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BIOL 6397 Cell Neuroscience Mo Wed 1-2.30pm - CELL NEURO Lecture 20 EPILEPSY II
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00:02 This is lecture 20 of cellular And last lecture we began talking about
00:10 and we ended talking about channel open and so these would be mutations and
00:18 that would result in different kinds of ease. And in particular, we
00:26 generalized epilepsy with febrile seizures and the for febrile seizures as well as
00:33 My chronic epilepsy of infancy, which also known as DR A syndrome.
00:39 we briefly touched on this I. . Which is an infantile spasms.
00:45 these are developmental early childhood seizures. we discussed that it's not necessarily that
00:55 vault educated sodium channels are involved in , but it seems to be that
01:00 are so many different parts of this protium that one mute once mutated the
01:07 assets within different parts of this complicated . You may end up with one
01:15 these uh epilepsy zor syndromes and notice say epilepsy is not epilepsy because there's
01:23 a variety of different types of epilepsy that it is essentially epilepsy these instead
01:31 just one epilepsy. Other mutations of that would be associated with other channels
01:39 be potassium channels and calcium channels uh we perceive apple, etc as imbalance
01:53 excitation and inhibition. However, this a simplified way of looking at
02:01 It's a simplified way in the sense everything that's balanced would be kind of
02:08 not necessarily in a straight line, like a pendulum. The pendulum is
02:13 back and forth, I'm actually gonna this back grabbing into the pendulum and
02:19 if there is all of a sudden pulled over the pendulum forward one side
02:25 not as much to the other, starts swinging toward excitation. And in
02:31 of the cases in epilepsy because you seizures you have too much excitation and
02:37 enough inhibition and most of the therapeutic and cellular strategies that address apple of
02:45 and the balance of excitation and the pharmacologically typically target gaba receptors and boost
02:55 . So these would be Gaba receptor for example. And when we looked
03:01 the glue dramaturgical gaba ergic signaling, talked about how Gaba a receptors aside
03:08 molecules called benzodiazepines and benzodiazepine agonists is example of an agonist for Gaba receptor
03:17 will boost inhibition or boost Gaba The other strategy which is not as
03:27 as dampening glutamate and it is not common because you will not find as
03:34 pharmaceutical drugs that are specifically in reducing dermatologic signaling. We know that there
03:43 many different aspects that we discussed for transmission. There is synthesis of trans
03:51 transmission. There is transport. So have to remember that some of the
03:58 from the synaptic cleft that will be back into the pre synaptic terminals and
04:03 have the transporters that are Surono and you'll have transporters that are the secular
04:10 we looked at the cycling of glutamate we said look glia is involved in
04:15 . And so if you have abnormal functioning, let's say glia is overproducing
04:23 bed or just the opposite not producing , it's overproducing. It might be
04:28 much of the excitation, not it might be too little of the
04:32 , which is typically not the case epilepsy. So remember that when you
04:38 about where along the pathway one can a disease. Most commonly. When
04:45 talk about pharmaceutical drugs, we talk receptive targets. So there's an agonist
04:50 this, there's an antagonist for this more rare. So that we're talking
04:57 pharmaceutical drugs that target particular release or especially transporters, uh particular transporters.
