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00:02 This is lecture 19 of cellular And we already touched upon electrons a

00:09 early in the chorus just by mentioning maybe. But we're gonna understand what

00:18 E. G. Or the electroencephalogram . And some of the techniques that

00:24 gonna talk about today and in particular E. G. And then another

00:29 called M E. G will reflect different that we talked about when we

00:39 imaging techniques such as Fmri and pet . So E E G. Is

00:46 measurement or is a measurement of electrical . It's not direct because it's not

00:54 from the brain, it's not from brain surface but rather from the

01:01 the surface of the scalp. And non invasive. The roots of E

01:07 . G uh date back to the century and human E. G.

01:16 first described by an Austrian psychiatrist, berger In 1929. So about 100

01:26 ago is when we gained understanding of E. G. Is. And

01:32 been 100 years of evolution of how record E e G. How to

01:38 these recordings as precise as possible, and as fast as possible temporarily.

01:47 So there was a significant changes of And this is one of the recordings

01:56 he'd taken from the head of his year old son Klaus. Uh This

02:02 a time herds time signal and this the first ever published E.

02:07 Rhythm. So all of the great and scientists, they always try things

02:14 sometimes with their family members to but it's about 100 year old technique.

02:21 so this is a kind of a that you would be picking up from

02:25 surface of the skull. And uh would be different positions. So we

02:36 talked about brain rhythms and we talked how you would record these different brain

02:42 . So we're gonna remind ourselves a bit about that. Then when we

02:46 about spatial specificity there are E. . Caps that will contain just a

02:56 electrodes. So they'll tell you it's frontal parietal temporal, there are

03:03 G. Caps that will contain tens electrodes there. I. E.

03:08 . Caps that can go as high hundreds of micro electrodes that get placed

03:15 the surface of the scalp. So more electrodes you have the more spatial

03:22 you have. However there's no way you're gonna be able to pick up

03:27 cell activity because of what exactly the . G. Signal represents. It

03:32 represent electrical activity from a single cell rather from the underlying neuronal network at

03:40 very surface of the cerebral cortex. we'll talk about this also. And

03:46 you can see also here that when picking up E. G signal is

03:52 weak. When we talked about amplitudes the action potential, it was in

03:59 of million volts, 70 100 million . We talked about E.

04:04 S. P. S. And PS PS. There were an order

04:07 million volts. But the signal that can record through the skull and you

04:15 up on the surfaces only on the of micro volts. So you get

04:22 filtered representation because the skull is a bone and you have a skin that

04:29 approximation if you will of electrical And also there has to be something

04:38 on in the brain for that activity show up. In other words,

04:43 circuits need to be actively engaged and synchronized and the more they are

04:51 The greater possibility is that these The G electrodes will pick up the

05:01 . So this is another example of E. G. Recording and you're

05:08 the difference between the two electors that each one of these traces represents the

05:15 between this electorate and this electorate in case traced to between electorate two and

05:20 and so on. And the subject awake And quiet. And recording sites

05:27 indicated here on the left. These the electrode positions. The first few

05:31 show normal alfa activity which has frequencies eight 2 13. So you can

05:37 these very fast Fluctuations of about 8 13/s. Yeah this is the second

05:47 . This is amplitude and micro holtz halfway through the recording, the subject

05:53 his eyes so you can see this artifact and so this also tells you

05:59 when you have E. G. you also have a lot of artifact

06:05 and you have to be able to or recognize that artifact activity. And

06:11 we're talking today about epilepsy and epilepsy one of the rhythmic disorders. And

06:18 e. G. Is a technique helps to diagnose this rhythmic disorder.

06:25 we're talking about that you are talking some people that will be moving during

06:31 procedure that will maybe having a that's exactly what I want to record

06:35 seizure activity. But there will be only blinking artifacts that will be muscle

06:41 artifacts, there was movement that they and so on, acceleration velocities,

06:46 of these things. And so the sophisticated instruments allow us to recognize and

06:54 filter those artifacts are often going to in the slower frequencies when it comes

07:00 some of the motive facts like blinking . But as soon as the subject

07:05 the eyes you can see that the of this rhythm has changed and now

07:12 have these beta rhythms and the amplitude these rhythms is not as hi.

07:20 also data rhythms will be in a frequency. So what are we recording

07:26 we were recording E. G. is an example of an E.

07:31 . G. Electrodes. This is scalp, the skull, we have

07:36 meninges, dura, arachnoid, subarachnoid and PM Otter. And then underneath

07:45 we have our cortical circuits and if recall we have these parameter cells in

07:53 cortex that will have their a pickle rights going upwards. Okay so the

08:01 of very small electrical fields by synaptic in Tehran. But all cells when

08:06 cells produce electrical activity, they also electrical fields around the movement of the

08:16 . But also they produce magnetic fields movement of the charge. Again in

08:22 case the active synapses on the other of the dendrite, the upper part

08:28 the dendrites. So you can see these are the inputs here coming in

08:32 where you have the arrow pointing and are the axons. So you have

08:38 that are coming in and exciting these down rights of parameter cells on the

08:46 upper part of the done drive. the apparent action fires the police synaptic

08:52 released glutamate which opens Catalonian channels. know all about that little bit channels

08:59 current flows into the dump drive. sodium, if it's an M.

