| 00:02 | This is lecture 22 of Neuroscience. before we talk about brain rhythms and |
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| 00:10 | as a rhythmic disorder, just a with some descriptions from your book on |
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| 00:15 | matter sensory system, the rearrangement, and therefore functional rearrangement of cortical organization |
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| 00:24 | cortical connectivity by reshaping these maps that responsible for digits because we looked at |
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| 00:32 | experiment where in monkey two digits were stimulated continuously and that resulted in the |
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| 00:39 | of the brain space in the somatosensory that is dedicated to processing information from |
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| 00:45 | these two active digits. There's also interesting description here that talks about violinists |
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| 00:55 | it says the functional imaging of S . So soens cortex, one shows |
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| 01:00 | the amount of cortex devoted to the of the left hand is greatly enlarged |
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| 01:05 | string positions. So if you think violence, most of the time it |
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| 01:12 | being held like this and these are active fingers and what is the other |
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| 01:16 | doing? It's doing this. So not really not much digit movement |
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| 01:23 | And therefore there is a lot noticeable here now. So it's likely that |
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| 01:28 | is an exaggerated version of a continuous process that goes on in everyone's brain |
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| 01:34 | each person's life experiences a diary. that's why we have different levels of |
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| 01:42 | . We have different talents and We're never the same. We perform |
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| 01:48 | . We perceive things differently. We things differently because we are sliced variants |
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| 01:53 | each other. And we have different and different arrangement of the brain because |
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| 02:01 | our own unique sensory. It's a sensory all sensory experiences and uh the |
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| 02:08 | that we're surrounded by. Uh when, when we talked about uh |
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| 02:15 | , we talked about how the anesthesia you recall is another interesting component there |
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| 02:22 | everything in the brain, there's way cells and synopsis when you're born than |
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| 02:27 | you're adult, there's a lot of that's nonspecific. And then as you |
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| 02:35 | all of these unique sensory motor, experiences throughout your life, you undergo |
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| 02:41 | process of plasticity. And part of plot process of plasticity during early development |
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| 02:47 | trimming the connections, trimming the And uh Doctor Ramachandran talked about this |
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| 02:55 | that has a number, the color the tone areas very closely anatomically spatially |
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| 03:05 | in the brain. And therefore, would be like cross wiring and |
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| 03:10 | And he suggested that there is a component, the gene that's responsible for |
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| 03:17 | this kind of a trimming that allows the connectivity to become very specific. |
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| 03:23 | this is an article about 10 years . But it's still relevant, the |
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| 03:27 | , more common autism. So a increase in synaesthesia prevalence and autism suggested |
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| 03:34 | two conditions may share some common underlying . Future research is needed to develop |
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| 03:40 | physical validation, but it is almost times greater than in controls. So |
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| 03:48 | Annes, there's three times greater possibility prevalence of synaesthesia in patients that have |
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| 03:56 | autism. Um interesting to think about very early discussions we had about autism |
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| 04:04 | disorder and fragile. You recall, talked about how the dendritic spine anatomy |
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| 04:12 | determine connectivity will determine function. And is an example that was an early |
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| 04:17 | disorder too. And this is an of, of of kind of a |
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| 04:22 | under the autism spectrum disorders of, know, uh abnormal connectivity in a |
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| 04:28 | or cross cross modal connectivity between different and their interpretations. Remember the slide |
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| 04:35 | showed you at the very beginning of course. And I think now you |
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| 04:42 | a lot more about neurons, you how individual neurons function, you understand |
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| 04:46 | glee are involved in supporting neuronal function also very actively is involved in synaptic |
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| 04:53 | , synaptogenesis, uh neuronal neurotransmitter um ionic uh regulations supported by |
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| 05:03 | But then you have neurons that form networks, these networks form nuclei, |
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| 05:07 | nuclei interconnect that form systems that we those visual system auditory system. And |
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| 05:14 | you have the lobes that have their specific functions. And I think that |
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| 05:19 | looking at the slide, you probably a much better and more interesting understanding |
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| 05:25 | interpretation of this image than what you . Hopefully, when I showed it |
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| 05:30 | you the very first time in this , so neurons eventually form networks and |
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| 05:39 | networks oscillate. So the way networks and engage each other is they have |
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| 05:46 | produce a rather strong synchronized depolarizing It has to typically repeat that depolarization |
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| 05:54 | that signal repetitively and communicate that to interconnected adjacent network. So one network |
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| 06:03 | start being active and it will typically start getting active at a certain frequency |
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| 06:10 | it will essentially oscillate at that frequency it will inform its own interconnected buddy |
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| 06:17 | . But look, I'm active and going up and down here in activity |
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| 06:20 | a certain frequency. And these it's like loosely coupled uh oscillators, |
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| 06:27 | connections to the other structure, they , oh there's something going on and |
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| 06:31 | they now synchronize their activity to the of the input that they're getting is |
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| 06:38 | input is all synchronized. And the we understand the rhythmicity of the brain |
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| 06:44 | from the E E G recordings and E G recordings are electrodes of follow |
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| 06:53 | these recordings that are performed when you a cap on the surface of the |