05:09 research suggests that south seizures reflect an of this balance of synaptic excitation and
05:15 . And I think that most of research will probably support that. But
05:21 is also not to say that this is a chronic state. It could
05:29 a chronic state. For example, you have abnormal sodium channel of the
05:34 interneuron. So there isn't enough inhibition that's chronic abnormal physiological state. But
05:41 some instances seizures are these spontaneous breakthrough that repeat themselves. If you're
05:50 only very rare only every few months few years if you're not so lucky
05:57 the severity of the problem, the and the chronic imbalance and the circuit
06:03 more severe and you're more likely to beginning the seizures. Now, when
06:08 talk about early childhood seizures, remember we talked about plasticity and we also
06:16 about critical period of development. And said that there is this soft spot
06:21 , the development where the circuits are themselves that were finding themselves. The
06:26 is becoming more precise. The function the different brain regions and circuit is
06:31 more complex and more precise. So imagine if a child that is developing
06:38 circuits and synapses developing is having seizures would be likened to a short circuit
06:46 the little explosion at the plug. now with these types of diseases,
06:53 severe types of apple Etsy's seizures can in hundreds a day. So this
07:01 something that that is important to keep mind that so in many cases seizures
07:06 sort of these sporadic accurate breakthroughs if may but maybe related to underlying severe
07:15 and other instances we don't know if underlying pathology is severe. So
07:27 Uh huh. FM All will bind Gaba, Gaba will bind to Gaba
07:33 . We already discussed this perpetuates ah anti epileptic drugs will bind to gather
07:43 agonists so they will keep Gaba receptor and there will be more influx of
07:50 . So there will be more hyper in the south and in the network
07:56 there are drugs that if they Yeah but such as the convulsant here
08:04 P. T. X. It blocks Gabba channel. So it can
08:09 used in the opposite way, reduce and promote convulsive or epileptic like
08:25 Mhm. Mhm mm hmm. Remember and we talked about reactive psychosis and
08:41 mechanism by which inflammation could boost astra ligament release. And most of the
08:51 release in astrocytes Zarathustra side is that this black uh shape of sorts here
09:03 then re actively opposes it because this reactive uh scientific visualizations scheme for control
09:13 a specific glutamate release by to g . The one is the medical tropic
09:19 receptor five WR five and the other is an 80 d receptor key to
09:27 one R. And through this specific . Because it's a medical tropic system
09:35 this GQ protium, they basically control amount of calcium and this calcium is
09:46 for real selves to recycling luna made a normal state. In some
09:56 Some one of the explanations for involvement in epilepsy and some epilepsy ease
10:06 WR five is up regulated and what says here and activated microglia as
10:17 As reactive astrocytes release TNF alpha which on TNF are one receptors which are
10:27 in glia that promote the prostate gland . So remember we talked about the
10:34 inflammatory cytokines and cytokine release and micro cells are involved in this process
10:42 And micro glial cells control the pro as a cytokine release. But when
10:52 is inflammation there can be a loss that control. There can be an
10:57 regulation and over excitation up regulation of receptor expression and over excitation of these
11:07 and now through the activation of TNF . One and this prospect land in
11:18 . Now we can also activate the . Q. Which has a receptor
11:27 intracellular calcium release and increased glutamate So you basically now boosted the pathway
11:38 through TNF alpha which is promoting prostaglandin , promoting prostaglandin formation and it's boosting
11:47 further. So now you have even glutamate release. So all of these
11:54 play into and if there's more glutamate by glia overproduction of that glutamate then
12:02 too much excitation in the circuit and can lead to that excitatory and give
12:06 an imbalance. Okay so we touched generalized seizures when we talked about generalized
12:19 , generalized apple of C. Brow seizures plus. And the big
12:26 distinction between generalized seizures versus partial seizures that you have loss of consciousness and
12:39 when you think of loss of consciousness you think of a person that's collapsed
12:43 the floor and is having convulsions and or she is unconscious But there are
12:50 types of seizures that are called absence that occur in Children and they expressed
12:56 sort of as a blind stand to and they can last anywhere from a
13:01 seconds to 15, 20 seconds or . And in that time period the
13:07 is completely unconscious of what happened. they're not conscious of the environment at
13:12 time that happens to Children is okay imagine if you're on the highway 65
13:19 and you blank out for seven seconds you don't know what happened to you
13:25 we talked about the pacemaker activity and talked about special properties and connectivity and
13:32 llama cortical circuits. And we said thalamus is a collection of these different
13:39 and different cortical parts can communicate to parts of thalamus. Hypothalamic nuclear received
13:45 of the input, the sensory nuclei most of the input from cortex,
13:50 from the periphery, not from the like the retina going into L.
