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00:02 | This is lecture 19 of cellular And we already touched upon electrons a |
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00:09 | early in the chorus just by mentioning maybe. But we're gonna understand what |
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00:18 | E. G. Or the electroencephalogram . And some of the techniques that |
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00:24 | gonna talk about today and in particular E. G. And then another |
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00:29 | called M E. G will reflect different that we talked about when we |
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00:39 | imaging techniques such as Fmri and pet . So E E G. Is |
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00:46 | measurement or is a measurement of electrical . It's not direct because it's not |
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00:54 | from the brain, it's not from brain surface but rather from the |
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01:01 | the surface of the scalp. And non invasive. The roots of E |
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01:07 | . G uh date back to the century and human E. G. |
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01:16 | first described by an Austrian psychiatrist, berger In 1929. So about 100 |
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01:26 | ago is when we gained understanding of E. G. Is. And |
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01:32 | been 100 years of evolution of how record E e G. How to |
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01:38 | these recordings as precise as possible, and as fast as possible temporarily. |
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01:47 | So there was a significant changes of And this is one of the recordings |
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01:56 | he'd taken from the head of his year old son Klaus. Uh This |
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02:02 | a time herds time signal and this the first ever published E. |
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02:07 | Rhythm. So all of the great and scientists, they always try things |
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02:14 | sometimes with their family members to but it's about 100 year old technique. |
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02:21 | so this is a kind of a that you would be picking up from |
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02:25 | surface of the skull. And uh would be different positions. So we |
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02:36 | talked about brain rhythms and we talked how you would record these different brain |
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02:42 | . So we're gonna remind ourselves a bit about that. Then when we |
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02:46 | about spatial specificity there are E. . Caps that will contain just a |
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02:56 | electrodes. So they'll tell you it's frontal parietal temporal, there are |
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03:03 | G. Caps that will contain tens electrodes there. I. E. |
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03:08 | . Caps that can go as high hundreds of micro electrodes that get placed |
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03:15 | the surface of the scalp. So more electrodes you have the more spatial |
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03:22 | you have. However there's no way you're gonna be able to pick up |
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03:27 | cell activity because of what exactly the . G. Signal represents. It |
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03:32 | represent electrical activity from a single cell rather from the underlying neuronal network at |
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03:40 | very surface of the cerebral cortex. we'll talk about this also. And |
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03:46 | you can see also here that when picking up E. G signal is |
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03:52 | weak. When we talked about amplitudes the action potential, it was in |
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03:59 | of million volts, 70 100 million . We talked about E. |
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04:04 | S. P. S. And PS PS. There were an order |
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04:07 | million volts. But the signal that can record through the skull and you |
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04:15 | up on the surfaces only on the of micro volts. So you get |
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04:22 | filtered representation because the skull is a bone and you have a skin that |
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04:29 | approximation if you will of electrical And also there has to be something |
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04:38 | on in the brain for that activity show up. In other words, |
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04:43 | circuits need to be actively engaged and synchronized and the more they are |
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04:51 | The greater possibility is that these The G electrodes will pick up the |
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05:01 | . So this is another example of E. G. Recording and you're |
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05:08 | the difference between the two electors that each one of these traces represents the |
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05:15 | between this electorate and this electorate in case traced to between electorate two and |
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05:20 | and so on. And the subject awake And quiet. And recording sites |
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05:27 | indicated here on the left. These the electrode positions. The first few |
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05:31 | show normal alfa activity which has frequencies eight 2 13. So you can |
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05:37 | these very fast Fluctuations of about 8 13/s. Yeah this is the second |
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05:47 | . This is amplitude and micro holtz halfway through the recording, the subject |
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05:53 | his eyes so you can see this artifact and so this also tells you |
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05:59 | when you have E. G. you also have a lot of artifact |
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06:05 | and you have to be able to or recognize that artifact activity. And |
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06:11 | we're talking today about epilepsy and epilepsy one of the rhythmic disorders. And |
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06:18 | e. G. Is a technique helps to diagnose this rhythmic disorder. |
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06:25 | we're talking about that you are talking some people that will be moving during |
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06:31 | procedure that will maybe having a that's exactly what I want to record |
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06:35 | seizure activity. But there will be only blinking artifacts that will be muscle |
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06:41 | artifacts, there was movement that they and so on, acceleration velocities, |
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06:46 | of these things. And so the sophisticated instruments allow us to recognize and |
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06:54 | filter those artifacts are often going to in the slower frequencies when it comes |
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07:00 | some of the motive facts like blinking . But as soon as the subject |
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07:05 | the eyes you can see that the of this rhythm has changed and now |
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07:12 | have these beta rhythms and the amplitude these rhythms is not as hi. |
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07:20 | also data rhythms will be in a frequency. So what are we recording |
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07:26 | we were recording E. G. is an example of an E. |
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07:31 | . G. Electrodes. This is scalp, the skull, we have |
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07:36 | meninges, dura, arachnoid, subarachnoid and PM Otter. And then underneath |
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07:45 | we have our cortical circuits and if recall we have these parameter cells in |
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07:53 | cortex that will have their a pickle rights going upwards. Okay so the |
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08:01 | of very small electrical fields by synaptic in Tehran. But all cells when |
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08:06 | cells produce electrical activity, they also electrical fields around the movement of the |
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08:16 | . But also they produce magnetic fields movement of the charge. Again in |
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08:22 | case the active synapses on the other of the dendrite, the upper part |
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08:28 | the dendrites. So you can see these are the inputs here coming in |
