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Biological Bases of Nervous System Disorders – Psychological Disorders (PSY)

by Tarry Ahuja, MD
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    00:03 Okay. So now what we’re going to do is we’re going to start going a little bit deeper into each specific state that I talked about.

    00:09 We’ll start with schizophrenia.

    00:11 And so we know that schizophrenia has a very strong genetic link and you can be genetically predisposed to this disorder.

    00:19 So the way we always figure this out is through twin studies and we looked at both monozygotic and dizygotic twins.

    00:26 And in twin studies, we know that if one twin has it, it’s a 50% chance that the other will have it or some type of form of schizophrenia.

    00:34 We know that genetics provides a biological predisposition and environmental stressors can elicit the onset.

    00:40 So, in English, if it runs in your family, so if your father or your mother or your grandfather or grandparents have it, it's passed on through genes and you might be what I like to say is prewired for it.

    00:52 It doesn’t necessarily mean you’re going to get it, but you’re prewired or you have the predisposition to potentially get it.

    00:58 And if the appropriate environmental stressors or triggers are there, you can initiate the disease or the onset of the disease.

    01:05 So there are a lot of debates sort of in the community around what causes it and I don’t think anybody agrees on the exact cause, but we do agree that there’s a strong genetic link, you would be predisposed and there are things in the environment around you that might trigger or activate that expression of the disease.

    01:24 Now, there’s a dopamine hypothesis of the disease and when you see terms like this, what they’re trying to do is understand and express the underlying mechanism behind why they think this disease is being expressed.

    01:36 This theory is still obviously up for debate, but it’s been around for long enough where I would say there’s merit to it.

    01:42 And the dopamine hypothesis states that some of the positive symptoms that we’re seeing are due to an over expression or overabundance of dopamine and you also can have hypersensitive receptors.

    01:53 So even if you have, say, the same amount of dopamine that you normally do but the receptors that are going to bind to the dopamine are hypersensitive, you would still have an exaggerated response and along with the hyperactivation of the temporal lobe.

    02:05 So collectively, these things all revolve around dopamine and this would explain some of the positive symptoms that we’re seeing.

    02:14 Now, the negative symptoms are believed to be linked to the hypofunctioning of the frontal lobes, also this something called brain atrophy, which is when the brain is actually smaller than a compared cohort, and we also have something called a decrease in convolution.

    02:33 So convolution is, if you look at an image of the brain it has all those with the folds and all that kind of wormy looking exterior structures of the cortex that the level of complexity of folding or convolution is an expression of complexity or knowledge state, so how much information is actually there.

    02:55 So the less convoluted or smooth the brain is, the worse off it is.

    03:00 So you want your brain to be nice and convoluted and folded because that represents a higher degree of functioning.

    03:08 Now, moving on to depression, we’re going to look at some of the biology behind that.

    03:12 And to do that, we’re going to have to revisit this image I’m sure you’ve seen before in the biology sections or some of the other modules that we’ve already covered and we’re looking at what’s happening at the synaptic cleft or synaptic junction between two neurons and this is outlining the process of synaptic transmission.

    03:30 So typically, a chemical, electric chemical signal is initiating from a presynaptic neuron, so what we’re seeing on the top, and it’s going to pass the signal down to the receiving postsynaptic side.

    03:42 So a couple of points that we’re going to highlight here, we have neurotransmitters, which are encased in synaptic vesicles, and these transmitters can include things like dopamine, GABA, glutamate.

    03:53 And when the appropriate signal comes, which would be an action potential coming down in axon, it would open voltage-gated calcium channels and that influx of calcium would trigger these vesicles to fuse to the presynaptic side, release their contents, which would be in this case let’s say it’s dopamine, cause the release of dopamine, and that dopamine is going to travel across the synaptic cleft, which is the gap between the presynaptic neuron and the postsynaptic neuron, and that the transmitter will interact with a receptor, and we call those postsynaptic receptors because of its location.