13:55 . M. But L. M receives most of its input from
13:59 . So these the llama cortical circuits very important and once they get synchronized
14:05 abnormal fashion that can lead to generalized or spread of epilepsy through the interconnected
14:14 and associated uh symptomology. So partial . Uh we will obviously discuss a
14:29 bit more about that. Um There simple partials partial seizures. But let's
14:35 talk about. Well I put the here but I'm talking focusing on generalized
14:41 since the Grand Mall is an example generalized seizure aura is typically a time
14:50 that precedes a seizure that a person somewhat uncomfortable about something. They can't
14:57 identify it unless they've learned they've had seizures. They've learned that they're about
15:04 have a seizure. The earliest the can detect while in observing a person
15:13 E. G. Recording prediction for . G seizures or maybe 20 seconds
15:20 seizure happens. If you have a good neurologist that has seen the seizure
15:28 before and it has very outwardly motor especially, or temperature changes of
15:35 seizure. Then maybe with the help E E G, you can predict
15:39 seizure happening a minute from now. that's very important because it, once
15:48 seizure begins and you have this massive , what I call electrical burn of
15:59 . It's really important to know why starts and how it starts and to
16:06 predict as early as possible before it and it will begin and today,
16:13 best predictor of seizure happening. Uh beautiful golden black lab, golden labrador
16:24 dogs that are specifically trained uh to their owners detect and prepare for
16:37 There's something in the chemistry of the , the dogs and behavior and motor
16:46 that other humans don't pick up or even machines, but dogs
16:53 and they can sometimes do that a of minutes before seizure starts. So
16:59 quite expensive. It takes a long to train them. They're service dogs
17:05 , and they're also trained that once person is having a seizure, that
17:09 supposed to do certain behavior around Uh So some people enjoy the auras
17:18 , and I believe it was alexander great that said that he wouldn't trade
17:24 feeling of epileptic aura to not having seizure that follows. And he probably
17:32 pretty severe seizures. So yeah questions related to the aurora. So um
17:42 . You can pick up figure out get a couple of minutes before but
17:47 it's an aura before that that would within the or a time period.
17:54 there hasn't been studying. Yeah of people really try to study. That's
18:00 I've spent a lot of time studying a cellular level, looking at what
18:05 excitatory inhibitory cells doing right before the of the seizure. And we still
18:11 have. We were forming an explanation certain types of seizures and epilepsy is
18:16 we still don't have all of the of what happens and how the network
18:24 and then the generalized seizure. You see this electrical activity across the entire
18:30 of all of the E. Electorates will see these synchronized massive waves
18:36 electrical activity similar to for us. so it's also a very good
18:46 So migraine or s may have a different expression and seizure auras. And
18:57 many people migraine or s have a component where uh they may start seeing
19:08 flickering a little bit out of focus or like slight losses partial losses,
19:19 fields but that is before the onset the pain than migraines. So that
19:27 considered a migrant or um the mechanisms seizures to cellular mechanisms and migrates.
19:35 believe we will be discussing that a bit, of course there are some
19:40 . So there are some cellular at substrates and cellular events that are happening
19:46 are similar that basically predetermined seizure formation migrates. The difference typically that one
19:59 starts seizures travel through the brain and different regions of the brain. If
20:06 will engage them, they will engage fairly fast. The wave of activity
20:14 gets formed by migraine is a very moving wave typically from the back of
20:23 brain, from the occipital lobe and doesn't have as much of a spiking
20:31 on it. But it's more of what we call a deep polarization
20:37 It's a it's a cell membranes get polarized. They no longer spike.
20:42 this deep polarization wave like very slowly travel. So, uh keep
20:51 Did you have a question that didn't to ignore you? Okay.
20:55 Sure. Can be like psychogenic uh it uh distinguished from the uh
21:20 different or is definitely associated with different and also the expression during the seizure
21:25 example, loss of consciousness is one , but the tonic clonic components,
21:32 tonic unresponsiveness of muscles and muscle rigidity the chronic, which is muscle spasms
21:38 relaxations. They can all take very shapes and forms and individuals to and
21:45 reason why people may have these uh or hallucinogenic advances because there's synchrony and
21:57 changes in synchrony in the structures. um obviously it will be different for
22:05 wars. And then the expression itself the syndrome is also very different.
22:11 after Grand mall seizure that has a clonic component, there's a post tropical
22:18 of the recovery phase. Uh typically still very quiet in the brain.
22:24 cells are very quiet and individual is very exhausted. And if it's a
22:32 phase, you know, it can days, sometimes weeks depending on the
22:37 of the seizure. If a person experiencing grand mal seizure then you ever
22:43 that you're in the present in the and there's nobody there that has medical
22:48 or degree and that person is not to seize. No, you you
22:55 cannot do much if the person collapses starts to having grand mal seizure with
23:01 tonic clonic component, except for make that they don't hurt themselves, Like
23:08 something under their head if they're in concrete um um backpack or anything that
23:16 piece of clothing uh and just try comfort them because they may be coming
23:24 and out of consciousness during that And if it is not stopping.
23:30 first of all, of course call medics, you know, call
23:35 But you also have to know that have about 45 minutes before that person
23:42 permanent damage or potentially reaches the stage mortality. So neurons cannot sustain these
23:51 of synchrony and electrical activity For longer about 45 minutes to an hour.