09:03 . A, sodium and calcium flowing the down dr leaving a slight negativity

09:11 the extra cellular fluid correct? Because more positive the neuron becomes outside of

09:21 neuron and the immediate surroundings it becomes negative. So positive current leading into

09:32 leaving slight negative into current spreads down done right and escapes from its deeper

09:39 , leaving the fluid slightly positive at sides. So when the inputs come

09:46 remember the dendrites are not insulated like . And so you first of all

09:53 to have a lot of excitatory synapses and a lot of excitatory synapses which

09:57 learn from the example circuits will be targeting distal parts of the down rights

10:03 a lot of the inhibitory synapses will targeting these para somatic areas. Recall

10:09 there's a lot more excitatory cells, of the population of these cortical cells

10:15 this parameter excitatory cells and only 10-20% be inhibitory cells. So there's inhibitory

10:24 have much greater diversity. There is far less number of them but also

10:29 have in many instances the priority of the parts of the soma around the

10:37 that are really important for the integrative of the cell so that the cell

10:42 produce an action potential or not. once the current goes in after some

10:46 it actually flows out in this area more positive so influence slightly positive at

10:52 sides. The E E G electrodes to. Uh Second lecture of some

10:58 away right here measures this pattern through tissue layer. Only thousands of cells

11:08 their small voltage in the signal large to reach the scalp surface. Notice

11:17 E. G convention of plotting the with negativity upward. Okay, so

11:23 deflection of positive deflection. That's just uh my convention because these signals are

11:32 small you have to have pretty powerful . Uh So you have to amplify

11:37 typically hundreds of times if not thousands times. And use very sophisticated

11:45 So you can for example use high filters, everything high frequency passes low

11:52 filters, everything low frequency passes band you can just tell your amplifier filter

12:00 in this band between 10 to 30 10 to 40 hertz. That's what

12:03 interested in. Everything else is doesn't . So so you have all of

12:09 techniques and all of the technologies that adjacent to picking up this activity.

12:16 the point being is that if one is active and is generating these electrical

12:23 that's not enough for the E. . To pick it up, it

12:26 somehow blend into, it's almost like noise and the strays. However if

12:31 have thousands of cells that become active in other words synchronized or maybe they're

12:39 a common inputs or they have a conductor or maybe something is happening in

12:44 vicinity of these thousands of cells such rises in potassium because our glial cells

12:51 a little bit behind and all of sudden there is a little bit of

12:54 in the cells are getting deep polarized 100,000 of them getting the polarized at

12:59 same time. That could also be causes of sort of a self organization

13:05 these cells without having a strong input organization into into synchronized response containing thousands

13:14 neurons acting at the same time. this is uh the generation of large

13:23 . G. Signal by synchronous activity population of parameters. Cell cells located

13:28 this one E E. G So this is still simplified. It

13:32 have thousands millions of cells. If inputs fire at irregular intervals the parameter

13:39 responses are not synchronized. So if inputs coming into 123456 these are different

13:46 just like they're coming in here it's different cells if they fire at different

13:52 and you look at the individual trace these cells that they're producing Small

13:59 P. S. P. But they're producing small E.

14:01 S. P. S at different right? Different. This is time

14:07 look at some E E G won't any particular synchronized pattern or any definitive

14:15 in there. Now if the same of inputs if these inputs six inputs

14:23 in onto these six South targeting these cells, excite them or produce action

14:31 will release glutamate on them within a time window and that's also spike timing

14:38 plasticity to everything within neurons. It within short time windows within milliseconds it's

14:43 meaningful. So if a lot of south's thousands hundreds of South then the

14:49 received this boom, one input excitatory all of them within milliseconds from each

14:56 . Now you can see that they're targeted about the same time and when

15:02 average or sum over all of the . G. Recordings to six recordings

15:08 six cells in this case at the of the E. G. Which

15:13 be recording from way more than But this is a simplified example of

15:18 . You will now pick up a which you will say well I think

15:21 see a very clear oscillation up and . 34 Maybe four. Very significant

15:30 . Torrey signals in there that are at a certain frequency. Okay so

15:36 important way to synchronize the cells. important way to synchronize the cells if

15:42 have a common driver or a common . Ok and so in in in

15:53 the lecture notes. Okay we're going come and talk about this and well

16:02 we'll come back and talk about that a second. So we already discussed

16:07 you have a variety of rhythms. have a variety of rhythms and uh

16:14 is a slight difference in frequencies of rhythms across the species. Uh It

16:22 that rather doesn't have alfa rhythm. the book says also don't be mad

16:27 the rabbit because maybe there wasn't enough the experiments down in alpha rhythm.

16:33 we need to still do and find frabjous habit. But in general you'll

16:41 these dominant frequencies across different species. and ripples. Spindles have contained this

16:52 is called a complex. Okay a important. Together with ripples for learning

17:00 memory ripples are probably the fastest oscillations have been recorded to date 200 to

17:09 hertz. 200 to 600 cycles a . The 2nd e. G.