    04:31 Once activated, that would open ion channels and allow the signal then to pass on and the electrical signal gets converted down to the postsynaptic neuron.

    04:42 So this really quickly high overview of the process of synaptic transmission is what happens in a quote unquote “normal individual” or let’s say a non-depressed individual.

    04:52 Now, in individuals with depression we see that this process gets altered or gets skewed.

    04:58 So again, we’re getting back to genetics, we know that this driver of depression is genetically linked.

    05:05 So if there’s depression in your family, in your immediate family members, your mom, your dad, your brothers and sisters, the likelihood that you would get it would be higher than a matched cohort of individuals who don’t have it running in their family.

    05:19 So what’s causing it and where are we seeing it? What we’re seeing issues are in the transmitter levels in certain specific structures of the brain including the frontal lobe, the cerebellum, the hippocampus, and few others.

    05:31 So these are just some of the large ones that come up, but we’ll know that there’s an inappropriate level or amount of either transmitter or receptor or reuptake of the neurotransmitter and that’s leading to some of the issues that we’re seeing leading to depression.

    05:48 So there’s the monoamine hypothesis of the disease and there are three kind of real monoamines that come up: dopamine, serotonin, and norepinephrine.

    05:58 And so, inappropriate levels of any these or a combination of these would lead to the expression of depression.

    06:05 And so a lot of the antidepressants that are out there that have been designed and formulated and identified work around the premise of modulating or reestablishing the appropriate level of either of these or all of these collectively, so dopamine, serotonin, and norepinephrine.

    06:23 So you should definitely know that for your MCAT, is you need to know the different transmitters that would be behind regulating and causing depression.

    06:33 Alzheimer’s disease is a disease I would say that is most highly expressed in elderly folk and it’s the most prevalent form of dementia characterized by memory loss.

    06:45 So depression is a catchall term that’s used to represent a couple of characteristic features.

    06:51 So, you know, and not to belittle the disease, but you might hear people saying, you know, “My grandparent is losing it,” or “My parents are losing and they’re forgetting things and they don’t know where they are.

    07:04 I tell them something one day and they forget it the next day.” So that generalized, those generalized characteristics would outline dementia.

    07:13 Alzheimer’s is a little bit more specific and it is the most prevalent, like we’re saying, form of dementia.

    07:21 So anterograde amnesia is one of the key characteristics of that and that’s the inability to form new memories.

    07:27 So let’s break down that term anterograde amnesia.

    07:30 Amnesia I think we all understand that means a sort of memory loss and forgetting things.

    07:35 So anterograde means that you’re forgetting things from this point forward versus, say, something like retrograde amnesia, where you’re forgetting things that you’ve already learned.

    07:45 So you’re forgetting things that have happened since where we’re looking right now.

    07:51 So, we know that Alzheimer’s is also a cortical disease affecting the outermost layer of the brain, the cortex.

    07:56 The cortex is what we’re mentioning with the convolution and the folding, so it’s actually impacting specific areas on that outer cortex, which is where we know a lot of that function happens.

    08:08 So, in terms of the pathogenesis of the disease or what’s causing the disease, our understanding is actually still evolving.

    08:17 And, you know, I was fortunate enough to actually do some research in the area.

    08:21 And back even 10, 15 years ago when this was happening, there was still the idea of like, "Well, what’s actually causing the disease?" So what we’ve at least collectively agreed upon is that there’s an increase in the amount and level of something called beta-amyloid.

    08:36 And beta-amyloid is a very sticky substance and it can stick upon itself and it creates these things called beta-amyloid plaques and neurofibrillary tangles or NTs.

    08:47 And, you know, for a long time they weren’t really quite sure what they do, but the working hypothesis is that the plaques, more specifically the tangles create what we call synaptic clutter.