23:57 that point they start dying. They just burned completely. Mhm absence seizure
24:06 not have a tonic clonic component, seizure will have a blank stare,
24:11 you will not see the convulsions and . It's still a generalized seizure.
24:22 partial seizure. So this is partial where you don't lose consciousness. Simple
24:28 versus partial, that is complex, . Uh in simple partials seizure,
24:38 typically don't have loss of consciousness, typically affecting one part of the
24:45 You may have, for example, in one limb. So it has
24:51 focal component and in complex partial meaning it has a focal component and focal
25:01 . That means the seizure begins in focus. But if it's complex and
25:07 starts involving other parts of the interconnected part of the brain, you
25:12 have impaired awareness. If not a of consciousness. Okay, so this
25:22 example, like an E. Recording in a way that precedes
25:27 With being aura and you can see E. G. Recordings, they
25:35 not even showing a lot of the activity because seizure per se. When
25:42 define a seizure in E. Has not started yet and in B
25:48 C. The person now expression of also depends what part of the brain
25:53 affected. So for example, if affects the emotional centers of the brain
25:59 a lot of times the executive functions the frontal cortex, it may have
26:05 like it looks like an episode of to personally starts screaming swearing and they're
26:12 not aware of it. So, they will come out of it,
26:17 brain activity will settle, they'll come and they'll ask everybody, what did
26:21 do, what did I say? bad was it so smart. Um
26:27 not pleasant. Now, this area we talked about hippocampus is very susceptible
26:33 damage by seizures. And so maybe why people have flashes of memories and
26:42 is not a store of memories. are distributed widely throughout the cortex,
26:48 a lot of times to recall a memory or something, you will activate
26:54 which will reach out to the other in the cortex to drag out that
27:01 of coordinated with the emotional centers in limbic system. So, because,
27:08 know, every story has uh the good and the evil and the,
27:14 know, the winner and the loser the lesson. So that area is
27:21 susceptible to damage and neuro degeneration. susceptible to generating epilepsy and seizures and
27:31 of the most common uh seizures epilepsy temporal lobe epilepsy said in humans.
27:38 the campus is located within the inter fold very close to the temporal
27:46 but it will also get damaged in disease and also will get damaged to
27:52 . So the structure is very susceptible damage. We call this rip
28:02 these salama cortical circuits that we were about and how you can start just
28:09 one stimulus current here and just with stimulus current you can start bursting
28:18 That's going to be like a pacemaker just with a single stimulus. And
28:26 are the exact circuits that are involved generation of abnormal activity and synchronization of
28:40 , thalamic cortical circuits during epilepsy and seizures. So when we talk about
28:48 network we need the limbic system and is part of it, part of
28:54 limbic system. And this is basically circles the red and the blue
29:11 the red one are all of the of cellular mechanisms that you have been
29:16 about that can lead to increased synchronization to upload optic activity. I'm not
29:27 if there is a start to this but it's always good to start with
29:32 potential firing which can lead to a of pasta synaptic potentials will be increase
29:38 extra cellular potassium and very active cells will be more deep polarization in the
29:43 which will lead to more synchronization. potentially changes in ph and modulators and
29:51 others which you know we all have significant others. So the authors meant
29:59 other chemicals in the mix, Norepinephrine serotonin or whatever else, not just
30:06 but also electrical communication through gap junctions very important in synchronizing the networks and
30:15 the firing between the south. So junctions will keep increasing the firing and
30:21 fire will keep spreading through the gap . Remember note that all of these
30:26 are bidirectional and then a thematic Remember when we talked about the intrinsic
30:34 signal I said that the translucence of reflective properties of the brain tissue
30:40 That's because when neurons are very active demand a lot of blood oxygen nutrients
30:48 they also swell and when they swell they start producing these electric fields that
30:57 talked about. The magnetic fields from . Remember when we talked about
31:03 G. And the south swell all a sudden they become very close to
31:09 other much closer than they were And so this is what these called
31:15 . A. Thematic effects now because the swallowing of the south. It's
31:19 even the gap charges. That's these interactions that can help increase the
31:26 That normal synchronization of the math works to decrease collective forms of colonization.