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| 06:59 | of the brain and you pick up underlying neuronal activity. And what was |
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| 07:05 | interesting is that the E E G So these patterns that we record in |
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| 07:11 | E G are characterized by amplitudes and and in particular frequencies that fall within |
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| 07:20 | dominant frequency bands. And that these frequency bands represent a different state of |
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| 07:32 | a different behavioral state, a different state. So alpha beta delta theta |
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| 07:43 | , they're all different dominant brain rhythms are produced by synchronized cellular activity in |
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| 07:51 | cortex. And it is picked up these E E G electrodes on the |
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| 07:56 | of the scalp. Alpha is corresponding relaxed wakefulness. And it's typically 8 |
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| 08:06 | 10 Hertz frequency beta, intense Matal activity and its 13 to 30 Hertz |
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| 08:14 | delta, low frequency oscillations and beta as a pathology doing what wakefulness but |
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| 08:22 | learning with beta is 4 to 74 turn 10 Hertz and gamma. And |
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| 08:29 | are even faster frequencies in gammas. Vertz. What does that mean? |
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| 08:33 | 10 that means that the cells synchronize they fire action potentials and they oscillate |
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| 08:40 | whole network oscillates 40 cycles per 40 Hertz really, really fast, |
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| 08:47 | , really fast oscillation that is communicated the interconnected networks. So you can |
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| 08:53 | that these are different E E G and amplitude and frequencies that represent different |
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| 09:01 | states, excited, relaxed drowsy as deep sleeve states. On this |
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| 09:07 | there's also a demonstration that beyond the E G recordings which are noninvasive because |
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| 09:14 | simply placing a cap with the electrodes somebody's head, there are invasive |
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| 09:21 | electrical recordings that are done in rare intraoperatively during operations or during the surgeries |
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| 09:29 | the operating room. If the for example, has abnormal seizure activity |
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| 09:35 | we'll talk about and that seizure activity generated in one specific area of the |
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| 09:41 | . If that person is not responsive medications, one of the alternatives is |
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| 09:47 | resect or cut that piece of the out. And in that case, |
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| 09:53 | you cut any piece of the brain , you have to really pinpoint the |
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| 09:59 | that might be responsible for that whether it's seizure pathology or maybe cancer |
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| 10:07 | . But you'd want to cut out smallest piece of the brain possible. |
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| 10:11 | you don't affect important functions. You affect parts of the brain that are |
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| 10:16 | for for really important functions and minimize amount of the cut tissue. So |
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| 10:22 | would then place these electrodes into Here. It's intracranial recordings inside the |
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| 10:31 | . The skull has been open. is the window. This is a |
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| 10:35 | Treon nation, a big opening window the placement of these electrode grids on |
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| 10:42 | very surface of the brain to before surgery to confirm the precise site and |
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| 10:49 | smallest possible resection site for that particular . Uh This is done by phd |
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| 10:56 | typically in the operating room that understand really well understand electrical activity in their |
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| 11:04 | . So a lot of times we have here even in, you |
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| 11:08 | Methodist or different uh uh university operating operating rooms, neurosurgeon is typically going |
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| 11:16 | be working with a neurophysiologist to interpret the activity from the surface of the |
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| 11:22 | and maybe neurologist which will be working , in interpreting the brain signal. |
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| 11:30 | what we call the brain waves or brain rhythms. So they're really |
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| 11:33 | right? They're rhythms because they occur different frequencies. That's a slow |
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| 11:40 | This is a fast frequency and this how your brain networks synchronize and produce |
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| 11:47 | different rhythms, right? We call rhythms and when these activity or rhythms |
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| 11:52 | across the brain and the interconnected we call them brain waves. |
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| 11:58 | how do we kind of uh perceive of the brain? And I I |
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| 12:02 | this book, you don't have to it. But if anybody is interested |
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| 12:06 | rhythms of the brain or neurology or , neuronal activity, how to interpret |
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| 12:12 | uh both physiologically biologically but also that's a great book, Rhythms of |
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| 12:18 | brain. But you and so the relationship between space time is packed into |
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| 12:27 | concept of space time, X Y T X Y Z three dimensions in |
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| 12:35 | time, the fourth dimension oscillations, synchronized activities by networks oscillations can be |
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| 12:43 | of and displayed in terms of either or time. The phase plane of |
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| 12:47 | sinusoid harmonic oscillator is a circle. can walk the perimeter of the circle |
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| 12:53 | twice of building the so that we get back to our starting point. |
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| 12:58 | has been is what will be and has been done is what will be |
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| 13:01 | . And there is nothing new under sun. This is the circle of |
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| 13:04 | and our walk on its perimeter is as dislocation. That's the circle of |
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| 13:10 | on the top left. An alternative this periodicity view of the universe is |
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| 13:15 | display periodicity as a series of sine . Like on the right now, |
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| 13:22 | can walk along the troughs and peaks the line without ever returning to the |
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| 13:28 | point time. Here is a continuum the cycle as its metric, the |
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| 13:34 | are identical in shape and the start end points of cycles from an infinite |
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| 13:38 | into the seemingly endless universe. So is uh April 17th and there's gonna |
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| 13:45 | April 17th next year and it's a cycle that is gonna pass and things |