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08:32 | where you have the arrow pointing and are the axons. So you have |
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08:38 | that are coming in and exciting these down rights of parameter cells on the |
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08:46 | upper part of the done drive. the apparent action fires the police synaptic |
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08:52 | released glutamate which opens Catalonian channels. know all about that little bit channels |
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08:59 | current flows into the dump drive. sodium, if it's an M. |
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09:03 | . A, sodium and calcium flowing the down dr leaving a slight negativity |
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09:11 | the extra cellular fluid correct? Because more positive the neuron becomes outside of |
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09:21 | neuron and the immediate surroundings it becomes negative. So positive current leading into |
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09:32 | leaving slight negative into current spreads down done right and escapes from its deeper |
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09:39 | , leaving the fluid slightly positive at sides. So when the inputs come |
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09:46 | remember the dendrites are not insulated like . And so you first of all |
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09:53 | to have a lot of excitatory synapses and a lot of excitatory synapses which |
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09:57 | learn from the example circuits will be targeting distal parts of the down rights |
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10:03 | a lot of the inhibitory synapses will targeting these para somatic areas. Recall |
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10:09 | there's a lot more excitatory cells, of the population of these cortical cells |
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10:15 | this parameter excitatory cells and only 10-20% be inhibitory cells. So there's inhibitory |
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10:24 | have much greater diversity. There is far less number of them but also |
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10:29 | have in many instances the priority of the parts of the soma around the |
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10:37 | that are really important for the integrative of the cell so that the cell |
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10:42 | produce an action potential or not. once the current goes in after some |
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10:46 | it actually flows out in this area more positive so influence slightly positive at |
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10:52 | sides. The E E G electrodes to. Uh Second lecture of some |
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10:58 | away right here measures this pattern through tissue layer. Only thousands of cells |
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11:08 | their small voltage in the signal large to reach the scalp surface. Notice |
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11:17 | E. G convention of plotting the with negativity upward. Okay, so |
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11:23 | deflection of positive deflection. That's just uh my convention because these signals are |
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11:32 | small you have to have pretty powerful . Uh So you have to amplify |
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11:37 | typically hundreds of times if not thousands times. And use very sophisticated |
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11:45 | So you can for example use high filters, everything high frequency passes low |
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11:52 | filters, everything low frequency passes band you can just tell your amplifier filter |
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12:00 | in this band between 10 to 30 10 to 40 hertz. That's what |
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12:03 | interested in. Everything else is doesn't . So so you have all of |
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12:09 | techniques and all of the technologies that adjacent to picking up this activity. |
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12:16 | the point being is that if one is active and is generating these electrical |
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12:23 | that's not enough for the E. . To pick it up, it |
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12:26 | somehow blend into, it's almost like noise and the strays. However if |
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12:31 | have thousands of cells that become active in other words synchronized or maybe they're |
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12:39 | a common inputs or they have a conductor or maybe something is happening in |
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12:44 | vicinity of these thousands of cells such rises in potassium because our glial cells |
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12:51 | a little bit behind and all of sudden there is a little bit of |
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12:54 | in the cells are getting deep polarized 100,000 of them getting the polarized at |
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12:59 | same time. That could also be causes of sort of a self organization |
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13:05 | these cells without having a strong input organization into into synchronized response containing thousands |
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13:14 | neurons acting at the same time. this is uh the generation of large |
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13:23 | . G. Signal by synchronous activity population of parameters. Cell cells located |
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13:28 | this one E E. G So this is still simplified. It |
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13:32 | have thousands millions of cells. If inputs fire at irregular intervals the parameter |
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13:39 | responses are not synchronized. So if inputs coming into 123456 these are different |
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13:46 | just like they're coming in here it's different cells if they fire at different |
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13:52 | and you look at the individual trace these cells that they're producing Small |
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13:59 | P. S. P. But they're producing small E. |
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14:01 | S. P. S at different right? Different. This is time |
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14:07 | look at some E E G won't any particular synchronized pattern or any definitive |
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14:15 | in there. Now if the same of inputs if these inputs six inputs |
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14:23 | in onto these six South targeting these cells, excite them or produce action |
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14:31 | will release glutamate on them within a time window and that's also spike timing |
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14:38 | plasticity to everything within neurons. It within short time windows within milliseconds it's |
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14:43 | meaningful. So if a lot of south's thousands hundreds of South then the |
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14:49 | received this boom, one input excitatory all of them within milliseconds from each |
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14:56 | . Now you can see that they're targeted about the same time and when |
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15:02 | average or sum over all of the . G. Recordings to six recordings |
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15:08 | six cells in this case at the of the E. G. Which |
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15:13 | be recording from way more than But this is a simplified example of |
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15:18 | . You will now pick up a which you will say well I think |
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15:21 | see a very clear oscillation up and . 34 Maybe four. Very significant |
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15:30 | . Torrey signals in there that are at a certain frequency. Okay so |
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15:36 | important way to synchronize the cells. important way to synchronize the cells if |
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15:42 | have a common driver or a common . Ok and so in in in |
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15:53 | the lecture notes. Okay we're going come and talk about this and well |
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16:02 | we'll come back and talk about that a second. So we already discussed |
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16:07 | you have a variety of rhythms. have a variety of rhythms and uh |
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16:14 | is a slight difference in frequencies of rhythms across the species. Uh It |
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16:22 | that rather doesn't have alfa rhythm. the book says also don't be mad |