31:38 uh in most of the cases when talk about decrease you also start thinking
31:46 therapies that are associated and the cellular behind these therapies. So sodium current
31:57 . So if we inactivate sodium currents won't be as much of action potentials
32:06 sodium currents are in the inhibitory cells . Mhm. So we need to
32:12 for volt educated sodium channels that are prevalent than the excitatory cells and the
32:19 that are going to target self specifically very specific channels rather than broadly sodium
32:28 inactivation promote hyper polarizing potassium curves, synaptic inhibition. That's gaba gaba gaba
32:41 . I think 2/3 of the drugs the market for epilepsy and seizures are
32:45 based electra genic pumps and significant Everybody has a significant data. Electra
32:54 pump has one too. So electra pumps a. T. T potassium
33:04 pump. Right https. That's Please sign up the control. That's
33:13 because you either have to decrease particular and binding or increased particular release in
33:21 . But you want to be You want to increase just inhibitory particular
33:28 or you want to decrease just excited have a secular release. And so
33:34 are all of the good strategies. that's an incomplete list. Some of
33:41 things that may be appearing in the . I believe we'll have to do
33:46 maybe electromagnetic control of seizure activity. neurons synchronize and produce these electromagnetic fields
33:56 the synchronize even further, then why we apply an electromagnetic field on the
34:03 of their heads to stop seizures. those are some of the interesting techniques
34:10 are right now the experimental neuroscience level deep brain stimulation. So stimulating the
34:20 and shocking. These circuits can stop and can stop synchronization to Yeah.
34:27 there's other ways in which you can the collaborative forms synchronization. Ah Let's
34:39 at what happens. We looked at genetic epilepsy and so you have abnormality
34:46 jean you have an abnormality in the such as both educated sodium channel.
34:52 now you have a drive A And that's a childhood epilepsy that we're
34:58 about. But it's quite different if epilepsy is a result of traumatic brain
35:10 . Okay so if you have a brain injury here there's two uh here
35:22 a rodent brain and we're talking about models of dramatic brain injury. It's
35:29 close skull injury. That's Avalon fluid percussion. Huh? That is
35:39 lateral and parasitical and controlled cortical impact is C. C. I.
35:48 like into your weight drop, controlled impact. Why do we need to
35:55 these models? Because what happens when a big bomb explodes? There's a
36:08 the blast wave? What happens if brick falls on somebody's head? That's
36:18 a weight drop on somebody's head? bullet was like a weight drop.
36:28 ? So we want to understand what the conditions? What are the
36:35 You want to control these of this particle impact. C. C.
36:40 . Is computer controlled down to the . It's like a computer controlled hammer
36:46 you can say banging this very small very fast and increased the velocity banging
36:54 and bank it slower and much much . So now you can study their
37:02 of injuries and how those injuries would in any long term changes when the
37:11 States was involved in the wars in and Afghanistan. There are a lot
37:18 I. E. D. there's a lot of bomb explosions and
37:22 of the most common injuries where the injuries And soldiers that had traumatic brain
37:30 ended up about 20% having epilepsy and seizures. So you typically hear about
37:38 , which is post traumatic stress which is more or less a neuropsychiatric
37:45 or mental disorder. Um but 20% the vets with traumatic brain injuries ended
37:55 having epilepsy and seizures. Now it's that when you have this way
38:02 well when you have an injury it's that you're epileptic immediately, you may
38:07 even experience a seizure. When that drops. When the injury happens,
38:13 may not even be epileptic for a or two, for two years or
38:21 years and this is called a latent . The latent period. How long
38:28 it take from the time of the two when there are certain molecular and
38:37 reorganizations happening that now your brain starts seizures. And uh so you have
38:49 reorganization such as alter gene expression which occur following a trauma acquired channel opened
39:00 , so instead of a genetic oh path eu have following a trauma
39:06 local changes potentially in that circuit that injured and you haven't acquired channel
39:13 you can have post translational modulation and can have also a genetic modulation.
39:20 all of these epigenetic molecules that really the gene code a lot and seemed
39:28 transfer between generations as well. Circuit . You have neuronal death, that
39:36 first of all acute. So if a blunt injury, shrapnel bullets to
39:42 head, you kill south's immediate plant then there's a delayed neuronal death.
39:49 there might be a delayed programmed cell apoptosis. There's also necrosis that could
39:54 happening. There's neurogenesis. So there's to be plasticity and new cells of
40:02 to regrow. There there will be cell death but there will be growth
40:06 glial cells and formation of the Glia genesis invasion of inflammatory cells.