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| 13:51 | gonna be kind of a the same , the earth is gonna be situated |
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| 13:54 | respect to the sun and the moon about the same position, but nothing |
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| 13:59 | gonna be the same room because you time is a dimension. So we |
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| 14:05 | , when we talk about activity in brain, when we look at those |
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| 14:09 | , we're looking at the activity now E E G recordings, always talking |
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| 14:13 | spatial temporal patterns of that activity space in space is that activity generated? |
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| 14:19 | in time is that activity generated fast and the pattern of it, how |
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| 14:24 | it spreading? Is it spreading through networks? Is it spreading through the |
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| 14:28 | brain and so on? How are different rhythms created? So again, |
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| 14:34 | the slowest rhythms, if you think the slowest rhythm in the brain is |
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| 14:39 | diurnal rhythm is your day, night that is controlled by the circadian master |
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| 14:47 | , master clock body regulator, super nucleus. Remember that super cosmetic |
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| 14:54 | it gets very small input from the to let super cosmetic nucleus know whether |
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| 14:59 | light or dark outside. So super nucleus was not configured in our primal |
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| 15:08 | right formation here in the exhibit Instead it gets this input of |
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| 15:13 | It's know it knows it's it's light and it starts expressing certain transcription |
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| 15:19 | it's getting cut off a little So I'll exit out of this. |
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| 15:22 | starts expressing certain transcription factors in the . OK. Start expressing certain molecules |
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| 15:30 | the cell that tell the whole brain body it's daytime. And then about |
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| 15:38 | typical, you're 16 depends on the day night cycle that you have different |
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| 15:44 | of transcription factors get turned on to different molecules. And now it informs |
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| 15:50 | brain and the body, it's night and you have slow rhythms that are |
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| 15:54 | rhythms. You have slow rhythms that uh metabotropic signaling. Why do we |
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| 16:01 | all of these different rhythms at different . 1.5 to 44 to 10, |
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| 16:06 | to 30. How are these rhythms ? And why do we have so |
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| 16:12 | of them? So from the very , we talked about different cellular |
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| 16:17 | And we said that you know especially in the hippocampus and also in |
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| 16:22 | cortex. If you look, we that these different neurons and in particular |
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| 16:28 | their inter neurons, they speak these subtypes of cells, they speak a |
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| 16:34 | different dialect where their main language is action potential. But the pattern, |
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| 16:41 | frequency of these action potential generation is different in all of these cellular |
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| 16:47 | So some of them are slow, of them are very fast. Uh |
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| 16:51 | a super, super fast. So having this variety of special inhibitory cells |
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| 16:57 | a certain connectivity by which inhibitor and is also connected in the brain, |
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| 17:02 | capable of producing different network rhythms because have individual cells like the players in |
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| 17:09 | orchestra, we have really fast flutes we can engage really fast flutes and |
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| 17:13 | will roll really fast rhythm, Or we can do the timing really |
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| 17:18 | and we have those types of cells . And that's how we generate these |
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| 17:22 | fast and slow rhythms in the Now we have neurotransmitters. So it's |
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| 17:31 | just the action potential frequencies and We have neurotransmitters, gao glutamate excitation |
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| 17:38 | condition but then we have neuro the means or beer and they change |
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| 17:44 | they influence these patterns by which individual fire and therefore by which the collective |
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| 17:50 | within the networks is going to be or modulated by them as well. |
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| 17:56 | entrainment. Let's think about what is entrainment, this sensory experience of stimulations |
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| 18:02 | are receiving constantly, somebody likes to to really fast music, you |
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| 18:10 | electronic techno, some people like really music. And why am I talking |
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| 18:18 | that? What does that have to ? The internal train as well? |
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| 18:23 | sound frequencies are gonna be slow, ? And that's gonna be in training |
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| 18:28 | to react to slow frequencies and and types of music is going to be |
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| 18:34 | . So you have different stimuli, only can perceive 20 to 20,000 Hertz |
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| 18:42 | , but we have different stimuli, to 700 they all come in different |
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| 18:46 | . They're like waves of activity in frequencies and amplitudes. So this is |
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| 18:51 | I mean by external entrainment is that are getting a certain input, we're |
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| 18:55 | process that the output from a certain is gonna be a certain output from |
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| 18:59 | brain. If we change the if we change the input, the |
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| 19:02 | is also going to change. Why so many aci regimes? So |
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| 19:07 | we're describing a few of them because have multiple tasks, cells have multiple |
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| 19:13 | , neurons have multiple tasks we as have multiple tasks, our bodies brains |
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| 19:18 | general, some of them are very and fast, others are very |
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| 19:23 | And by having the variety of different types and the variety of these dominant |
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| 19:29 | , we're able to produce distinct levels computation, sometimes parallel and parallel along |
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| 19:37 | or three different frequencies within the same and encode that information and compute that |
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| 19:44 | . And then when we need to that information such as memories such as |
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| 19:48 | tasks and other types of performances that put these rhythms here. Penton and |
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| 19:55 | in 2003, looked at L N here uh natural log and they see |
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| 20:04 | frequency and they take these dominance uh that are recorded by E G |