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16:27 | the rabbit because maybe there wasn't enough the experiments down in alpha rhythm. |
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16:33 | we need to still do and find frabjous habit. But in general you'll |
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16:41 | these dominant frequencies across different species. and ripples. Spindles have contained this |
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16:52 | is called a complex. Okay a important. Together with ripples for learning |
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17:00 | memory ripples are probably the fastest oscillations have been recorded to date 200 to |
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17:09 | hertz. 200 to 600 cycles a . The 2nd e. G. |
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17:16 | up A signal to 100 hertz. if you have a two kHzertz Sampling |
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17:24 | what does that mean? That means sampling 2000 electrical signals in your oscilloscope |
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17:32 | second. That's 10 2 kilohertz. may have 10 kilohertz was very expensive |
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17:38 | but you have 10,000 samples. So higher the sampling rate you would have |
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17:44 | more of this very fast activity you pick up. And so you'll see |
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17:49 | a lot of developing countries for example IgI recordings are not as sophisticated both |
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17:55 | the prospective number of electrodes. The , the temporal resolution of processing of |
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18:00 | amplifiers. And the third thing is processing. So what I've been telling |
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18:05 | about filtering and stuff like that that digital power. That takes computers. |
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18:10 | takes all of types of things that not everybody in the world is lucky |
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18:15 | to have. But so we will up these fast rhythms and these slower |
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18:20 | And also note that neuronal populations can overlapping rhythm frequencies. So you'll have |
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18:27 | very slow wave and the slow wave repeat Every half a second. But |
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18:33 | top of that very slow wave or slow rhythm you will have this buzzing |
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18:39 | of about 200 or 300 oscillations per . So there is overlapping these dominant |
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18:47 | . We don't necessarily perceive them as as as uh resonance of one |
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18:57 | But there is resonance in these Physical resonance in these rhythms. And |
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19:03 | call that a different rhythm means different or uh behavioral state. Now when |
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19:17 | talked about pet um and F. . R. I. We were |
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19:25 | about metabolism, we were talking about oxygenation and glucose. Mhm. Uh |
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19:40 | you want deep imaging it's really FmR Pat is typically done more on this |
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19:47 | morna. Cortical imaging. Yeah. g. It's different. E |
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19:57 | Is electrical activity so we're no longer metabolism and by the way when we |
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20:05 | tracking metabolism, pet and F. . R. I. There's no |
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20:09 | cell resolution there is no five cell . There's 10 no 10 cell |
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20:15 | You're still looking at clumps of activity are or not clumps of activity or |
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20:22 | . That has been averaged over collections clumps of hundreds if not thousands of |
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20:30 | in the imaging techniques. The same with the E. G. The |
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20:35 | of E E. G. It's activity reporting. Plus the skull is |
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20:39 | is a is a filter. It's low pass filter. It filters the |
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20:45 | through the bone. So you want sometimes look deeper and find deeper sources |
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20:55 | activity. E. G. Apart tracking this normal synchrony that represents these |
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21:03 | that represent different behavioral states. G within the context of epilepsy is |
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21:11 | to detect abnormal rhythms or pathological But if you have the sources of |
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21:20 | pathological rhythms on the surface coming from cortex, that's very insightful. |
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21:29 | a lot of these abnormal rhythms come Salaam IQ areas and come from the |
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21:37 | cortical circuits that we alluded to. example, when we talked about the |
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21:43 | system. So there's thalamus to the , salama, cortical and cortical Islamic |
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21:50 | . And these loops a lot of are important in generating not only normal |
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21:56 | also abnormal activity. So if you only picking up activity from the surface |
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22:01 | the cortex is one thing. But if your focus or faux side which |
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22:09 | referred to a small area in the that is generating abnormal activity? What |
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22:15 | your foe sigh of seizures or normal activity of normal synchronization are deep? |
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22:24 | M. E. G. Is better technique and in this case |
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22:30 | E. G. Speaking of magnetic . So a person is receiving an |
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22:35 | . E. G. Scam here in this magnet, this massive magnet |
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22:42 | , the tiny magnetic signals generated by on the brain are detected by an |
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22:47 | of 150 sensitive magnetic detectors. But have the ability to actually reduce three |
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22:57 | locations of these magnetic signals and magnetic , electrical signals, electromagnetic activity is |
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23:09 | . Researchers use the signals to calculate location of sources of neural activity color |
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23:14 | in in this image where there's a of neural activity where there's little neural |
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23:19 | and so on. So if for example had a patient that had |
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23:26 | brain activity and you did an E . G. Recording and you said |
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23:32 | I can see and we picked up seizure and it's very clear that it's |
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23:38 | on the cortex here. So you not go that extra step of getting |
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23:43 | . E. G. It's sort like an X ray with M. |
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23:46 | . I. Went to spring your . You know, they do an |
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23:49 | ray and they say wow. You , if you don't feel good still |
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23:54 | weeks from now come back and we'll if we do them right And you |
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23:59 | , probably 90% of the people never back because they don't need to. |
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24:02 | it's a spring. But you so the same way if you if |
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24:07 | E. G a lot of times also the healthcare plans, it's the |
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24:12 | of time, it's availability. Accessibility these machines who has these semi G |
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24:17 | , not everybody not everywhere around the and so on. When you do |
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24:21 | extra step you have abnormal brain E. G. Allows you to |
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24:27 | it out from the surface. E. G. Allows you to |
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24:31 | it deeper within the brain. Now have a much better understanding of this |
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24:36 | of where this abnormal pathological rhythm is from and you are directly measuring activity |
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24:44 | longer, you're measuring the metabolism. you wonder are there circuits in the |