40:14 glial cells can invade the area. can become unchecked with the cytokine release
40:19 just keep promoting the inflammation axonal So no firing axonal sprouting the opposite
40:28 response to injury. Axon will respond sprout more of the collaterals. You
40:35 dendritic plasticity, you can have loose brain barrier and blood vessels associated with
40:43 brain barrier and damage consequently the traumatic injury of blood brain barrier. But
40:50 also can have angiogenesis the formation of blood vessels. Uh so it's a
40:58 bag of things. Okay. And really what it is called the myriad
41:04 molecular and uh and uh circuit changes can happen at the level of the
41:13 . So after brain injury, if don't have, for example, epilepsy
41:20 , you become more susceptible to epilepsy seizures. So one concussion, you
41:25 not develop epilepsy seizures. Five you actually may adapt developing epilepsy
41:31 So having a concussion, we're having dramatic breed injury predisposes you in the
41:39 to have increased susceptibility and expression of . Epilepsy is when you have spontaneous
41:49 . So when somebody has a highbrow once or twice in their childhood because
41:54 were super hot, 104 105 they don't have epilepsy. If somebody
42:06 some event that evokes a shock and seizure, they don't have a for
42:14 , If they have a bank on head and they undergo epileptic seizure,
42:19 don't have epilepsy. But if their are spontaneous and repeated, they have
42:29 apps meaning that you don't know There was no trauma, Nobody flashed
42:36 flashlight or strobe light in their but they're still having seen you change
42:41 diet, they're still having, there's known cause there's no provoked, but
42:48 lot of times the brains that are to seizures are also susceptible to being
42:55 to have a seizure. An example , such as an audio genic
43:01 The vote by sound and people that audio, audio genic epilepsy, they're
43:07 sensitive to sound on certain pictures and and amplitudes of sound when we talk
43:14 disease. This is a term that hear and you may have heard already
43:23 , comorbidities is other things that are with the disease. So if it's
43:30 brain injury with seizures and epilepsy, can cause motor impairment and affect the
43:37 gait can affect the person's driving Can cause emotional impairment, can cause
43:46 of memory or partial loss of especially if you have damage to the
43:52 . All of these things are called because collectively together with seizures and
44:00 they will kill you faster. They you more morbid. And uh and
44:10 when you're treating a neurological disorder and treating epilepsy, it's not just the
44:16 mechanism of the drug and the receptor that you're treating and counting the number
44:23 seizures. And looking at the IgI . You also have to think about
44:31 social memory support systems and even motor therapies that would be necessary.
44:46 , models of epilepsy and like we , there's many different ways of having
44:54 causing epilepsy models of epilepsy tried to what happens to humans. A very
45:04 model is a chemo convulsive model that you're using a chemical which causes cause
45:10 seizures or epilepsy. Another very common is to use electric shock. What
45:16 called kindling is to repeatedly shocked the and high frequencies. And so following
45:25 repeated shock. The fiber survived What happens to that network, that
45:32 is plastic in that network large. now very small stimulus. Just like
45:37 heavy and and graham is going to massive response which would be a seizure
45:43 . And after some time the stimulus not even needed to spontaneous stimuli about
45:51 seizures. In apple. I've seen disturbance such as uh to recreate developmental
46:00 pathology. Hypothermia is very common. would be recreating federal seizures in the
46:08 of overheating hypoxia depriving oxygen. Genetic of transgenic models knock out, knock
46:22 post traumatic couple of seats. These the models that we just talked about
46:28 we looked at the traumatic brain So controlled cortical impact, fluid
46:34 there's other models too infection. So some instances uh infection can lead to
46:44 and can lead to apple apps and , temporal lobe epilepsy, abbreviated
46:50 L. E. Is the most form of human epilepsy. Already mentioned
46:56 it's now in your nose. So will be on the test. Um
47:03 often involves hit the campus and if the hippocampus is not necessarily the site
47:09 initiating the seizures, it is still much susceptible to seizures. And the
47:16 for initiating the seizures varies depending on cellular mechanisms underlying genetic mechanisms underlying chemical
47:28 so on. Mhm. Synchrony. gonna talk about secret e.