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| 20:11 | And they're seeing that they fall somewhat integer apart on this L N scale |
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| 20:19 | is it the classes, this is frequencies and this is the integer scale |
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| 20:24 | . So it's kind of interesting that they're trying to do here is they're |
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| 20:27 | to ask the question. Is there mathematical way to explain this is a |
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| 20:32 | system? Because in the end, talking about computational processes in the brain |
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| 20:37 | processing the incoming inputs and sensory information such. OK. So here is |
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| 20:45 | example of a happy student sitting with E G cap, noninvasive eyes |
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| 20:51 | She has algorithms certain amplitude, certain beta waves eyes are open, the |
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| 20:57 | decreases the frequency changes, eyes it goes back into the alpha |
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| 21:02 | And this is pretty classical. You actually detect that rhythm. Now to |
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| 21:06 | that rhythm in E E G, have to synchronize a number of cells |
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| 21:12 | you can see this, it looks a very busy cap in the sense |
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| 21:16 | it has what maybe 64 electrodes. there are 64 different probes that are |
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| 21:22 | on the surface of the skull. have to interpret it where it |
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| 21:25 | some of them are temporal lobes, of them ex frontal and so on |
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| 21:29 | so forth. Yeah. So it's complicated. But in order to pick |
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| 21:35 | the activity under one of these you actually have to synchronize hundreds if |
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| 21:40 | thousands of cells, right. So is again, there's a larger image |
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| 21:45 | distinction that E E G is non . But when we talk about intracranial |
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| 21:51 | physiological recordings that typically is related to procedure and it is invasive and it |
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| 21:58 | require opening the brain and placing the of the electrodes directly on the brain |
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| 22:04 | , right? It's something for you to now keep in mind there are |
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| 22:10 | oscillations. And why do we talk brain rhythms and epilepsy? Because one |
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| 22:15 | the major definitive diagnosis for epilepsy is . And the way that you diagnose |
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| 22:22 | is not just by observing a person's but actually recording their brain activity, |
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| 22:28 | the E E G patterns using the on the surface of the skull that |
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| 22:35 | were discussing. So what what typically done here is a, here is |
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| 22:41 | a an interesting pattern in the We may have seen this image before |
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| 22:48 | has 16 electrodes distributed in different probes different parts of uh uh of, |
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| 22:57 | the head. And in a this is pretty calm in this person is |
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| 23:04 | what is called an aura. So lot of epileptic seizures will be preceded |
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| 23:09 | aura. Aura is typically a feeling something is going to happen. Some |
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| 23:14 | feel horror. Some people uh feel satisfaction from that feeling, but then |
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| 23:21 | happens and that is seizure. And can see that in B at the |
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| 23:26 | of the or there's already synchronized activity , you cannot really detect any dominant |
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| 23:32 | in any of these electrode traces. when you do electrode recordings, you |
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| 23:37 | electrode activity and electrode nine versus 10 to 11, 11 versus |
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| 23:41 | And so on, you don't see really distinct rhythms in any of these |
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| 23:46 | traces. Each one of these lines the one probe, one of those |
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| 23:51 | probes in this color. But and b you start seeing activity and |
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| 23:56 | activity is a rising, maybe I say somewhere here between 9 14, |
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| 24:03 | , 15 electrodes and sometime later, happens is this activity that means it |
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| 24:11 | localized and starts locally in a certain , it starts locally in one |
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| 24:18 | Now, after some time, what is activity of normal synchronized activity spreads |
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| 24:24 | the entire brain. And therefore, you see engagement and synchronized in activation |
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| 24:33 | the entire brain surface, which typically referred as generalized seizure also and can |
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| 24:41 | in the loss of consciousness. epilepsy is a rhythmic disorder and it's |
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| 24:48 | as such and there are certain features of, of this ethnicity. It's |
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| 24:58 | . Hm. OK. Chocolate. love chocolate chokes. OK. So |
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| 25:13 | is part of this image shows that structure here is the hippocampus and the |
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| 25:20 | is very susceptible to damage by And we studied hippocampus from the very |
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| 25:25 | , we talked about different subtypes of in the hippocampus. We talked about |
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| 25:29 | functions of the hippocampus. A part the limbic system processes memories, encodes |
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| 25:35 | . It helps with the memory it doesn't store the memories. Uh |
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| 25:41 | it is highly susceptible to damage by and epilepsy. In general temporal lobe |
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| 25:46 | and it's located very close uh by temporal lobe. Uh The hippocampus is |
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| 25:53 | most frequent source. The most common of epilepsies are temporal lobe epilepsies. |
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| 25:59 | therefore there's substantial damage in these areas associated with seizures and pathology. |
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| 26:07 | when, when these networks synchronize what's happening is that you can think |
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| 26:11 | everything being short circuited. So just in your computer or when you put |
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| 26:17 | in a plug in, it starts of a spark up, it's getting |
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| 26:21 | circuited. So this abnormal synchronized activities of like spark up abnormal sparks in |
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| 26:27 | brain that can eventually kill the These are neurodegenerative disorders. So, |
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| 26:34 | is a neurodegenerative disorder because if you contain seizures and 30% of patients are |
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| 26:40 | responsive to pharmaceutical treatments. If you contain seizures, there is neuro degeneration |