17:16 up A signal to 100 hertz. if you have a two kHzertz Sampling

17:24 what does that mean? That means sampling 2000 electrical signals in your oscilloscope

17:32 second. That's 10 2 kilohertz. may have 10 kilohertz was very expensive

17:38 but you have 10,000 samples. So higher the sampling rate you would have

17:44 more of this very fast activity you pick up. And so you'll see

17:49 a lot of developing countries for example IgI recordings are not as sophisticated both

17:55 the prospective number of electrodes. The , the temporal resolution of processing of

18:00 amplifiers. And the third thing is processing. So what I've been telling

18:05 about filtering and stuff like that that digital power. That takes computers.

18:10 takes all of types of things that not everybody in the world is lucky

18:15 to have. But so we will up these fast rhythms and these slower

18:20 And also note that neuronal populations can overlapping rhythm frequencies. So you'll have

18:27 very slow wave and the slow wave repeat Every half a second. But

18:33 top of that very slow wave or slow rhythm you will have this buzzing

18:39 of about 200 or 300 oscillations per . So there is overlapping these dominant

18:47 . We don't necessarily perceive them as as as uh resonance of one

18:57 But there is resonance in these Physical resonance in these rhythms. And

19:03 call that a different rhythm means different or uh behavioral state. Now when

19:17 talked about pet um and F. . R. I. We were

19:25 about metabolism, we were talking about oxygenation and glucose. Mhm. Uh

19:40 you want deep imaging it's really FmR Pat is typically done more on this

19:47 morna. Cortical imaging. Yeah. g. It's different. E

19:57 Is electrical activity so we're no longer metabolism and by the way when we

20:05 tracking metabolism, pet and F. . R. I. There's no

20:09 cell resolution there is no five cell . There's 10 no 10 cell

20:15 You're still looking at clumps of activity are or not clumps of activity or

20:22 . That has been averaged over collections clumps of hundreds if not thousands of

20:30 in the imaging techniques. The same with the E. G. The

20:35 of E E. G. It's activity reporting. Plus the skull is

20:39 is a is a filter. It's low pass filter. It filters the

20:45 through the bone. So you want sometimes look deeper and find deeper sources

20:55 activity. E. G. Apart tracking this normal synchrony that represents these

21:03 that represent different behavioral states. G within the context of epilepsy is

21:11 to detect abnormal rhythms or pathological But if you have the sources of

21:20 pathological rhythms on the surface coming from cortex, that's very insightful.

21:29 a lot of these abnormal rhythms come Salaam IQ areas and come from the

21:37 cortical circuits that we alluded to. example, when we talked about the

21:43 system. So there's thalamus to the , salama, cortical and cortical Islamic

21:50 . And these loops a lot of are important in generating not only normal

21:56 also abnormal activity. So if you only picking up activity from the surface

22:01 the cortex is one thing. But if your focus or faux side which

22:09 referred to a small area in the that is generating abnormal activity? What

22:15 your foe sigh of seizures or normal activity of normal synchronization are deep?

22:24 M. E. G. Is better technique and in this case

22:30 E. G. Speaking of magnetic . So a person is receiving an

22:35 . E. G. Scam here in this magnet, this massive magnet

22:42 , the tiny magnetic signals generated by on the brain are detected by an

22:47 of 150 sensitive magnetic detectors. But have the ability to actually reduce three

22:57 locations of these magnetic signals and magnetic , electrical signals, electromagnetic activity is

23:09 . Researchers use the signals to calculate location of sources of neural activity color

23:14 in in this image where there's a of neural activity where there's little neural

23:19 and so on. So if for example had a patient that had

23:26 brain activity and you did an E . G. Recording and you said

23:32 I can see and we picked up seizure and it's very clear that it's

23:38 on the cortex here. So you not go that extra step of getting

23:43 . E. G. It's sort like an X ray with M.

23:46 . I. Went to spring your . You know, they do an

23:49 ray and they say wow. You , if you don't feel good still

23:54 weeks from now come back and we'll if we do them right And you

23:59 , probably 90% of the people never back because they don't need to.

24:02 it's a spring. But you so the same way if you if

24:07 E. G a lot of times also the healthcare plans, it's the

24:12 of time, it's availability. Accessibility these machines who has these semi G

24:17 , not everybody not everywhere around the and so on. When you do

24:21 extra step you have abnormal brain E. G. Allows you to

24:27 it out from the surface. E. G. Allows you to

24:31 it deeper within the brain. Now have a much better understanding of this

24:36 of where this abnormal pathological rhythm is from and you are directly measuring activity

24:44 longer, you're measuring the metabolism. you wonder are there circuits in the

24:55 That can generate. So 11 slide think I'd like to throw in

25:02 That is not. And uh in presentation is this one this is what

25:11 talking about. When I say that are mechanisms of synchronizing. So this

25:16 a common input or common conductor A of times it's referred to as

25:23 We all have pacemakers. They're very in the brains. Well some of

25:30 are very slow like circadian super charismatic that nucleus has a very slow rhythm