47:42 Yeah. We're gonna talk about See talk about secret aid now and
47:51 we talk about anti epileptic drugs. yeah, I should tell you about
47:56 of my work on synchrony I'm trying have to torture you for too
48:02 Okay so top eight pyramidal neurons P thin lines of different color oscillate synchronously
48:13 2025 hertz frequency range with no inhibitory . So you can see that each
48:20 here py sent for prominent south and is prominent self spikes. And you
48:26 see that you can see all of colors yellow, green, red,
48:31 , black, dark green. It's drama neurons. So you should be
48:39 to see eight colors. So here they synchronized here? No they're firing
48:48 . Maybe there is a sequence to firing but they're not firing in
48:55 And there you see this triangle here 200 milliseconds of gabber allergic signal from
49:07 neuron to parameter cells. This is feedback. It was activated. So
49:15 you activate the inhibitory cells, what then at this late stage here of
49:22 trace? All of the spikes are overlapped in time and they're very synchronized
49:33 here what you see is LF. . Which stands for local field
49:42 So when we talk about epileptic activity E E. G. Recordings were
49:47 up those E. G. Recordings the skull. When we do experimental
49:52 recordings we do local field potential recordings these are essentially large electrodes that pick
50:00 activity from hundreds or thousands of selves the local network in some ways this
50:09 similar to an E. G. because only in a way that it
50:15 an average of the network response that seeing in local area local field
50:24 But you can see that and when cells are not synchronized you will not
50:28 a pronounced local field financial. And the cells become synchronized you can see
50:34 there is a local field potential that a certain frequency that circumstance vorticity.
50:43 let me tell you tell you about experiments. And and and I was
50:47 these experiments and I was doing a of experiments and I was going and
50:53 at the microscope for hours and I stabbing cells and I was listening to
50:59 and I was going blind and that so much fun. But so for
51:09 this is a good way for you visualize and everything that we've talked about
51:15 an experimental setup. And this is my um from one of my papers
51:22 was my student Dr Fong goo who these experiments together with me. I
51:30 him how to do them and how do neurophysiology or electrophysiology dr Thang and
51:39 I'm going to stanford to work with David Prince who is an amazing legend
51:48 and fang uh currently has two or offers standing offers for faculty positions.
51:55 it looks like fungus pursuing that that he's a medical doctor by training from
52:01 . So when he came here and have a job and joined my lab
52:06 was already an M. D. so this is some of the experiments
52:13 did together with Fong. So this line indicates the temperature and we're increasing
52:18 temperature here. And we typically would the temperature in a dish. This
52:24 in the mutual recording the whole cell . All right. You guys allow
52:29 this stuff sell extra cellular recording would like local field potential recordings or
52:37 And the temperature to Zia logically is . Uh huh degrees. When you
52:46 in vitro recordings and rodents, we keep it around 30. But in
52:51 experiments we keep it at physiological temperatures 37 and we rise it typically to
52:57 42°C. So as you can see as temperature rises the cell becomes very active
53:08 you have this Prolonged activity. This 32nd timescale here. And these are
53:14 potentials. And you are recording local potential activity. And you can see
53:19 the straights that local fuel potential in order of fraction of my levels.
53:24 also show these very synchronized large synchronized but will not really pick up individual
53:33 or spiking activity. Mm hmm. if you zoom in you zoom in
53:42 this event here you can see the spiking activity and the extra cell with
53:49 potential. And you can see that these individual bursts and the local field
53:55 are also synchronized. So this is of the features quite often they're referred
54:01 as inter Richtel bursts. When you're at the electrical activity of seizures in
54:09 these prolonged seizures that can last for . There are these intermittent bursts like
54:18 called inter rectal spikes on intellectual So neurologists if they were to look
54:25 the E. G. Signal and not record a seizure because a person
54:30 not experience a seizure during that let's say, for four hours from
54:34 hospital. They may look for things inter rectal spiking or inter rectal bursting
54:43 of very small tiny potential regions of that would predict to them that this
54:51 abnormal network. Although I'm not seeing seizure, we're seeing these spikes and
54:57 spikes should not be there were detecting . Okay, so now this animal
55:07 a mutation involved educated sodium channel. it's a transgenic mouse model that replicates
55:14 McLaren a couple of safe infancy or a decent girl. You guys also
55:18 that. And so this is a type animal, which means it didn't
55:25 a mutation and this is heterocyclic this , it means it had a
55:30 And so whenever we increase the temperature of 25, You can see out
55:37 these 27 animals experiments, Close to of the uh mutated cells mutated tissue
55:49 these abnormal federal seizure like events. what FSL east has for febrile seizure