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| 26:47 | cell death with repeated seizures, Ramonica over 100 years ago. Think about |
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| 26:58 | . Think about this drawing how forward he was. He said that there's |
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| 27:03 | connectivity, there's certain way directionality we know about the backdrop of getting |
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| 27:08 | But nonetheless, he talked about also the rearrangement, you know, |
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| 27:14 | he didn't see uh uh E E recordings. I don't know if he |
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| 27:19 | . He may have seen E E recordings. So he really came into |
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| 27:22 | in the 19 twenties when we're picking activity from the surface here. This |
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| 27:30 | the cortical surface. We're really picking activity, remember the six layers of |
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| 27:35 | cortex and that we have the parameter projecting their apical dendrites. We're really |
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| 27:42 | up activity from these apical dendrites of cells. And it's not just one |
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| 27:49 | , you have to have synchronization of if not thousands of cells. So |
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| 27:54 | activity can be picked up by an E G recording electron. Um We're |
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| 28:04 | skip this and move next to what Um Actually let me pause here. |
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| 28:13 | I can. But with uh with slide shows when the boots back up |
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| 28:33 | , what this slide shows is that actually, when we talk about different |
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| 28:39 | of cells, we can record, can place inside the brain, these |
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| 28:45 | electrodes that will have multiple reporting sites them. We can use triangulation laws |
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| 28:52 | mathematics to determine what subtypes of cells when they fire to produce these different |
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| 28:58 | , right? Because they said you these different subtypes of cells, let's |
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| 29:03 | in hippocampus, you have over 23 24 different subtypes of cells and they |
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| 29:09 | speak different dialects and they produce these . So the next logical question, |
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| 29:15 | you can pick up this rhythm with E G recording on and basically understand |
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| 29:20 | network dynamics. What are the underlying cellular dynamics in generating these rhythms? |
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| 29:28 | so there are some answers that were achieved in understanding different rhythms that showed |
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| 29:35 | different cells will be active at different with their respective frequencies and amplitudes of |
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| 29:42 | of action. For controls neurons and have a characteristic behavior. They produce |
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| 29:53 | spikes. That means that I if place a, a cap E G |
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| 30:00 | on a normal person, you will see any synchronized activity. If that |
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| 30:04 | is epileptic, you will start seeing we call per multi depolarizing shifts or |
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| 30:11 | spikes. Uh And they're about 5200 in duration, 20 to 40 millivolts |
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| 30:19 | depolarization with a number usually few to action potentials riding on top of this |
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| 30:29 | . And so this is a repetitive activity and it is formed because cells |
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| 30:35 | different ionic channels with different properties. , it's intrinsic properties of neuronal membranes |
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| 30:42 | they have and also synaptic connectivity and signaling, inhibitory exci fast, slow |
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| 30:51 | and so on. So this is really interesting is that you have this |
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| 30:57 | activity and this repetitive activity will be . And in order to have this |
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| 31:03 | like activity, that is typical synchronization hundreds or thousands of cells in order |
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| 31:09 | pick up this activity in the Although we can pick up that activity |
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| 31:14 | individual neurons as is shown here. this is the intracellular recording in a |
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| 31:19 | cell. And this is extracellular recording shows us that extracellular recording picks up |
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| 31:26 | from hundreds of neurons in the vicinity the tissue. So it's somewhat close |
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| 31:32 | or more representative of the E E recordings. Extracellular recordings will pick up |
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| 31:39 | activity of local neuronal networks. So shows you that individual cells will be |
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| 31:45 | these bursts of activity as well as will be synchronized within the networks. |
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| 31:49 | whole network producing these abnormal inter bursts activity. A person may have a |
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| 31:57 | or two or three and then they go into a doctor's office and have |
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| 32:02 | place for four hours and they may have a seizure and they may have |
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| 32:06 | come back and do 24 hour recording they still may not have a |
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| 32:10 | And there's still limited understanding of what's and where it's happening in the |
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| 32:16 | So in those cases where again, cannot control seizures, a person may |
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| 32:21 | to stay for a few days in medical facility with the E G cap |
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| 32:27 | in order for neurologists and the doctors see what exactly is going on and |
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| 32:32 | , what is the right? What the? So this is happening in |
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| 32:38 | areas of the brain that are responsible generating seizures. Right. Again, |
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| 32:44 | not happening everywhere. Typically, there a source of seizure and then there |
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| 32:48 | a spread of that seizure involving larger of the brain. There is an |
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| 32:54 | of excitation and inhibition typically to generate seizures and to have abnormal synchrony because |
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| 33:03 | like symphony is abnormal symphony. You not see this kind of a repetitive |
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| 33:11 | , empirical bursting in cells networks or G recordings in normal brains and there's |
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| 33:19 | a rhythmicity to it. So it's from these other dominant rhythms. So |
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| 33:23 | could be overlapping in frequencies with some these dominant rhythms that we discussed. |
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| 33:29 | if you have imbalance of excitation and , you typically have too much activation |
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| 33:35 | glutamic system, too much of activation A and MD A receptor is too |
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| 33:41 | of glutamate release. If glia gets , they actually start releasing more |