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24:55 | That can generate. So 11 slide think I'd like to throw in |
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25:02 | That is not. And uh in presentation is this one this is what |
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25:11 | talking about. When I say that are mechanisms of synchronizing. So this |
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25:16 | a common input or common conductor A of times it's referred to as |
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25:23 | We all have pacemakers. They're very in the brains. Well some of |
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25:30 | are very slow like circadian super charismatic that nucleus has a very slow rhythm |
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25:36 | and night. We have pacemakers in heart, the sino atrial node and |
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25:44 | constantly produces electrical activity and through gap electrical connectivity it d polarizes the cardiac |
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25:54 | and you get constructions and contracts and and contracts and slows down and speeds |
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25:59 | and it's basic, basic, basic . And so this is sort of |
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26:05 | common pacer or conductor. And then are situations in which neurons, like |
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26:12 | said, there's something maybe in the . Maybe there's inflammation. Maybe there's |
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26:17 | regulation of the chemistry neurotransmitters ions that changes activity in all of these neurons |
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26:25 | all of these neurons without the conductor of like a second line just start |
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26:30 | the rhythm together. So this is you're generating these synchronous rhythms. And |
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26:39 | talked about the Islamic cells and then Islamic sauce you constantly have active excitatory |
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26:50 | and if you will say okay if have this pattern, if you have |
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26:53 | pattern too you have this pacemaker So what does your heart do with |
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27:00 | pacemaker pattern? Pace contract pace, pace, contract pace contract. It |
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27:08 | that pacemaker rhythm. 121121121. If doesn't you're in trouble. Now neurons |
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27:16 | we now receive a lot of these neurons are excitatory and inhibitory cells. |
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27:24 | an exciting yourself is going to be . And we also learned about what |
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27:29 | cells will do inhibitory cells may have feedback inhibition. So when one excitatory |
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27:38 | contacts another excitatory so it's excited. that excited to resell all excited inhibitory |
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27:44 | that inhibited neurons within the negative feedback will reduce excitation. And so you |
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27:51 | the excitatory input and you can see excitatory input and excitatory salads receiving this |
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27:58 | input and then with some delay you this delay is here. This trans |
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28:05 | communication to the inhibitory style. With delay you have a rhythm that is |
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28:11 | in the inhibitory cells and what we what we have in the colonists of |
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28:27 | we have in the cortex is a similar situation where you have input that |
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28:34 | coming into the thalamic relay cells. we also if you recall we have |
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28:42 | thalamic particular nucleus which is abbreviated here T around the lama. In particular |
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28:50 | is a really interesting nucleus. So have Kalanick nuclei that have dedicated provision |
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28:57 | was a lot of the nucleus nucleus we talked about. The hypothalamic nuclei |
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29:01 | had dedicated for every sound. So auditory there was going to be mediagenic |
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29:07 | nucleus for some matter sensor information. going to be ventral basal lateral nucleus |
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29:16 | the thalamus and all of these salam nuclei and Stalin. This is really |
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29:21 | collection of these sensory nuclei, their and surrounded by the Islamic particular nucleus |
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29:28 | switches collection of the inhibitory cells. whenever there's an excited input coming into |
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29:34 | thalamus relay solid thalamic relay sale is and it sends an input to the |
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29:41 | . This is all a salama cortical at the same time. And also |
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29:46 | sense of excitatory input onto the ridiculous inhibitory cells. And those particular inhibitor |
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29:55 | in the negative feedback Now quench the of these the thalamic relay cells at |
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30:04 | one level. Now also once the goes into cortex we know that there |
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30:09 | intra cortical connectivity. So cortex to neurons will be connected and these cortical |
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30:16 | can also activate ridiculous cells so they excite to the inhibitory cells. |
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30:24 | And the ridiculous salsa are interconnected with other. So you can have inhibition |
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30:30 | inhibition. Right? one inhibitory cell releases Gaba can hyper polarized another inhibitory |
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30:40 | and that inhibitory cell will be inhibited well. Yeah wow so do I |
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30:47 | to memorize everything here while you need know to Islamic relay sounds constant input |
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30:54 | in and then you will excite excited into the results the lamb in particular |
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31:00 | this inhibitory cells and this negative feedback that goes back into the cortical loop |
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31:07 | have inter cortical connectivity we will remind and then you have cortical salama. |
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31:14 | the reason why we're highlighting the circuit also this circuit is really important in |
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31:19 | and synchronizing some of these rhythms that talking about. And just because |
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31:25 | G. Will be picking up these of the cortex, we want to |
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31:28 | what's going on going on in the cellular circuits that lead to the generation |
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31:35 | these rhythms. And when I say rhythms says there are some cells that |
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31:41 | they receive a stimulus instead of producing constant output of action potentials they start |
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31:52 | bursts of activity. And so this the feature of some of these thalamic |
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31:58 | salama cortical cells because they receive a input D polarizes of the start firing |
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32:05 | potentials in the thalamus. The excited Islamic cells and what particular economic cells |
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32:13 | they inherited these cells. And so have the hyper polarization and then again |
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32:19 | there's constant input. You do polarize cell again you produce a burst. |
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32:23 | instead of this constant stimulus this is you can turn a constant stimulus into |
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32:30 | activity through the excitatory inhibitory circuit And this bursting activity at the level |
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32:38 | a single cell means many action potentials produced at the same time. But |
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32:43 | the level of the circuit if you many cells producing bursts at the same |
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32:48 | this is very highly synchronized activity that now going to be picked up. |
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32:53 | E. E. G. Or any G. Recordings. Uh |
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32:59 | These are some of the details here we're talking about. Okay so diagram |
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33:07 | the thalamic cortical network showing connections between somatosensory cortex. The venture bezel. |