55:56 event. Federal because it's with seizure like event because it's in
56:01 So you cannot really call it in as a seizure. Very high incidents
56:06 these mutants. And then you can that this incident is low 30% in
56:11 type animals. It's still there because temperatures are so high, they're abnormally
56:18 high. Uh And so this is developing animal. So this is like
56:24 true federal seizure without a mutation. you can see that heterosexuals animals,
56:30 raise the temperature to about 38 And they're having seizures. But for
56:37 wild type animals that temperature has to much higher For them to have a
56:41 approximately 40 degrees 40 plus degrees And then the duration of these seizures
56:49 much longer. And the animals that a mutation in that vault educated sodium
56:54 that we're talking about. So in my other work, I studied synchrony
57:08 when you looked at the level of E. G, of course it
57:14 thousands of cells underneath the skull. you look at the local field potential
57:19 , it's still hundreds and thousands of . And I was an experimental
57:28 I was pretty stubborn and I said want to know what different cells are
57:33 . So look in the hippocampus and said I'm going to record from two
57:37 self so I have this nice, know, intracellular also recordings. Extra
57:43 recordings. I'm gonna record from two ourselves parameters? Saw one parameter,
57:48 , suit, what are they What's the local field potential and what's
57:51 synchrony? So I studied the synchrony excited to be excited for spike
57:57 Then we cut out the spikes and studied the sub threshold activity, all
58:01 fluctuations underneath the spikes and the security the sub threshold activity. That was
58:09 cool. That was enough. So there were nights at I was doing
58:19 2nd post Dr. George Mason University Fairfax Virginia. I would stay up
58:26 I would have like three cells, electrodes I was recording from, you
58:32 , I thought I was like some , you know like it's this huge
58:37 like five people cared really. But but why? And what was the
58:43 is I told you early on that have a variety of different inhibitory cells
58:49 that excited results kind of pretty boring or 2 different subtypes of cells?
58:55 the question always was and still and maybe it's only partial. The
59:02 is what sells starts seizures? How they start? What cells synchronized person
59:07 excited ourselves and synchronized and start Does it inhibitors cells that synchronized?
59:13 it inhibitory and excited? Is it at the same time? What is
59:20 ? So it's very difficult to go human and say excuse me, can
59:24 catch a few cells in your brain you have a seizure for me and
59:31 see what's going on. So you to again go into slices and we
59:35 into a slice And this is a one area of the Hippocampus, you
59:40 know all of this too. And recorded from parameter cells and I recorded
59:46 the inhibitory cells and this is uh molecule area or lamenting euro. And
59:54 I found very surprising is that the cells were active and this is a
60:00 a purity and model of seizures. this case we're blocking potassium channels and
60:06 does some other things. There is channel blockade, there's accumulation of potassium
60:12 decreases the di valent ions screening across plasma membrane. That is essentially a
60:19 model of inducing seizures. And sometimes also aided by inducing uh by reducing
60:28 . So what we were surprised to is the inhibitory styles became active first
60:35 synchronized first and then they failed. when they failed during this, what
60:40 call deep polarization block, that's when excitatory cells we produced most of the
60:45 potentials. Then they stopped when the cell. Then they started again firing
60:52 the excitatory self started firing inhibitory, failing inhibitory sale and failing. So
60:58 call this interplay excitatory inhibitory interplay. was basically differences in exchange inhibitory self
61:08 , failing excitatory self synchronizing and when synchronize they produced these large bursts of
61:16 And that activity because the excitatory what we call is runaway excitation and
61:22 excitatory activity. Because that excitatory activity be communicated to the interconnected regions from
61:29 hippocampus is to other areas obviously campus the cortex. So then once the
61:36 is given, once there is a in the environment, once there is
61:41 change in the chemical composition and you the excitatory and inhibitory circuits You can
61:50 start generating this rhythmic activity. And long would these seizures go on
61:55 I'm just showing you a segment that for about 40 minutes here mm
62:02 With this experiment went on for probably hour and a half. And what
62:07 the stimulus? I wasn't shocking. tissue over and over and blocked the
62:13 chemical composition has changed. And because had the excitation and you had the
62:20 of the circuit now, because of differences in synchronization of these different subtypes
62:26 cells were able to produce this repetitive activity and study how this activity
62:34 So this will conclude today's lecture and third lecture and epilepsy will be about
62:40 anti epileptic drugs and targets for treating and some of the uh strategies that
62:47 already alluded to earlier today. Thank . And I will also let you
62:53 about the quiz or you will just it on casa.
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