25:36 and night. We have pacemakers in heart, the sino atrial node and

25:44 constantly produces electrical activity and through gap electrical connectivity it d polarizes the cardiac

25:54 and you get constructions and contracts and and contracts and slows down and speeds

25:59 and it's basic, basic, basic . And so this is sort of

26:05 common pacer or conductor. And then are situations in which neurons, like

26:12 said, there's something maybe in the . Maybe there's inflammation. Maybe there's

26:17 regulation of the chemistry neurotransmitters ions that changes activity in all of these neurons

26:25 all of these neurons without the conductor of like a second line just start

26:30 the rhythm together. So this is you're generating these synchronous rhythms. And

26:39 talked about the Islamic cells and then Islamic sauce you constantly have active excitatory

26:50 and if you will say okay if have this pattern, if you have

26:53 pattern too you have this pacemaker So what does your heart do with

27:00 pacemaker pattern? Pace contract pace, pace, contract pace contract. It

27:08 that pacemaker rhythm. 121121121. If doesn't you're in trouble. Now neurons

27:16 we now receive a lot of these neurons are excitatory and inhibitory cells.

27:24 an exciting yourself is going to be . And we also learned about what

27:29 cells will do inhibitory cells may have feedback inhibition. So when one excitatory

27:38 contacts another excitatory so it's excited. that excited to resell all excited inhibitory

27:44 that inhibited neurons within the negative feedback will reduce excitation. And so you

27:51 the excitatory input and you can see excitatory input and excitatory salads receiving this

27:58 input and then with some delay you this delay is here. This trans

28:05 communication to the inhibitory style. With delay you have a rhythm that is

28:11 in the inhibitory cells and what we what we have in the colonists of

28:27 we have in the cortex is a similar situation where you have input that

28:34 coming into the thalamic relay cells. we also if you recall we have

28:42 thalamic particular nucleus which is abbreviated here T around the lama. In particular

28:50 is a really interesting nucleus. So have Kalanick nuclei that have dedicated provision

28:57 was a lot of the nucleus nucleus we talked about. The hypothalamic nuclei

29:01 had dedicated for every sound. So auditory there was going to be mediagenic

29:07 nucleus for some matter sensor information. going to be ventral basal lateral nucleus

29:16 the thalamus and all of these salam nuclei and Stalin. This is really

29:21 collection of these sensory nuclei, their and surrounded by the Islamic particular nucleus

29:28 switches collection of the inhibitory cells. whenever there's an excited input coming into

29:34 thalamus relay solid thalamic relay sale is and it sends an input to the

29:41 . This is all a salama cortical at the same time. And also

29:46 sense of excitatory input onto the ridiculous inhibitory cells. And those particular inhibitor

29:55 in the negative feedback Now quench the of these the thalamic relay cells at

30:04 one level. Now also once the goes into cortex we know that there

30:09 intra cortical connectivity. So cortex to neurons will be connected and these cortical

30:16 can also activate ridiculous cells so they excite to the inhibitory cells.

30:24 And the ridiculous salsa are interconnected with other. So you can have inhibition

30:30 inhibition. Right? one inhibitory cell releases Gaba can hyper polarized another inhibitory

30:40 and that inhibitory cell will be inhibited well. Yeah wow so do I

30:47 to memorize everything here while you need know to Islamic relay sounds constant input

30:54 in and then you will excite excited into the results the lamb in particular

31:00 this inhibitory cells and this negative feedback that goes back into the cortical loop

31:07 have inter cortical connectivity we will remind and then you have cortical salama.

31:14 the reason why we're highlighting the circuit also this circuit is really important in

31:19 and synchronizing some of these rhythms that talking about. And just because

31:25 G. Will be picking up these of the cortex, we want to

31:28 what's going on going on in the cellular circuits that lead to the generation

31:35 these rhythms. And when I say rhythms says there are some cells that

31:41 they receive a stimulus instead of producing constant output of action potentials they start

31:52 bursts of activity. And so this the feature of some of these thalamic

31:58 salama cortical cells because they receive a input D polarizes of the start firing

32:05 potentials in the thalamus. The excited Islamic cells and what particular economic cells

32:13 they inherited these cells. And so have the hyper polarization and then again

32:19 there's constant input. You do polarize cell again you produce a burst.

32:23 instead of this constant stimulus this is you can turn a constant stimulus into

32:30 activity through the excitatory inhibitory circuit And this bursting activity at the level

32:38 a single cell means many action potentials produced at the same time. But

32:43 the level of the circuit if you many cells producing bursts at the same

32:48 this is very highly synchronized activity that now going to be picked up.

32:53 E. E. G. Or any G. Recordings. Uh

32:59 These are some of the details here we're talking about. Okay so diagram

33:07 the thalamic cortical network showing connections between somatosensory cortex. The venture bezel.

