for little while. So when people were |
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| 42:13 | me like where where, what's your ? And I'm in the middle of |
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| 42:16 | migraine. I cannot tell them And you know, and I'm not |
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| 42:21 | I can't remember or I can't see something or I can't hear properly. |
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| 42:26 | , it's very confusing. So it's clear if cortex initiates it, but |
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| 42:31 | and amplifies the sensory inputs, other and migraine on the thalamic cortical |
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| 42:39 | hypothalamic brain stem and drin gang of term gang mu is five. |
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| 42:55 | That's your sensory and motor face and head and also the tri terminal |
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| 43:03 | complex that's associated with the blood vessels there is no pain receptors in the |
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| 43:09 | itself. Brain feels well paved. there's no self death. So this |
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| 43:18 | different from seizures. Typically, it's neurodegenerative. So, but it's a |
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| 43:27 | metabolic part which means that your brain to recover for a day before you |
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| 43:31 | punch your problem. This this trigeminal activation by CS P. So this |
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| 43:42 | the proposed cascade, let's go through bigger signaling advances in the cortical surface |
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| 43:50 | that triggers this trio vascular activation and had a pain because we're trying to |
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| 43:59 | there's a cellular mechanism for neuronal cortical spreading depression, more. Where's |
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| 44:04 | pain coming from? So see, V evokes transient opening of this neuronal |
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| 44:11 | channels, which is followed by release proinflammatory signaling molecules have mobility, pro |
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| 44:17 | B one and interleukin one B among pro inflammatory actions. These there follows |
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| 44:26 | of astray nuclear factor of cap of nuclear translocation and cell expression of the |
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| 44:34 | nitric oxide system. And cyclooxygenase two ST along with the state cytokine across |
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| 44:40 | gland production. Wow, that's a of information. Well, what's going |
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| 44:47 | who control cytokine and uh uh inflammatory and the C N S glial |
|
| 44:57 | So, a lot of it is cells. And what's going on is |
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| 45:01 | you have inflammation and the release of inflammatory molecules is you have to create |
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| 45:09 | symptom that I just read. Cy's problem, lamb release from G |
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| 45:14 | . Oops, I just said that cross the glial attempts to reach sensory |
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| 45:20 | following discharge of P and dural trigeminal , dual matter p impulses are carried |
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| 45:30 | to the trigeminal ganglion cells and trigeminal coal T N C not showing all |
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| 45:37 | consequences of impulses transmitted and to, . So this is what's happening is |
|
| 45:45 | there is this communication here that it, it implicates what it implicates |
|
| 45:57 | . It I implicates uh release of of pros noid or pross by leo |
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| 46:06 | , which then essentially informs these ending endings that something is going on and |
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| 46:12 | signal pain. So this is how brain expresses its pain, not of |
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| 46:23 | pain, because of the pain receptors thalamic cells, but because of the |
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| 46:30 | uh nuclear system here that we're what is the CS E, this |
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| 46:38 | all vision mili balls from wrestling number shaw. And this is the cortical |
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| 46:44 | depression. So one of the best to evolve cortical spreading depression is to |
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| 46:51 | high extracellular concentration of potassium or high concentration of potassium chloride. And this |
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| 47:03 | that there's massive depolarization. And this depolarization in the early phase is happening |