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33:14 | is a matter of sensory neurons and ridiculous thalamic nucleus. RTM. Now |
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33:25 | a lot of information in this. we can walk through it together under |
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33:31 | physiological conditions. Two sensor signal from peripheral relate to the cortex the |
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33:36 | B. N. And R. . N. Neurons by anatomical and |
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33:39 | deep polarization. So if you have a constant stimulus so matter sense their |
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33:45 | . And these cells the relay cells be producing uh tonic firing. Reticulated |
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33:53 | neurons will produce these bursting which will turn this tonic firing in the thalamic |
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34:00 | into this bursting activity. Mhm. and once you have this bursting activity |
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34:10 | loops can self propagate this activity. burst and burst and burst and burst |
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34:16 | burst and burst and burst pattern. becomes self propagated meaning you no longer |
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34:22 | a sensory input in order to generate repeated oscillation. It's sort of like |
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34:29 | started something like a pendulum and now swings back and forth and swings back |
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34:34 | forth and swings back and forth and back and forth. This oscillation |
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34:39 | You just needed to start the pendulum now it will go on for a |
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34:44 | time until something else happens that stops pendulum gets in the way. In |
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34:49 | case would be another electrochemical activity in circuit. This is d you have |
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35:02 | firing in particular nucleus and these are epileptic rat model of absence epilepsy. |
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35:11 | you will understand a little bit later the next two hours. What absence |
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35:16 | is? It's a generalized form of . Garis epileptic rad. There's a |
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35:25 | that tries to replicate the human epilepsy a rodent. So we will talk |
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35:31 | animal models. Chemical models, genetic , viral models of apple apps. |
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35:39 | so and it correlates with burst firing our tm. Upper panel shows |
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35:47 | G. Recording. So this is . G. Recording. This is |
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35:51 | and this is to what is happening lower panel shows corresponding intracellular recordings in |
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36:00 | R. T. N. So this is a single cell |
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36:03 | So this is the power of experimental if you had no ability to do |
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36:11 | intracellular recording in the whole brain as doing E. G. Recording. |
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36:16 | would really have no ability to liken compare the two signals to gotta. |
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36:21 | this is really neat and you have single cell. Single cell is de |
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36:27 | and even what single cell is firing potentials here but doesn't produce a burst |
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36:36 | which basically represents synchronized activity. These action potentials at the level of the |
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36:44 | . G. Trace. They're really indistinguishable from the background noise. However |
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36:50 | minute you get this repetitive bursting activity on top of each of these deep |
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36:56 | is you have a train of action writing you can now very clearly during |
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37:02 | seizure during the abnormal synchronization of the . You very clearly start picking up |
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37:10 | clearly defined oscillations from the E. . Signal. This is the thalamus |
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37:26 | generate rhythmic activity because the intrinsic properties neurons and because of its synaptic interconnections |
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37:34 | the thalamus Green represents the population of styles neurons and black represents population of |
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37:40 | inhibitory neurons. This is what we at. So there are two really |
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37:47 | why these networks are capable of generating written activity and specific rhythmic activity of |
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37:56 | bursting activity to tolerance. We talked synaptic connections inside the core inhibitor, |
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38:05 | about common input and then intrinsic properties neurons. So what are intrinsic properties |
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38:19 | the intrinsic properties of neurons are different of channels that they expressed. And |
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38:25 | lot of thalamic relay cells will have threshold voltage gated calcium channels. So |
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38:33 | little bit of voltage will cause a increase in cal suit. So it's |
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38:40 | just enough that you have the drive you have the connectivity but with different |
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38:46 | and for different bursting activity and frequency that activity. You have to have |
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38:57 | special in the intrinsic properties and the properties of the member of response properties |
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39:04 | these cells. This is again the that we already looked at. So |
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39:12 | visual it would be from L. . M. You have the cortical |
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39:17 | LG N. Will also have this nuclear interaction too. Inside layers 23 |
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39:28 | spread the information to extra stride long outside of the visual cortex. In |
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39:33 | case outside of the somatosensory cortex there's cortical loop. So the cells within |
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39:40 | cortex will also communicate which we didn't about here and then there's corticosteroid Landeck |
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39:48 | . So these are the same circuits we were talking about. Okay cellular |
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39:58 | . Just the introduction of decided more but it's also the introduction and a |
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40:06 | to us the scales that we're looking . So the macro scales that we're |
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40:12 | at with E G M M E at best Mezza Skah pick scale you |
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40:21 | maybe derived by a combination of G and M E. G. |
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40:28 | that there are cellular networks salam IQ Kalama cortical network. Within those networks |
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40:36 | are rules that we talked about feed feedback inhibition. There is neuro modulator |
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40:46 | substances to change those rules change and the color stretch the learning time, |
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40:55 | the plasticity from potentially ation to All of these factors are very important |
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41:04 | normal functioning in the brain. The . The chemistry of the connectivity and |
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41:13 | inputs. Also normal brains can be out normal if there is enough of |
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41:20 | repetitive input, could be audio visual input, it's called torture. |
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41:26 | it doesn't stop and brain circuits can . Get rewired in those situations. |
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41:36 | we will undoubtedly talk about mechanisms and and we'll come back to ions and |
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41:44 | again In Epilepsy but for the next or so 20 minutes we're gonna withdraw |
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41:54 | home. Talk a little bit about terms like prevalence C. Or incidents |
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42:03 | new epilepsy cases in this case for . Epilepsy is one of the major |
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42:10 | disorders that affects one To 2% of population. I know it's a very |