33:14 is a matter of sensory neurons and ridiculous thalamic nucleus. RTM. Now

33:25 a lot of information in this. we can walk through it together under

33:31 physiological conditions. Two sensor signal from peripheral relate to the cortex the

33:36 B. N. And R. . N. Neurons by anatomical and

33:39 deep polarization. So if you have a constant stimulus so matter sense their

33:45 . And these cells the relay cells be producing uh tonic firing. Reticulated

33:53 neurons will produce these bursting which will turn this tonic firing in the thalamic

34:00 into this bursting activity. Mhm. and once you have this bursting activity

34:10 loops can self propagate this activity. burst and burst and burst and burst

34:16 burst and burst and burst pattern. becomes self propagated meaning you no longer

34:22 a sensory input in order to generate repeated oscillation. It's sort of like

34:29 started something like a pendulum and now swings back and forth and swings back

34:34 forth and swings back and forth and back and forth. This oscillation

34:39 You just needed to start the pendulum now it will go on for a

34:44 time until something else happens that stops pendulum gets in the way. In

34:49 case would be another electrochemical activity in circuit. This is d you have

35:02 firing in particular nucleus and these are epileptic rat model of absence epilepsy.

35:11 you will understand a little bit later the next two hours. What absence

35:16 is? It's a generalized form of . Garis epileptic rad. There's a

35:25 that tries to replicate the human epilepsy a rodent. So we will talk

35:31 animal models. Chemical models, genetic , viral models of apple apps.

35:39 so and it correlates with burst firing our tm. Upper panel shows

35:47 G. Recording. So this is . G. Recording. This is

35:51 and this is to what is happening lower panel shows corresponding intracellular recordings in

36:00 R. T. N. So this is a single cell

36:03 So this is the power of experimental if you had no ability to do

36:11 intracellular recording in the whole brain as doing E. G. Recording.

36:16 would really have no ability to liken compare the two signals to gotta.

36:21 this is really neat and you have single cell. Single cell is de

36:27 and even what single cell is firing potentials here but doesn't produce a burst

36:36 which basically represents synchronized activity. These action potentials at the level of the

36:44 . G. Trace. They're really indistinguishable from the background noise. However

36:50 minute you get this repetitive bursting activity on top of each of these deep

36:56 is you have a train of action writing you can now very clearly during

37:02 seizure during the abnormal synchronization of the . You very clearly start picking up

37:10 clearly defined oscillations from the E. . Signal. This is the thalamus

37:26 generate rhythmic activity because the intrinsic properties neurons and because of its synaptic interconnections

37:34 the thalamus Green represents the population of styles neurons and black represents population of

37:40 inhibitory neurons. This is what we at. So there are two really

37:47 why these networks are capable of generating written activity and specific rhythmic activity of

37:56 bursting activity to tolerance. We talked synaptic connections inside the core inhibitor,

38:05 about common input and then intrinsic properties neurons. So what are intrinsic properties

38:19 the intrinsic properties of neurons are different of channels that they expressed. And

38:25 lot of thalamic relay cells will have threshold voltage gated calcium channels. So

38:33 little bit of voltage will cause a increase in cal suit. So it's

38:40 just enough that you have the drive you have the connectivity but with different

38:46 and for different bursting activity and frequency that activity. You have to have

38:57 special in the intrinsic properties and the properties of the member of response properties

39:04 these cells. This is again the that we already looked at. So

39:12 visual it would be from L. . M. You have the cortical

39:17 LG N. Will also have this nuclear interaction too. Inside layers 23

39:28 spread the information to extra stride long outside of the visual cortex. In

39:33 case outside of the somatosensory cortex there's cortical loop. So the cells within

39:40 cortex will also communicate which we didn't about here and then there's corticosteroid Landeck

39:48 . So these are the same circuits we were talking about. Okay cellular

39:58 . Just the introduction of decided more but it's also the introduction and a

40:06 to us the scales that we're looking . So the macro scales that we're

40:12 at with E G M M E at best Mezza Skah pick scale you

40:21 maybe derived by a combination of G and M E. G.

40:28 that there are cellular networks salam IQ Kalama cortical network. Within those networks

40:36 are rules that we talked about feed feedback inhibition. There is neuro modulator

40:46 substances to change those rules change and the color stretch the learning time,

40:55 the plasticity from potentially ation to All of these factors are very important

41:04 normal functioning in the brain. The . The chemistry of the connectivity and

41:13 inputs. Also normal brains can be out normal if there is enough of

41:20 repetitive input, could be audio visual input, it's called torture.

41:26 it doesn't stop and brain circuits can . Get rewired in those situations.

41:36 we will undoubtedly talk about mechanisms and and we'll come back to ions and

41:44 again In Epilepsy but for the next or so 20 minutes we're gonna withdraw

41:54 home. Talk a little bit about terms like prevalence C. Or incidents

42:03 new epilepsy cases in this case for . Epilepsy is one of the major

42:10 disorders that affects one To 2% of population. I know it's a very

42:15 range 1-2%. There are some geographical in the incidence of of seizures and

42:26 and as you can see there is high incidence of epilepsy in newborns and

42:40 and then you have high incidents of list. This is inverted U.