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| 33:48 | producing calcium waves, calcium waves and can cause what is called calcium cytotoxic |
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| 33:57 | glutamate excitotoxic and start eventually killing neurons blue cells. So, uh you |
|
| 34:07 | , let's keep talking about hyper There are some specific currents that can |
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| 34:12 | these bursts. There's involvement of leon glia is regulating potassium glia is regulating |
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| 34:20 | . In particular, glutamate reuptake glutamate into glutamine and also glutamate release on |
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| 34:28 | own calcium regulation because they have calcium , uh glycine to a certain |
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| 34:36 | which serves as a an MD, cofactor release. So they can influence |
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| 34:41 | MD A receptor opening also through the regulation. And typically the, the |
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| 34:53 | , if you recall, we talked neurotransmitter systems. And when we talked |
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| 35:02 | inhibition, we talked about Gaba. this is the glutamatergic system that's typically |
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| 35:11 | and enhanced and increased and it's enhanced increased for a number of reasons. |
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| 35:16 | a number of different causes of, , of epilepsy. Yeah, but |
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| 35:23 | glutar system is enhanced. And uh we talked about gag system, we |
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| 35:33 | about how Gaba will bind to Gabba receptors and it's an agonist and it |
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| 35:40 | increase the inhibition. And we said it also has other different binding sides |
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| 35:47 | ethanol. But also for benzodiazepines. a lot of anti seizure drugs will |
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| 35:56 | Gabba a channel. A lot of will be agonous for gabba a receptor |
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| 36:03 | to increase the inhibition. So, of the treatment and epilepsy is still |
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| 36:10 | try to increase the inhibition to balance this abnormal hyperexcitability that is happening through |
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| 36:18 | glutamatergic systems. Uh Now, uh lot of my years uh here at |
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| 36:34 | of age, about 10 or went into studying Drive syndrome or severe |
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| 36:42 | epilepsy of infancy. Uh And uh , I think we're gonna leave the |
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| 36:54 | of that. And the reason why started studying Dr Syndrome is because Dr |
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| 37:03 | is a mutation in voltage gated sodium . Yeah, I'm a lot of |
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| 37:11 | and the other reason, but it's because of that is because these kids |
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| 37:15 | you see here that have a Drive also known as severe mylo epilepsy of |
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| 37:23 | . OK. I do, I . OK. So we're gonna look |
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| 37:31 | this again because when we record E , we have this difference in electrodes |
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| 37:36 | , we're picking up on the This is a much better representation. |
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| 37:41 | why I was like I have a representation of this. This is a |
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| 37:45 | G electrode. When the neurons are , it's typically the surface neurons closer |
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| 37:53 | the surface of the neo cortical neurons they have to synchronize. So you |
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| 37:58 | to have a lot of hundreds of of these cells underneath the single electrode |
|
| 38:03 | be active in order to pick up of those synchronized spikes or one of |
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| 38:09 | rhythms of activity. Uh And this an example of six cells and they're |
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| 38:16 | receiving inputs. And when these inputs coming at different times, each cell |
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| 38:22 | of has its own thing that it's . And if you some activity across |
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| 38:26 | different six cells, you don't see of the kind of a dominant either |
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| 38:31 | or amplitude pattern. But here and these traces represent when all six of |
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| 38:40 | cells receive the same common input, very strong input. And what it |
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| 38:46 | it then engages the cells, all 12356 to respond at the same |
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| 38:51 | And the sum recording of E E or network activity now represents a dominant |
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| 38:57 | and amplitude of this oscillation. So this is like I said, |
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| 39:02 | just going to reinforce it in a way. Now, epilepsy, this |
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| 39:07 | the slide that I was missing. let's talk about epilepsy because I said |
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| 39:11 | it's important to understand is the developmental . Is it a middle age |
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| 39:17 | We talked about several neurological conditions and is a U shaped curve for the |
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| 39:23 | of new epilepsy in 100,000 people. affects about 1 to 2% of population |
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| 39:31 | general and most of the incidents or and diagnosis of epilepsy occurs in early |
|
| 39:40 | . Then you have a slowdown and you have again an increase in epilepsy |
|
| 39:45 | seizures in the population 50 and So 55 over, you also are |
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| 39:50 | susceptible to degenerating to having Alzheimer's And there's actually overlap between the |
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| 39:56 | If you have Alzheimer's disease, there something like 50 times more likely to |
|
| 40:01 | seizures and epilepsy too. So there's between some of these neurological conditions. |
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| 40:08 | is more common in developing countries. Naturally, it's not as good of |
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| 40:14 | health care. The higher rates of childhood epilepsy, high rates of infection |
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| 40:19 | pre and post natal care. Who ? I think we have there for |
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| 40:25 | prenatal care. It's being regulated uh politicians all the time that occurs most |
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| 40:33 | in young Children. And among the childhood, epilepsy is usually congenital. |
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| 40:39 | caused by genes and mutation in genes disease or abnormality that is present at |
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| 40:46 | or developmental abnormality. Elderly tend to so congenital versus acquired epilepsy. Chore |
|
| 40:56 | is a consequence of conditions such as , tumors. Alzheimer's disease, |
|
| 41:01 | many different causes. Uh uh that lead to it. Epilepsy is more |
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| 41:08 | a symptom of a disease and in , uh it, it is typically |
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| 41:12 | now by neurologist as epilepsies because they be so different in how they uh |
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| 41:19 | seizures happen. What parts of the are involved, how it affects the |
|
| 41:23 | lifestyle and their livelihood. Uh tumors is a common cause gliosis, |
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| 41:33 | reactive gliosis, scar tissue formation the tissue blood vessels that start growing |
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| 41:40 | the tumor space. They all can to formation of seizures and epilepsy, |