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42:15 | range 1-2%. There are some geographical in the incidence of of seizures and |
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42:26 | and as you can see there is high incidence of epilepsy in newborns and |
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42:40 | and then you have high incidents of list. This is inverted U. |
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42:47 | a sorry it's a U shaped curve shows again Ages 60 and plus there's |
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42:56 | possibility of developing epilepsy also. So are all in this kind of a |
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43:06 | spot here at least for a couple scenes interestingly enough. Alzheimer's goes up |
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43:17 | about similar fashion. There is no Alzheimer's but it goes up in a |
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43:22 | fashion in the 50 plus and we'll about Alzheimer's when we talk about Alzheimer's |
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43:28 | how that correlates with epilepsy and So it's more common in developing countries |
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43:40 | a number of reasons, detection services of something like an infection that may |
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43:50 | to development of epilepsy in the It's a politic infection, mosquito, |
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43:57 | things like that. At the same , there is not enough reporting in |
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44:06 | developing countries. So it's hard to . Sometimes there is maybe some interesting |
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44:15 | in India suggesting that curcumin which is very big part of the diet and |
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44:23 | has anti inflammatory properties. Could be with slightly lower levels of apple etc |
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44:31 | India. But there are also concerns in many developing countries stigma that is |
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44:40 | by neurological disorders, migraines and epilepsy seizures. Somebody having convulsions in an |
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44:47 | that doesn't have very good educated healthcare may discard that as an obsession as |
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44:55 | as a some sort of a crazy . Just not diagnose that person rightfully |
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45:02 | with with the disease also. So don't think there is a standard really |
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45:07 | tracks this around the world. There no standard healthcare system. There's no |
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45:12 | standard healthcare reporting around the globe. it's about 1-2% higher rates of untreated |
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45:21 | epilepsy because people don't detect, recognize other infections, poor prenatal, post |
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45:30 | care can all contribute to higher rates epilepsy and that's important because it occurs |
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45:37 | often in young Children and then again the elderly childhood epilepsy is typically |
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45:45 | caused by genes or disease or abnormality at birth. So typically the earlier |
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45:52 | see symptoms of epilepsy, the more it is a genetic cause rather than |
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46:00 | sort of a sporadic chemical environmental cause epilepsy has many causes elderly tend to |
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46:10 | epilepsy as a consequence of conditions such stroke, tumors, dramatic brain |
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46:20 | increased inflammation in the brain and also , very strong correlation to dementia and |
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46:27 | disease. And we'll talk about But I'll make sure that if you |
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46:32 | Alzheimer's disease in your 60s, you're like 50 more times likely to have |
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46:38 | and seizures. But if you don't at that age, Alzheimer's disease |
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46:46 | dementia, epilepsy is more symptom of disease than the disease itself. And |
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46:54 | , when people looked at epilepsy, was the convulsions that were repeated convulsions |
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47:00 | a lot of times severe, even coming out of people's mouths. And |
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47:05 | was recognized as epilepsy. But we it's a symptom, it's an expression |
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47:11 | what is happening in the brain. cellular mechanisms chemistry genetic causes tumors can |
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47:22 | epilepsy cleo sis when leah becomes too and to overactive, it's called reactively |
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47:32 | and too much of glial activity is leah will start proliferating and we'll start |
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47:39 | tissue scar and so you will have lesions and then scarring around those |
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47:48 | just like on your skin. You , when there's no scar, if |
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47:53 | injury is smaller, there's no you don't see it in that area |
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47:57 | the skin a few months or a later. But if there was a |
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48:00 | , you may see that. So have scar tissue formation, damaged the |
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48:07 | because of the tumors and glioblastoma. glial tumors are the most common brain |
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48:17 | and as glioblastoma as well, then of normal metabolism and their sequester a |
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48:23 | of oxygen, A lot of blood be sucking everything into that area to |
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48:29 | keep proliferating basically and growing. And is gonna try to do, it's |
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48:34 | really good job but then it's gonna its job and its neurons as they |
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48:41 | . Then you have these lesions or that are left in the brain blood |
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48:48 | not as efficient of uh ah of , tumors and tumor genesis will require |
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48:58 | lot of new vasculature forming around it , and that may detract from the |
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49:05 | of supply to the neurons that are the area to trauma. So, |
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49:10 | brain injury. Hit on the multiple precautions, um severe dramatic brain |
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49:19 | which is penetrative shrapnel or other objects the brain tissue with the loss of |
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49:26 | in that area. You can make area hyperactive and become the focus of |
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49:32 | seizures uh genetics. We will look genetic components of genetic types of seizures |
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49:40 | epilepsy, metabolic dysfunction. So that's that people don't think about or |
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49:47 | But you actually can study mitochondria, can study the amounts of a teepee |
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49:52 | energy and clearance of and and metabolism sugars for example, or build up |
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50:00 | sugars. Um infections in the brain lead to epilepsy for viral infections. |
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50:13 | and and and syphilitic viral infections, infections for example. Meningitis is can |
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50:23 | both. Meningitis can be caused by a viral infection or bacterial infection. |
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50:30 | , inflammation of the brain and infection the brain into the spinal fluids. |
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50:37 | as far as viral infection, there different types of viruses. Uh uh |
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50:47 | covid 19, potentially there's a reported of epilepsy and the person that had |
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50:54 | 19. But I don't know if a definitive Uh huh connection there, |
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51:00 | there's a definitive connection between democratic and activity following covid 19 infection which was |
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51:08 | common in the background of chemical changes before these physical changes. So of |
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51:21 | , I think chemical changes probably occurred physical changes occur. Like in everything |
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51:27 | . I think chemistry changes and before have physical changes but in the case |
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51:37 | the injury it's opposite actually have physical that's followed by a chemical imbalance. |