42:47 a sorry it's a U shaped curve shows again Ages 60 and plus there's

42:56 possibility of developing epilepsy also. So are all in this kind of a

43:06 spot here at least for a couple scenes interestingly enough. Alzheimer's goes up

43:17 about similar fashion. There is no Alzheimer's but it goes up in a

43:22 fashion in the 50 plus and we'll about Alzheimer's when we talk about Alzheimer's

43:28 how that correlates with epilepsy and So it's more common in developing countries

43:40 a number of reasons, detection services of something like an infection that may

43:50 to development of epilepsy in the It's a politic infection, mosquito,

43:57 things like that. At the same , there is not enough reporting in

44:06 developing countries. So it's hard to . Sometimes there is maybe some interesting

44:15 in India suggesting that curcumin which is very big part of the diet and

44:23 has anti inflammatory properties. Could be with slightly lower levels of apple etc

44:31 India. But there are also concerns in many developing countries stigma that is

44:40 by neurological disorders, migraines and epilepsy seizures. Somebody having convulsions in an

44:47 that doesn't have very good educated healthcare may discard that as an obsession as

44:55 as a some sort of a crazy . Just not diagnose that person rightfully

45:02 with with the disease also. So don't think there is a standard really

45:07 tracks this around the world. There no standard healthcare system. There's no

45:12 standard healthcare reporting around the globe. it's about 1-2% higher rates of untreated

45:21 epilepsy because people don't detect, recognize other infections, poor prenatal, post

45:30 care can all contribute to higher rates epilepsy and that's important because it occurs

45:37 often in young Children and then again the elderly childhood epilepsy is typically

45:45 caused by genes or disease or abnormality at birth. So typically the earlier

45:52 see symptoms of epilepsy, the more it is a genetic cause rather than

46:00 sort of a sporadic chemical environmental cause epilepsy has many causes elderly tend to

46:10 epilepsy as a consequence of conditions such stroke, tumors, dramatic brain

46:20 increased inflammation in the brain and also , very strong correlation to dementia and

46:27 disease. And we'll talk about But I'll make sure that if you

46:32 Alzheimer's disease in your 60s, you're like 50 more times likely to have

46:38 and seizures. But if you don't at that age, Alzheimer's disease

46:46 dementia, epilepsy is more symptom of disease than the disease itself. And

46:54 , when people looked at epilepsy, was the convulsions that were repeated convulsions

47:00 a lot of times severe, even coming out of people's mouths. And

47:05 was recognized as epilepsy. But we it's a symptom, it's an expression

47:11 what is happening in the brain. cellular mechanisms chemistry genetic causes tumors can

47:22 epilepsy cleo sis when leah becomes too and to overactive, it's called reactively

47:32 and too much of glial activity is leah will start proliferating and we'll start

47:39 tissue scar and so you will have lesions and then scarring around those

47:48 just like on your skin. You , when there's no scar, if

47:53 injury is smaller, there's no you don't see it in that area

47:57 the skin a few months or a later. But if there was a

48:00 , you may see that. So have scar tissue formation, damaged the

48:07 because of the tumors and glioblastoma. glial tumors are the most common brain

48:17 and as glioblastoma as well, then of normal metabolism and their sequester a

48:23 of oxygen, A lot of blood be sucking everything into that area to

48:29 keep proliferating basically and growing. And is gonna try to do, it's

48:34 really good job but then it's gonna its job and its neurons as they

48:41 . Then you have these lesions or that are left in the brain blood

48:48 not as efficient of uh ah of , tumors and tumor genesis will require

48:58 lot of new vasculature forming around it , and that may detract from the

49:05 of supply to the neurons that are the area to trauma. So,

49:10 brain injury. Hit on the multiple precautions, um severe dramatic brain

49:19 which is penetrative shrapnel or other objects the brain tissue with the loss of

49:26 in that area. You can make area hyperactive and become the focus of

49:32 seizures uh genetics. We will look genetic components of genetic types of seizures

49:40 epilepsy, metabolic dysfunction. So that's that people don't think about or

49:47 But you actually can study mitochondria, can study the amounts of a teepee

49:52 energy and clearance of and and metabolism sugars for example, or build up

50:00 sugars. Um infections in the brain lead to epilepsy for viral infections.

50:13 and and and syphilitic viral infections, infections for example. Meningitis is can

50:23 both. Meningitis can be caused by a viral infection or bacterial infection.

50:30 , inflammation of the brain and infection the brain into the spinal fluids.

50:37 as far as viral infection, there different types of viruses. Uh uh

50:47 covid 19, potentially there's a reported of epilepsy and the person that had

50:54 19. But I don't know if a definitive Uh huh connection there,

51:00 there's a definitive connection between democratic and activity following covid 19 infection which was

51:08 common in the background of chemical changes before these physical changes. So of

51:21 , I think chemical changes probably occurred physical changes occur. Like in everything

51:27 . I think chemistry changes and before have physical changes but in the case

51:37 the injury it's opposite actually have physical that's followed by a chemical imbalance.