|
| 41:47 | , traumatic brain injury, repeated concussions penetration or penetrative traumatic brain injuries such |
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| 41:54 | shrapnel from explosive device, which used be just in, in wars. |
|
| 41:59 | now we're fighting wars in this country day with having um not skiing every |
|
| 42:08 | . Uh genetics. So genetic genetic components, mostly childhood epilepsies, |
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| 42:14 | dysfunction, infections. What are viral infections such as bacterial infections, |
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| 42:22 | infections, both meningitis can be Bacterial or viral source? There isn't |
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| 42:27 | much reports from COVID-19 and seizure So there's a few but it's, |
|
| 42:31 | not emerging as a as a really correlation. At least the last time |
|
| 42:35 | checked to my, to my um the vascular disease, abnormal |
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| 42:41 | microvessels, shrinkage of vessels and so . Uh neurons need oxygen and |
|
| 42:47 | So when you start cutting them off that supply, they start either dying |
|
| 42:51 | generating abnormal seizure activity. Environmental, many case, environmental chemicals exposure to |
|
| 43:00 | , for example, or uh you can say, well, uh |
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| 43:05 | mosquito bite that leads to encephalitis that to seizure sy epilepsy. Yeah. |
|
| 43:11 | You said that um the neurons die they don't get enough oxygen. Is |
|
| 43:15 | why? Like in some cases like in patients, uh they give some |
|
| 43:23 | . Uh uh hypoxia, hypoxia is one of the ways and one of |
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| 43:28 | models in which you can induce Yeah. So, uh typically before |
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| 43:34 | die, they go through some sort abnormal synchronized activity as their last attempt |
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| 43:40 | , to, to wake up the autonomic system and everything and then |
|
| 43:45 | probably give up and they give up , they start giving up within two |
|
| 43:49 | . So if a person has oxygen , cut off for two minutes or |
|
| 43:55 | , it's, it's bad news and why a lot of times when a |
|
| 44:01 | , uh when there is a, a person passes out, they have |
|
| 44:05 | stroke or they have something like that they're revived a lot of times. |
|
| 44:11 | more, one most important things you to know. How long, how |
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| 44:15 | was it before the person lost the and they were revived. And um |
|
| 44:21 | you hear like 10, 15 it's like, oof, that's bad |
|
| 44:24 | , especially without CPR, maybe with that can be prolonged because you're still |
|
| 44:29 | the blood and uh giving, you , oxygen supply. But without that |
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| 44:35 | minutes, you know, the, survival rate of neurons decreases dramatically. |
|
| 44:41 | of the most sensitive cells in the to uh loss of oxygenation that hypo |
|
| 44:47 | this chocolate all over. Uh In cases, the causes of epilepsy |
|
| 44:53 | are not known. You simply don't . The doctor cannot tell. I |
|
| 44:58 | know if you have a mutation. don't know what happened to you. |
|
| 45:00 | don't know if you had a brain . I don't know if you have |
|
| 45:04 | . You have, you know the of seizures and sy. Now uh |
|
| 45:09 | is what what um happens is that is voltage gated sodium channel N ad |
|
| 45:16 | . Remember voltage gated sodium channels that responsible for producing action potentials. So |
|
| 45:22 | shows that there's multiple mutations. So mutations but sodium channel or subunits six |
|
| 45:35 | segments, S four is a voltage . This is the selectivity four between |
|
| 45:41 | five and the segments five and segment . And anywhere you're seeing these green |
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| 45:47 | here, that means a mutation in gene. The codes or, and |
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| 45:56 | codes a certain sequence of amino acids this protein can result in G EFS |
|
| 46:05 | which is generalized epilepsy with febrile seizures . So generalized epilepsy, you lose |
|
| 46:16 | , feb seizures is the most common of seizures. It actually occurs in |
|
| 46:24 | Children. Feb seizures are hyperthermia. just talked about hypoxia, lack of |
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| 46:35 | , talking about hypothermia when a child a fever, an infection and their |
|
| 46:43 | goes up to 100 and four you call the doctor. One of |
|
| 46:48 | suggestions is that if you cannot not to a health care professional to doctor |
|
| 46:54 | hospital, place your child in an bath. Obviously, you know, |
|
| 47:00 | tried uh lowering their temperature with medications things like that and you shouldn't freeze |
|
| 47:05 | child, but literally lower the temperature if it goes up to 100 and |
|
| 47:10 | F. There is a fear that person may have a seizure and it's |
|
| 47:15 | common in Children and Children may go beyond 100 and four and they may |
|
| 47:19 | into this twitching like kind of a seizure activity and they'll never have one |
|
| 47:25 | or they'll be sick again two years and have one. It doesn't mean |
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| 47:28 | have epilepsy. So to have you have to have repeated seizures. |
|
| 47:35 | when we say feb seizures here, , the Children that have this genetic |
|
| 47:43 | uh in anywhere alone, these green , if you mess up the sequence |
|
| 47:50 | the code in this voltage gated sodium , you end up with having G |
|
| 47:57 | F S plus. Um Now, does that mean? Does that mean |
|
| 48:03 | the body temperature in these Children go to 100 4 constantly and they have |
|
| 48:09 | ? No, they're actually a lot susceptible to small increases in body and |
|
| 48:15 | temperature. So 100 and four is 42 C. Our physiological temp body |
|
| 48:22 | is 37 C 36.6. So if normal Children of 42 C, you'll |
|
| 48:30 | a febrile seizure. Children that have mutation, their temperature, body temperature |
|
| 48:36 | go up to 40 C 39 9900 degrees Fahrenheit and they will have |
|
| 48:44 | seizures and it's not only the internal temperature, it's also the ambient external |
|
| 48:51 | a lot of Children that have this and have a syndrome. Their parents |
|
| 48:58 | happy when winter comes about because they that there is a reduction in the |
|
| 49:05 | of seizure seizures during the colder months the year. So they're very |
|
| 49:11 | not only to internal but also external rises. SME I stands for severe |
|
| 49:21 | epilepsy of infancy. And anywhere you a red dot that mutation along the |
|
| 49:30 | channel can result in the different sub of epilepsy. So everywhere you have |
|
| 49:37 | green mutation, you end up with . Everywhere you have a red |
|
| 49:42 | you may end up with sme I marron epilepsy in influence. It will |
|
| 49:47 | different but it's affecting the same channel a different sequence in this channel and |
|
| 49:54 | already causing two different syndromes. And just through one voltage gated sodium channel |
|
| 50:02 | and congenital. Uh epilepsies are not due to sodium channel mutations, it |
|
| 50:10 | be potassium channel mutations, calcium channel . You think about many different mutations |
|
| 50:17 | MD A Java and so on. can be involved in this exci or |
|
| 50:22 | signaling regulation. So these are the that have or had Dr Syndrome, |
|
| 50:31 | syndrome or severe myronic cap of infancy I um over 30% of these kids |
|
| 50:39 | unresponsive to pharmaceutical treatments. 20 or percent of these Children die from what |
|
| 50:48 | called severe, unexpected or severe unexplained . And epilepsy typically happens at |
|
| 50:55 | And that's why these type of epilepsies referred to as catastrophic, developmental type |
|
| 51:02 | epilepsy because it's catastrophic. Not only a child, it's also catastrophic for |
|
| 51:07 | family to have a, have a that suffers from uncontrollable seizures and, |
|
| 51:14 | the loss of life when you, you care for somebody and, and |
|
| 51:18 | love them so much. So, some of these Children have passed. |
|
| 51:24 | This is from the uh Syndrome Foundation E S F I was one of |
|
| 51:32 | scientific advisor for a number of And that's what really touched me to |
|
| 51:38 | on S N E I. And here at the University of Houston, |
|
| 51:43 | why I'm interested on showing you this I did spend 10 years trying to |
|
| 51:48 | the cellular mechanisms of seizures and network in a mouse model which had a |
|
| 51:58 | mutation in the voltage gated sodium which reproduced a lot of symptomology of |
|