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51:47 | vascular disease or micro vessel disease. also sometimes when people talk about dementia |
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51:56 | talk about forms of dementia. There's micro vessel disease and what happens, |
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52:00 | in the older people that micro vessels deliver enough oxygen and nutrients and the |
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52:09 | areas are don't access. The micro are abnormal anatomically, that may be |
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52:19 | , that maybe exaggerated only certain parts the brain. There are environmental causes |
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52:26 | epilepsy. There are environmental sensory There are fundamental chemical causes of |
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52:34 | Right? And in many cases, cause of epilepsy is not known, |
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52:40 | with many neurological disorders or many diseases general and in many diseases in many |
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52:49 | diseases, we also quite often are symptoms and that's because we don't know |
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52:56 | causes or we don't even sometimes know mechanisms. And so when you talk |
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53:05 | a neurologist that has a case of and a child Has tried three medications |
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53:12 | none of them worked to control That neurologist will tell you that what |
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53:17 | doing is trial and error. Treatment a doctor's supervision, trial and |
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53:26 | Because three medications already failed. What's next step? Maybe potentially a cocktail |
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53:35 | two or 4 medications. What's the step? Each step is three |
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53:43 | six months of supervised observations, Medication work for a child who is developing |
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53:52 | months is a very, very long not to be able to control |
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53:57 | But this is how you deal with lot of problems in this country and |
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54:02 | know, there's shortage of specialists. when somebody has a problem, a |
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54:09 | disorder and they see the neurologist, don't usually get a slip, come |
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54:15 | see me next week. I usually a notice. I think I can |
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54:20 | you next time three months from now 20 minutes And then three months from |
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54:27 | for another 20 minutes. Uh So is, you know, we're talking |
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54:33 | american healthcare, which is really good to the rest of the world. |
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54:40 | that is I didn't say the It's really good compared to the rest |
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54:45 | the world. But a lot of in any healthcare, any advanced healthcare |
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54:53 | . Doctors and nurses are sometimes as as a patient that is being treated |
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55:02 | maybe is inquisitive is telling more information may reveal something about their symptoms or |
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55:08 | disease that are trying to help themselves doing something else. Apart of just |
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55:13 | the pill. And so so so , it's insisting for another test because |
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55:19 | reading the test results saying maybe you to check for Gerard dia, whatever |
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55:28 | do, we still have the I'm sorry. Okay, so let's |
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55:36 | where we are genetic mutations, brain areas, mechanisms, synchrony |
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55:48 | drugs, drugs involvement of cannabis and , etc. Etc. Mm |
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55:57 | Let's just talk about today. Let's this, these two slides. This |
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56:06 | remember Jase jasper's basic mechanisms of So it was a data there on |
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56:12 | glutamate that we looked at blue dramaturgical information or we studied glutamate. So |
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56:20 | is a trance membrane sodium channel. educated sodium channel. Those guys will |
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56:28 | four sub units six Trance Member Ring . Remember you have a voltage sensor |
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56:35 | S. 4? That's why they voltage sensitive channels, voltage gated |
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56:41 | You have between S. Five and . Six. You have this |
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56:46 | Okay, you have the nitrous terminus here. You have the car |
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56:54 | L. C. 02 terminals They're both intracellular are located. All |
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57:03 | , this is our channel. It's modulation here, modulate the channel and |
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57:13 | just extra cellular. And you can the channel by activating this voltage sensor |
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57:21 | S. four. But why are talking about voltage gated channel? Because |
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57:31 | you have a genetic mutation in a it leads to what is called the |
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57:38 | apathy. And mutations involved educated sodium are very comma in childhood apple up |
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57:49 | . It is not to say that channels potassium or involved educated calcium channels |
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57:57 | have mutations that lead to epilepsy. both educated sodium channels not only lead |
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58:06 | lead to epilepsy but there are several and not just several areas, dozens |
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58:14 | areas along this protein where mutations in vault educated sodium channel can lead to |
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58:21 | forms of epilepsy. So sodium channels channels calcium channels mutations. If any |
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58:29 | these ion channels will be called channel . And this is what we're seeing |
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58:36 | commonly in childhood epilepsy ease channels. happens to these channels sodium channels? |
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58:43 | may stay open longer than normal along sodium card to enter the neurons of |
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58:48 | making neurons hyper excitable. Sorry? if you recall something about this channel |
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58:56 | gated sodium channel is that these are channels that fast acting when there is |
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59:01 | deep polarization. The small educated sodium will open up just for one or |
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59:06 | milliseconds and then we'll get an activity they will close basically. And then |
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59:11 | have to hyper polarize the salad in to change the confirmation and get it |
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59:16 | to open. So the transient will it if you mutate amino acid sequences |
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59:24 | you have a genetic mutation that ends and abnormal folding of one of these |
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59:30 | or something like that, you affect kinetics of this channel and instead of |
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59:38 | opening and closing within 12 milliseconds, if it now staying open for four |
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59:45 | , five milliseconds. That's twice as of sodium that can come in. |
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59:50 | means that that action potential is going be so much longer to because the |
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59:56 | keeps coming in and coming in. happens if you have a mutation and |
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60:02 | channel? So this is more sodium opening If you have a mutation. |
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60:08 | if you have a mutation that closes channel So you have a mutation that |
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60:13 | potassium channel and keeps it close then happens to the positive charge potassium charge |
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60:22 | accumulating. Accumulating accumulating the self keeps polarizing polarizing polarizing. So you have |
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60:28 | mutations that will make channels more You have mutations that will make channels |