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| 47:11 | the dendrites and then it happens in SOMA. This is the voltage for |
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| 47:18 | drive voltage for SOMA. And a followed by if you look into |
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| 47:25 | this huge huge depolarizing wave. Remember talked about certain features, cellular features |
|
| 47:33 | epileptic P S. We talked about Burt discharges spike wave discharges post bar |
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| 47:42 | we said, well, there were like 15 to 2200 m in |
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| 47:47 | There's bur 70 100 MLL in This is a time scale here. |
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| 47:57 | and very large depolarization. And that is can be recorded not just in |
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| 48:07 | in individual cells but in the entire . This is the illustration of B |
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| 48:15 | this blue wade. Here is a cortical depression painted in red because blue |
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| 48:21 | brown but it's painful. So it the mix. So concentration of |
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| 48:28 | sodium chloride and calcium on the OK. And glutamate during CS D |
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| 48:37 | . So this is the depolarization glutamate levels rise, calcium levels, |
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| 48:47 | drop, sodium chloride levels, extra drop. That means all of the |
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| 48:53 | fluoride is rushing inside the cells. is all coming out and you have |
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| 48:58 | huge wave of potassium mixed cell. what it's just is it the the |
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| 49:08 | is mainly mediated by the diffusion of , high potassium concentration is that high |
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| 49:15 | concentration on the outside? Because everything glutamate on the outside and high potassium |
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| 49:21 | the outside now can start moving kind as a slow wave. And that |
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| 49:28 | on the outside, if you recall potassium will drive the membrane potential to |
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| 49:36 | . So this high concentration of potassium the outside will now spread through the |
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| 49:41 | and it will involve other cells and will involve gap junction signaling to and |
|
| 49:47 | in a very slow fashion. This spreading depression, very slow. It's |
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| 49:53 | very slow amount if the re build to. So I and this is |
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| 50:07 | , this is mass Bartlet asterisk uh uh with number signs here with |
|
| 50:17 | So if it is before the it's pre, if there is some |
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| 50:24 | I bursting, it will be But then look at this, this |
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| 50:28 | a long time period. There's nothing about a minute after of this |
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| 50:34 | So there's a postal depression and then have bursting activity, bursting activity, |
|
| 50:41 | , burst and then silence again. these would be called in right, |
|
| 50:46 | the kind of will occur in between seizures. But we don't know when |
|
| 50:51 | don't know if there is a specific to them. And this is what |
|
| 50:54 | going to uh to be potentially picked . You can see extracellular recording them |
|
| 51:01 | those spikes because enough of the network to be picked up by an extracellular |
|
| 51:09 | , which is similar to what could picked up by E E G recordings |
|
| 51:13 | seizure activity recording, right? These bursts or uh spike wave discharges that |
|
| 51:19 | called the E E G recordings. they will show up on the |
|
| 51:25 | And I here we're still looking at in vitro and the seizure model here |
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| 51:33 | and reduced magnesium. We're looking at 32nd duration, maybe 42nd duration. |
|
| 51:42 | this is pre bursting. This for example is having pre bursting. |
|
| 51:47 | cell is not and this is the inhibitory interplay. This is the inhibitory |
|
| 51:53 | . This is the excitatory paranal It is excited to inhibitor activity interplay |
|
| 52:00 | and on this cell, I post Barton but the cell doesn't. So |
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| 52:05 | cells will contribute differently to these pre eco postal inter events in their synchronizations |
|
| 52:12 | we have a number of different subtypes neurons with their own number properties and |
|
| 52:20 | physiological properties versus seizures and CS So this is an example of cortical |
|
| 52:29 | depression. What's different about cortical spreading is in many cases, you'll see |