51:47 vascular disease or micro vessel disease. also sometimes when people talk about dementia

51:56 talk about forms of dementia. There's micro vessel disease and what happens,

52:00 in the older people that micro vessels deliver enough oxygen and nutrients and the

52:09 areas are don't access. The micro are abnormal anatomically, that may be

52:19 , that maybe exaggerated only certain parts the brain. There are environmental causes

52:26 epilepsy. There are environmental sensory There are fundamental chemical causes of

52:34 Right? And in many cases, cause of epilepsy is not known,

52:40 with many neurological disorders or many diseases general and in many diseases in many

52:49 diseases, we also quite often are symptoms and that's because we don't know

52:56 causes or we don't even sometimes know mechanisms. And so when you talk

53:05 a neurologist that has a case of and a child Has tried three medications

53:12 none of them worked to control That neurologist will tell you that what

53:17 doing is trial and error. Treatment a doctor's supervision, trial and

53:26 Because three medications already failed. What's next step? Maybe potentially a cocktail

53:35 two or 4 medications. What's the step? Each step is three

53:43 six months of supervised observations, Medication work for a child who is developing

53:52 months is a very, very long not to be able to control

53:57 But this is how you deal with lot of problems in this country and

54:02 know, there's shortage of specialists. when somebody has a problem, a

54:09 disorder and they see the neurologist, don't usually get a slip, come

54:15 see me next week. I usually a notice. I think I can

54:20 you next time three months from now 20 minutes And then three months from

54:27 for another 20 minutes. Uh So is, you know, we're talking

54:33 american healthcare, which is really good to the rest of the world.

54:40 that is I didn't say the It's really good compared to the rest

54:45 the world. But a lot of in any healthcare, any advanced healthcare

54:53 . Doctors and nurses are sometimes as as a patient that is being treated

55:02 maybe is inquisitive is telling more information may reveal something about their symptoms or

55:08 disease that are trying to help themselves doing something else. Apart of just

55:13 the pill. And so so so , it's insisting for another test because

55:19 reading the test results saying maybe you to check for Gerard dia, whatever

55:28 do, we still have the I'm sorry. Okay, so let's

55:36 where we are genetic mutations, brain areas, mechanisms, synchrony

55:48 drugs, drugs involvement of cannabis and , etc. Etc. Mm

55:57 Let's just talk about today. Let's this, these two slides. This

56:06 remember Jase jasper's basic mechanisms of So it was a data there on

56:12 glutamate that we looked at blue dramaturgical information or we studied glutamate. So

56:20 is a trance membrane sodium channel. educated sodium channel. Those guys will

56:28 four sub units six Trance Member Ring . Remember you have a voltage sensor

56:35 S. 4? That's why they voltage sensitive channels, voltage gated

56:41 You have between S. Five and . Six. You have this

56:46 Okay, you have the nitrous terminus here. You have the car

56:54 L. C. 02 terminals They're both intracellular are located. All

57:03 , this is our channel. It's modulation here, modulate the channel and

57:13 just extra cellular. And you can the channel by activating this voltage sensor

57:21 S. four. But why are talking about voltage gated channel? Because

57:31 you have a genetic mutation in a it leads to what is called the

57:38 apathy. And mutations involved educated sodium are very comma in childhood apple up

57:49 . It is not to say that channels potassium or involved educated calcium channels

57:57 have mutations that lead to epilepsy. both educated sodium channels not only lead

58:06 lead to epilepsy but there are several and not just several areas, dozens

58:14 areas along this protein where mutations in vault educated sodium channel can lead to

58:21 forms of epilepsy. So sodium channels channels calcium channels mutations. If any

58:29 these ion channels will be called channel . And this is what we're seeing

58:36 commonly in childhood epilepsy ease channels. happens to these channels sodium channels?

58:43 may stay open longer than normal along sodium card to enter the neurons of

58:48 making neurons hyper excitable. Sorry? if you recall something about this channel

58:56 gated sodium channel is that these are channels that fast acting when there is

59:01 deep polarization. The small educated sodium will open up just for one or

59:06 milliseconds and then we'll get an activity they will close basically. And then

59:11 have to hyper polarize the salad in to change the confirmation and get it

59:16 to open. So the transient will it if you mutate amino acid sequences

59:24 you have a genetic mutation that ends and abnormal folding of one of these

59:30 or something like that, you affect kinetics of this channel and instead of

59:38 opening and closing within 12 milliseconds, if it now staying open for four

59:45 , five milliseconds. That's twice as of sodium that can come in.

59:50 means that that action potential is going be so much longer to because the

59:56 keeps coming in and coming in. happens if you have a mutation and

60:02 channel? So this is more sodium opening If you have a mutation.