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60:35 | . If that voltage gated sodium channel more active and excitatory cells it will |
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60:39 | more excitation. What if this bolt sodium channels more active on the inhibitory |
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60:49 | ? There will be more inhibition. where are these channels expressed? So |
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60:54 | depends on where these channels expressed the of these channels. In the accident |
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60:59 | segment we had an 81.2 and A. V. 1.6. High |
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61:05 | gated voltage sodium channels, low threshold voltage sodium channels. And you have |
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61:11 | subtypes of these voltage gated sodium So that's important. It's not just |
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61:18 | that's everything, it's where the mutation located. What's that type of this |
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61:23 | ? What cells express this channel? is it going to affect the circuit |
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61:29 | ? Now, locally? And this here everywhere, you see a green |
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61:41 | everywhere there is a mutation along the and the amino acid sequences marked by |
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61:48 | green circles can lead to generalized stands. G. E. |
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61:56 | S. Stands for federal seizures plus other complications. We'll talk about what's |
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62:05 | epilepsy versus generalized versus partial epilepsy, generalized epilepsy lose consciousness. Fi brow |
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62:16 | . Everybody should know with cerebral seizures because maybe you even have experienced it |
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62:25 | . Or have seen somebody have a seizure, especially if you've raised Children |
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62:29 | being around their little Children. It's most common type of seizure that happens |
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62:34 | Children when they have infection or inflammation their temperature goes up beyond 104°F. That's |
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62:45 | when somebody has a fever and you a nurse and you have a |
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62:52 | what's the temperature? It's the first , 102, uh, you |
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62:58 | you have to watch 104, the thing very likely. They'll tell you |
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63:06 | that child in the eyes bath, down the temperature, put the head |
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63:12 | front of the air condition, do it takes. Lower down the |
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63:17 | The most effective, it's really cold or ice bath. And it happens |
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63:22 | that lowering down the temperature can prevent you have fi brow seizures, basically |
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63:30 | induced seizure and it's not uncommon for Children to have a few brown |
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63:37 | Once they had fever, grew up 104, it's a short Debrowski seizure |
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63:44 | they may have convulsions and then when come out of the infection, their |
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63:48 | goes down, they'll never have a again. You'll never have epilepsy |
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63:54 | I don't know of any longitudinal studies correlation between those that had a few |
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63:59 | seizure Once and does that then 50 plus over on the upper side of |
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64:05 | U-shaped curve developing upper since seizures later life. I don't know if there |
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64:10 | that longitude and a long longitudinal study been done would be very interesting to |
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64:17 | into. So if eyebrow seizures febrile seizures repeat, it's like an |
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64:25 | that we talked about with hub. show a stimulus, a stimulus, |
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64:31 | brain circuits get activated, remember the , then you show partial stimulus. |
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64:36 | brain circuits remember to fill in for partial stimulus that get activated much easier |
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64:42 | just a partial stimulus. So these seizures and the activity in the circus |
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64:47 | also learned. So you have one policies were too few procedures with that |
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64:52 | into turns into abnormal chronic circuit activity having one seizure febrile seizure. It's |
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64:59 | enough to say that you have We would have way way higher prevalence |
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65:04 | epilepsy is if we counted every child had a febrile seizure, it happens |
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65:09 | adults by the way to the temperature up. You have everywhere you have |
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65:17 | dots here, but we're talking about sodium channel here. You have what |
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65:22 | called severe my chronic epilepsy of S. M. E. |
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65:28 | severe my chronic epilepsy of infancy is known as DR A syndrome. |
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65:34 | R A V E. T. we'll talk about that because most of |
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65:39 | drugs actually that are out there are Dravet syndrome patients, pharmaceutical cannabis |
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65:46 | So it's very interesting why in particular CBD cannabidiol is effective for treating severe |
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65:57 | chronic epilepsy of infancy, it's one the most effective treatments. Um |
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66:06 | there's a lot of other abbreviations so I won't really talk about them |
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66:11 | we need to get into more I want you to be responsible for |
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66:17 | , generalized epilepsy. Fi browse You will know more about generalized epilepsy |
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66:23 | partial if you browse seizures. this definition for sure, severe my |
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66:30 | epilepsy of infancy will come back and about it some more, but please |
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66:34 | that it's very strong linkage to voltage sodium channel mutations. It's one of |
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66:40 | most severe forms a lot of times I and also infantile spasms. |
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66:47 | S. Um Children may have hundreds seizures a day, so they're they're |
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66:56 | by either having seizures or buy really drug doses to to maintain those seizures |
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67:04 | to control them so severe. My epilepsy of infancy and infantile spasms are |
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67:13 | referred to as catastrophic forms of epilepsy their catastrophic for Children, catastrophic for |
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67:22 | development. Infantile spasms has indicated that in infants. There are also catastrophic |
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67:32 | families. The whole family has to their lifestyle to having a child that |
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67:40 | having uncontrollable seizures. A lot of are faced with such challenges that they |
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67:49 | hold up as families. It's catastrophic 20 severe mountain climbing, couple of |
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68:02 | and Children die in their sleep. despite all the efforts to control their |
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68:12 | make their lives better keep the family very sadly. One of the five |
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68:19 | perished what is called sudden, unexpected and antelopes, or Sudafed, |
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68:27 | unexpected or sudden unexplained death in Okay, so these are really awful |
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68:35 | neurological disorders, but we'll talk about then we'll come back and talk more |
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68:39 | what happens to the cellular mechanisms and imbalance of chemical imbalance and how to |
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68:46 | it, and how cannabinoids play into picture here, too. Thanks very |
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68:51 | everyone. We'll see you all next |
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