|
| 52:36 | in ectal activity in seizures. You'll pre postictal activity. Ok. Pre |
|
| 52:44 | activity in cortical spreading depression. This extracellular recording. You see this is |
|
| 52:51 | recording. I see there's nothing in trace that tells you that anything is |
|
| 52:56 | to happen. When you look at , there's typically look, there's extracellular |
|
| 53:02 | , the extracellular trace, it tells something is going on. Lots of |
|
| 53:08 | . It depicts a synchronized burst before massive seizure or that happens. There's |
|
| 53:14 | of that sort of the migraine or the pressure. There's no activity in |
|
| 53:21 | , there's no synchronized activity extracellularly. then boom, you have this massive |
|
| 53:28 | . You don't have much firing because cells enter what we call here. |
|
| 53:33 | depolarization block. The depolarization block means the cell numbering potential is depolarized above |
|
| 53:40 | threshold for action potentials, but it's from producing action potentials physiologically, it |
|
| 53:46 | cannot produce action potentials and look what here. Nothing. Nothing, no |
|
| 53:51 | . Extra cell, no sign in boom. First, a few |
|
| 53:58 | This is one minute duration. So , five minute long spreading depression. |
|
| 54:10 | . And this is done with application high potassium chloride. And that's why |
|
| 54:17 | or raising your cellular potassium, applying concentration of potassium chloride can evoke and |
|
| 54:24 | a good model for evoking cortical spreading , which we think is the cellular |
|
| 54:31 | for migraines. But this very slow migraine wave. The two main hypotheses |
|
| 54:39 | the ideology of CS D A vertical depression. It's one of the activation |
|
| 54:48 | an MD A receptor. I want barrier for me, low magnesium |
|
| 54:59 | So it's all pointing to depolarizations, brain barrier glutamate and an M B |
|
| 55:05 | signal. So that's one hypothesis. glutamate is the main culprit, |
|
| 55:11 | We talked about how glutamate and potassium up. So as it spreads, |
|
| 55:15 | is like what is the etiology of ? Who is kind of a starting |
|
| 55:18 | thing? So then came up with . Awesome. And the other |
|
| 55:26 | his name is Grain. Thank you doing this work gentlemen, but they |
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| 55:31 | up with the potassium grain in his accumulation of extracellular potassium which depolarizes neurons |
|
| 55:39 | causes glutamate release chicken before the egg increases in potassium can also diffuse to |
|
| 55:48 | areas. Yes. And both potassium glutamate can be cleared out by glial |
|
| 55:59 | . The particular astro glial cells. does that suggest? Well, if |
|
| 56:05 | had an impaired glutamate transporter in glia glial glutamate transporter could lead potentially to |
|
| 56:14 | and C uh CCS D events, seizures or spreading depression, wave of |
|
| 56:20 | wheel depolarization that spreads with a velocity 3 to 6 millimeters per minute, |
|
| 56:27 | cerebral cortex. And this is the of cellular that that's underlying my |
|
| 56:35 | autos of cortical depression grain for potassium applications. As we talk about |
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| 56:41 | you can apply glutamate manipulation of sodium . So rebuilding and recharging off the |
|
| 56:49 | of potential or resting number of potential stimulation. We can stimulate the tissue |
|
| 56:57 | models to produce cortical spreading depression. , remember we talked about kindling in |
|
| 57:04 | . You can produce seizures by electrically the pathway and then delivering one shock |
|
| 57:09 | producing a seizure. Alright, making system plastic to provoke seizures in this |
|
| 57:17 | or hypothermia. So he again similarity febrile seizures, hyperthermia, du feb |
|
| 57:27 | , local injury to the brain, electrical pulses to the brain uh or |
|
| 57:35 | or experimental c is accompanied by high of glutamate and glutamate induced toxicity. |
|
| 57:43 | but it it's toxic, but I it doesn't kill that. Many cells |
|
| 57:49 | the changes in the brain. this is a very busy slide. |
|
| 57:54 | a very busy slide. And what's point of the slide that there are |
|
| 58:00 | in the more form morphology, more metrics of the brain, how large |
|
| 58:07 | small or certain structures in the I don't want you to remember all |
|
| 58:11 | of this except that there are more metric changes and there are functional changes |
|
| 58:16 | are associated with people that have There's many different ones. We have |
|
| 58:22 | increase in gala decrease. Oh Look at that. Isn't that similar |
|
| 58:27 | our seizures too? We have made in gao decrease. Here is one |
|
| 58:32 | the uh uh that is happening three or but there's basically functional and more |
|
| 58:45 | me change. So parts of the are changing medications for migraines, they |
|
| 58:57 | pain. Uh the best way to a migraine is if you can start |
|
| 59:04 | the onset of flora, best way stop seizure, you can start feeling |
|
| 59:10 | onset of HOA. The best way stop seizure is to have a seizure |
|
| 59:15 | . Because remember I told you that are the best victor, they can |
|
| 59:19 | seizure about two minutes before it Uh and getting yourself ready, preparing |
|