60:08 if you have a mutation that closes channel So you have a mutation that

60:13 potassium channel and keeps it close then happens to the positive charge potassium charge

60:22 accumulating. Accumulating accumulating the self keeps polarizing polarizing polarizing. So you have

60:28 mutations that will make channels more You have mutations that will make channels

60:35 . If that voltage gated sodium channel more active and excitatory cells it will

60:39 more excitation. What if this bolt sodium channels more active on the inhibitory

60:49 ? There will be more inhibition. where are these channels expressed? So

60:54 depends on where these channels expressed the of these channels. In the accident

60:59 segment we had an 81.2 and A. V. 1.6. High

61:05 gated voltage sodium channels, low threshold voltage sodium channels. And you have

61:11 subtypes of these voltage gated sodium So that's important. It's not just

61:18 that's everything, it's where the mutation located. What's that type of this

61:23 ? What cells express this channel? is it going to affect the circuit

61:29 ? Now, locally? And this here everywhere, you see a green

61:41 everywhere there is a mutation along the and the amino acid sequences marked by

61:48 green circles can lead to generalized stands. G. E.

61:56 S. Stands for federal seizures plus other complications. We'll talk about what's

62:05 epilepsy versus generalized versus partial epilepsy, generalized epilepsy lose consciousness. Fi brow

62:16 . Everybody should know with cerebral seizures because maybe you even have experienced it

62:25 . Or have seen somebody have a seizure, especially if you've raised Children

62:29 being around their little Children. It's most common type of seizure that happens

62:34 Children when they have infection or inflammation their temperature goes up beyond 104°F. That's

62:45 when somebody has a fever and you a nurse and you have a

62:52 what's the temperature? It's the first , 102, uh, you

62:58 you have to watch 104, the thing very likely. They'll tell you

63:06 that child in the eyes bath, down the temperature, put the head

63:12 front of the air condition, do it takes. Lower down the

63:17 The most effective, it's really cold or ice bath. And it happens

63:22 that lowering down the temperature can prevent you have fi brow seizures, basically

63:30 induced seizure and it's not uncommon for Children to have a few brown

63:37 Once they had fever, grew up 104, it's a short Debrowski seizure

63:44 they may have convulsions and then when come out of the infection, their

63:48 goes down, they'll never have a again. You'll never have epilepsy

63:54 I don't know of any longitudinal studies correlation between those that had a few

63:59 seizure Once and does that then 50 plus over on the upper side of

64:05 U-shaped curve developing upper since seizures later life. I don't know if there

64:10 that longitude and a long longitudinal study been done would be very interesting to

64:17 into. So if eyebrow seizures febrile seizures repeat, it's like an

64:25 that we talked about with hub. show a stimulus, a stimulus,

64:31 brain circuits get activated, remember the , then you show partial stimulus.

64:36 brain circuits remember to fill in for partial stimulus that get activated much easier

64:42 just a partial stimulus. So these seizures and the activity in the circus

64:47 also learned. So you have one policies were too few procedures with that

64:52 into turns into abnormal chronic circuit activity having one seizure febrile seizure. It's

64:59 enough to say that you have We would have way way higher prevalence

65:04 epilepsy is if we counted every child had a febrile seizure, it happens

65:09 adults by the way to the temperature up. You have everywhere you have

65:17 dots here, but we're talking about sodium channel here. You have what

65:22 called severe my chronic epilepsy of S. M. E.

65:28 severe my chronic epilepsy of infancy is known as DR A syndrome.

65:34 R A V E. T. we'll talk about that because most of

65:39 drugs actually that are out there are Dravet syndrome patients, pharmaceutical cannabis

65:46 So it's very interesting why in particular CBD cannabidiol is effective for treating severe

65:57 chronic epilepsy of infancy, it's one the most effective treatments. Um

66:06 there's a lot of other abbreviations so I won't really talk about them

66:11 we need to get into more I want you to be responsible for

66:17 , generalized epilepsy. Fi browse You will know more about generalized epilepsy

66:23 partial if you browse seizures. this definition for sure, severe my

66:30 epilepsy of infancy will come back and about it some more, but please

66:34 that it's very strong linkage to voltage sodium channel mutations. It's one of

66:40 most severe forms a lot of times I and also infantile spasms.

66:47 S. Um Children may have hundreds seizures a day, so they're they're

66:56 by either having seizures or buy really drug doses to to maintain those seizures

67:04 to control them so severe. My epilepsy of infancy and infantile spasms are

67:13 referred to as catastrophic forms of epilepsy their catastrophic for Children, catastrophic for

67:22 development. Infantile spasms has indicated that in infants. There are also catastrophic

67:32 families. The whole family has to their lifestyle to having a child that

67:40 having uncontrollable seizures. A lot of are faced with such challenges that they

67:49 hold up as families. It's catastrophic 20 severe mountain climbing, couple of

68:02 and Children die in their sleep. despite all the efforts to control their

68:12 make their lives better keep the family very sadly. One of the five

68:19 perished what is called sudden, unexpected and antelopes, or Sudafed,

68:27 unexpected or sudden unexplained death in Okay, so these are really awful

68:35 neurological disorders, but we'll talk about then we'll come back and talk more

68:39 what happens to the cellular mechanisms and imbalance of chemical imbalance and how to

68:46 it, and how cannabinoids play into picture here, too. Thanks very

68:51 everyone. We'll see you all next

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