| 52:05 | I. So these Children will have , they can have dozens of seizures |
|
| 52:09 | day. Sometimes sme I Children may have feb seizures, not always, |
|
| 52:15 | they may have them. And when common pharmaceutical drugs don't work, when |
|
| 52:23 | doesn't work, a neurologist will suggest second one. Um maybe the second |
|
| 52:29 | doesn't work, they may suggest a of three drugs. Uh And if |
|
| 52:35 | talk to neurologists, it's very difficult you're trying to interpret. Do |
|
| 52:40 | do these Children have a mutation Ok, they have a mutation. |
|
| 52:43 | you know something about it. What you don't know the cause of that |
|
| 52:47 | ? You're a neurologist, you are intelligent. You studied it for |
|
| 52:51 | you have these E G recordings, have to do something with the |
|
| 52:55 | The patient is having seizures. And you talk to neurologists of practice for |
|
| 52:59 | while, of course, they have lot of experience and they can be |
|
| 53:02 | in pinpointing the pharmaceutical treatment for certain and certain conditions. A lot of |
|
| 53:08 | they will say it's trial and So if this doesn't work, you |
|
| 53:11 | back three months later and you try different, this doesn't work, you |
|
| 53:15 | back and you try something different. these Children don't run out of |
|
| 53:20 | meaning that there is no more Plus you have to realize that if |
|
| 53:26 | child that has syndrome is taking a packet of pills like that every |
|
| 53:34 | um Benzodiazepines, for example, ethanol binds together receptor. So what |
|
| 53:41 | these Children feel like? They feel they're drunk, you know, outside |
|
| 53:45 | fact they're literally stumbling, hitting themselves the chairs and tables. It's also |
|
| 53:51 | burden on other organs. So we talked about, I want you guys |
|
| 53:55 | think about smart drugs. You we're gonna talk about medical cannabinoids, |
|
| 54:00 | in general, think about smart uh penetrable through blood brain barrier. |
|
| 54:07 | it is not easily penetrable to the , it becomes a systemic burden. |
|
| 54:13 | affecting your other organs. It's affecting liver, it's affecting your kidneys. |
|
| 54:17 | liver has to metabolize. Imagine you to take 20 Advil every day. |
|
| 54:23 | probably not recommended. You know. what happened with Drive Syndrome? And |
|
| 54:29 | why we start introducing the medical And then the cannabinoid system is a |
|
| 54:36 | of these Children were not responsive to cocktails of drugs. And so they |
|
| 54:41 | no alternative. And this is a , a story of Charlotte figgy. |
|
| 54:47 | is a girl that had gravity S C N one A is the |
|
| 54:52 | that codes for voltage gated sodium And she had a confirmed gravity syndrome |
|
| 54:58 | S C M one A mutation and were very conservative parents, both uh |
|
| 55:06 | and and tried all of the options their neurologist for pharmaceutical treatments. Moved |
|
| 55:12 | Colorado and started a drunkard therapy, means in addition to their existing treatments |
|
| 55:20 | a mix of cannabidiol and delta nine hydro Canino CBD and T H C |
|
| 55:28 | a specific strain of cannabis that was named after her in part called Charlotte's |
|
| 55:34 | . Unfortunately, this girl that brought to to this whole kind of a |
|
| 55:42 | uh idea of treatment of epilepsy, has been around for thousands of years |
|
| 55:49 | of epilepsy with, with cannabis But this renewed idea in legalized states |
|
| 55:54 | legalized cannabis where it was accessible because not really accessible through the pharmaceutical prescriptions |
|
| 56:00 | the pharmacies, but it is accessible these medical cannabis programs that are state |
|
| 56:06 | . We moved to Colorado and the was that this extract which had CBD |
|
| 56:14 | T H C reduced trial seizure frequency nearly 50 convulsive seizures per day to |
|
| 56:22 | to 3 naternal convulsions per month. this was a, this was the |
|
| 56:29 | stark example of 2014. And since , there's many different studies, reports |
|
| 56:38 | cannabidiol uh enriched cannabis and pediatric treatment epilepsies. Since then, there's also |
|
| 56:45 | drug that is CBD or Cannabidiol based we'll talk about in the next |
|
| 56:50 | I believe when we talk about more medical cannabis in respect of the cannabinoid |
|
| 56:56 | too. And really unfortunate. There's charlotte piggy pass lot here. So |
|
| 57:03 | , this is a devastating kind of and that's why people seek alternatives. |
|
| 57:08 | when there is no help that you find in the doctor's office and in |
|
| 57:14 | case, they found a neurologist which great and uh medical campus programs, |
|
| 57:19 | should really think about them. It's something that you have a card and |
|
| 57:23 | buy weed in the dispensary. That's medical, that's a pretense of medical |
|
| 57:28 | , to get recreational stuff. Medical you work with a medical practitioner and |
|
| 57:35 | this state in Texas or any other that have medical programs, people typically |
|
| 57:41 | supervising medical practitioners and understands these things Edward Mob, the first authors and |
|
| 57:48 | that work with Charlotte's figure have worked these preparations that are not from the |
|
| 57:53 | , but rather from the dispensaries or the producers. So it's quite interesting |
|
| 57:59 | brought to light a lot of things we have forgotten about. In |
|
| 58:04 | the United States government in 99 published patent cannabinoids as antioxidants and neuro |
|
| 58:13 | So, cannabis is still considered a one substance which in pharmaceutical terms, |
|
| 58:21 | means it has no medicinal value. highly addictive and dangerous. Uh But |
|
| 58:28 | the same time, there's this pattern treatment of diseases. Alzheimer's Park |
|
| 58:33 | even though non psychoactive can happen on dial. Um So the United States |
|
| 58:42 | America is represented by the Department of and Human Services. So what we |
|
| 58:48 | is as always, we have dual of one reality and then the |
|
| 58:55 | the legal reality of what's happening, ? We have the reality of abortion |
|
| 59:00 | and then we have the reality of abortion pills. Then we have a |
|
| 59:04 | of five more days for abortion pills then we'll decide what happens. So |
|
| 59:08 | it's, it's, it's everything is . So here it's a very strong |
|
| 59:14 | that even the US government believe in values that uh uh of cannabis |
|
| 59:21 | Now, the person that didn't believe medical cannabis was this guy Sanjay |
|
| 59:25 | He works as a chief medical correspondent CNN and I think he started this |
|
| 59:32 | Weed and I think it's up to now, maybe this is Montel Jordan |
|
| 59:36 | is uh uh treating his MS with cannabis and has his own cannabis |
|
| 59:41 | . Actually, this guy is got caught off Montel Jordan. |
|
| 59:46 | look into his biography. This guy bat languages. He's like a uh |
|
| 59:51 | , navy seal marine, like incredible but has a mask and has his |
|
| 59:57 | cannabis company and he's treating his own mess with, with these preparations. |
|
| 60:01 | so Sanjay Gupta didn't believe in any this. He's a neurosurgeon and he |
|
| 60:06 | into this, I think six or years ago exploring what's going on here |
|
| 60:11 | Colorado with this little girl Charlotte figgy other things. And he turned, |
|
| 60:17 | think within a year or so and being convinced that although there is no |
|
| 60:25 | uh pathway for cannabis plant or consuming smoking cannabis or something like that, |
|
| 60:32 | saw a real benefit in in many . Now we'll talk about the cannabis |
|
| 60:37 | its own negative effects. Uh It negative effects on psychosis, it has |
|
| 60:45 | effects on performance and memory. It negative effects on some people's personalities. |
|
| 60:51 | doesn't agree with people. You can in cannabis. Good news is you |
|
| 60:57 | die on cannabis and it stinks. your Children, when you bust |
|
| 61:02 | you know what they have, but cannot tell that about fentaNYL, which |
|
| 61:07 | really a lot more dangerous to And so this is what the the |
|
| 61:11 | that are getting involved in this medical processes, they're evaluating harm versus |
|
| 61:19 | What is, what is more what is more beneficial and how to |
|
| 61:22 | this lightly. And that's why I that medical candidates truly and cannabinoids that |
|
| 61:27 | through state programs should be physicians supervised regulated with their advice and their knowledge |
|
| 61:32 | understanding what's going on with these zoological far as negative effects. Uh, |
|
| 61:38 | address some of them again. And the fact that when I talk about |
|
| 61:43 | cannabinoids of most of these people, they talk about medical cannabinoids, they |
|
| 61:47 | about natural plant, the right chemicals than semi synthetic or synthetic in |
|
| 61:55 | which are completely different and can have very bad effect on your brain or |
|
| 61:59 | . Ok. Well, I'm here and we'll pick up, uh, |
|
| 62:04 | we left off at the next |
|