| 59:26 | taking medication. All of this hypersensitivity happens with migrants, audio visual |
|
| 59:36 | We uh learned uh because we have and my family, we learned that |
|
| 59:45 | have to exit whatever you're doing, have to exit to prevent the migraine |
|
| 59:52 | the first earliest sign of horror or will pay for it a lot. |
|
| 59:59 | will pay for it that day because the migraine attack and, and the |
|
| 60:03 | day too by exiting. I I've been in situations where I was |
|
| 60:08 | my graduate students committee uh talking about dissertation defense and I had a massive |
|
| 60:16 | attack and I had to be driven the emergency room. And the reason |
|
| 60:22 | it was at that point is because thought I was gonna get through |
|
| 60:25 | I thought that maybe I'm just gonna an Advil or two, I'm |
|
| 60:30 | maybe it's gonna calm down. I'm sit through it and it got a |
|
| 60:34 | , a lot of worse. And what we learned is that the first |
|
| 60:38 | of a, in any disease and or migraines, you do everything you |
|
| 60:45 | get, exit off, get off highway, turn off the music, |
|
| 60:49 | on cool air, cover your no bright lights, no stimulation. |
|
| 60:56 | the medication if you have it on . Uh, but don't try some |
|
| 61:00 | through it because the consequences can can be lethal actually, medications. |
|
| 61:08 | , so of course, it will it for a sign of oncoming migraine |
|
| 61:12 | soon as signs and symptoms of migraine pain relievers is still quite effective in |
|
| 61:18 | headache for migraine. So don't treat , doesn't mean that there's gonna be |
|
| 61:22 | migraine attack. So people can have every month, every week. It's |
|
| 61:27 | that common every week, every a couple of times a month, |
|
| 61:30 | 23 times. It's pretty common. few times a year is very common |
|
| 61:35 | . Uh Seiner treatments is the brand but targeting serotonin pack, I don't |
|
| 61:46 | you to remember the brand names. don't doin gene related peptide receptor is |
|
| 61:53 | another medication, target opioid medications. in severe cases of headaches and opioids |
|
| 62:01 | gonna die uh anti pain. Then , so they, they help with |
|
| 62:08 | migraines, anti of drugs because you get nauseated when you are having a |
|
| 62:15 | attack and uh and you can vomit . Uh now, uh don't talk |
|
| 62:26 | about cannabis here and migraines there there is, there is treatments you |
|
| 62:33 | that it helps with migraines and but literature actually hasn't researched this, |
|
| 62:39 | particular and compared to epilepsy or it's a lot more about that expect |
|
| 62:47 | stimulation. So, in some severe of pharmacologically controllable migraines, you could |
|
| 62:58 | , I believe even dangerous nerve stimulation some instances out. But guess what |
|
| 63:04 | want to stimulate here. Very general . Yeah, because we're talking about |
|
| 63:13 | trigeminal uh sensory and all of So that's something that's an experimental treatment |
|
| 63:21 | now. Preventive medications, blood lowering medications. Oh yes, blood |
|
| 63:28 | can go through the roof and I know why exactly. It's we're talking |
|
| 63:35 | about these mechanisms here and that have do with the, the secular |
|
| 63:43 | It has to do with this proinflammatory , blood blood brain barrier interaction that's |
|
| 63:50 | on. Uh antidepressants, wide So a lot of antidepressants target serotonin |
|
| 64:02 | . And that could be as a and anti seizure drugs, Botox |
|
| 64:09 | migraines, calcitonin gene related C G P molo antibodies. Bo Botox is |
|
| 64:18 | approved treatment for migraines because when uh who are getting Botox treatment for aesthetic |
|
| 64:27 | they noticed that I'm, I'm not a migraine attack this month or at |
|
| 64:34 | two months. And so we started into and prove that the air treatment |
|
| 64:39 | migraines, phototoxic ions wouldn't be around uh the same areas that people do |
|
| 64:45 | a study reasons. All right. this actually concludes our lecture today and |
|
| 64:53 | are on time, but we got migraine so that I think that you |
|
| 64:57 | start recognizing some of the cellular dynamic between seizures and epilepsy. Um And |
|
| 65:07 | when we meet again, we'll be about another neurological disorder schedule in |
|
| 65:15 | I believe we have uh Alzheimer's. . And I believe in general, |
|
| 65:21 | just have two more lectures left. today is one day migraines. We |
|
| 65:32 | Alzheimer's correct on Wednesday, uh having uh COVID-19 and the brain is |
|
| 65:46 | already covered and they can have a system. So I won't, |
|
| 65:50 | I won't go into more details on that uh, inflammation side causes |
|
| 65:57 | brain injury. And basically, next is our last meeting in person on |
|
| 66:04 | . We'll have the exam with you and then you're taking it two weeks |
|
| 66:11 | on Wednesday online unless we maybe next , decide on a different date that |
|
| 66:19 | would like to, er, to as an alternative of. And it |
|
| 66:25 | help you too because of some of things that we have to do with |
|
| 66:29 | family that, um, not very show. Um, anyways, we'll |
|
| 66:37 | here today and I'll see everyone in , if not on Wednesday. Then |
|
| 66:43 | |
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