    08:58 So if you go back to the previous diagram that we had of the synaptic junction with the pre and postsynaptic neuron and the synaptic cleft and we had transmitter moving, the idea is these tangles can actually get in there and get into the cleft and block and get in the way and create garbage.

    09:15 So it prevents the presynaptic neuron to communicate with the postsynaptic neuron.

    09:21 So if you imagine one neuron trying to talk to the other and you have something in the way, that signal will not be able to pass and therefore you cannot communicate.

    09:30 Now, let’s imagine in this scenario that the information being passed is a memory.

    09:35 So memory is going from the pre to post and you need to access that memory.

    09:39 All of a sudden, you have synaptic clutter or garbage or NTs in the way that are preventing that from happening, there goes transmission of that memory.

    09:48 So you now kind of lost a memory or aren’t able to form a memory.

    09:52 So that is sort of the working model in a real, real brief abbreviated form of how we think Alzheimer’s is actually initiated and is expressed.

    10:03 So abnormalities in the activity of acetylcholine in the hippocampus, is where the memory center of the brain, is also believed to be involved.

    10:11 So we have a combination of beta-amyloid and we have an issue and abnormality in levels of acetylcholine in the hippocampus.

    10:20 Okay. So let’s move on to the Parkinson’s disease and this is a disease that’s associated with some movement disorders.

    10:26 And what’s happening here is we’re seeing a disorder because of the death of a group of cells that typically generate the transmitter dopamine, and there are two specific areas that we’re talking about, one is the basal ganglia.

    10:40 So you can see here the basal ganglia.

    10:41 It’s fairly deep in the brain, so this isn’t something you see on the surface, and we also have something called the substantia nigra, two very important structures that are generating the transmitter dopamine.

    10:53 And so deficiency in these areas of dopamine is what’s causing Parkinson’s disease.

    11:00 So, we’re going to work through sort of this figure here.

    11:03 On the left we have a healthy patient, and on the right we have a patient with Parkinson’s.

    11:08 So in a healthy patient, you have the presynaptic neuron and it would release dopamine, the dopamine would be captured by the cells on the postsynaptic side and you would have your typical response.

    11:18 In a PD patient, you have less dopamine being released and therefore you’re not activating enough of the receptors and you start to see some of the issues.

    11:27 And some of those symptoms that we’re talking about are resting tremor, which is when just sitting there doing nothing you would see a hand shake, slow movement, rigidity of movements especially in the face.

    11:40 So if you’re trying to go grab a pen, it seems like a lot of work to try and just go grab your pen and it seems quite slow, and you also have this rigidity in the face.

    11:51 So what we’re referring to here is normally, you know, people are quite animated when they’re talking, some more than others, but you know, you see movements of the eyes, the face, the cheeks.

    11:59 Individuals with Parkinson’s, they seem like there is no expression of movement in their face.

    12:06 So they speak slow, their face seems kind of rigid, and this is again characteristic of the fact that there’s not enough dopamine.

    12:15 So an obvious solution would be, "Well, how can I somehow increase levels of dopamine?" So the easy answer is giving something called L-Dopa, which is sort of a precursor form of dopamine.

    12:26 Biochemically, we’re not going to get in to all the specifics, but it gets broken down to release dopamine and we see an increase in levels of dopamine.

    12:33 Well, recently they’ve come up with agents that are dopamine agonists.

    12:36 You can even have things that cause a blockade of the reuptake of dopamine, so that ends up staying in the synaptic cleft a little bit longer.

    12:44 So everything is pretty much anchored on trying to increase the amount of dopamine that’s available.

    12:50 So, we’re going to get into sort of a new late breaking area, which is, you know, we say new, but we’re looking at about 10, 15 years of research, and that is looking at stem cells to regenerate neurons in the central nervous system.

    13:07 So the central nervous system is an area where you don’t see a lot of regrowth of neurons, especially in areas like the spine.

    13:13 And so, stem cells are undifferentiated cells that are, you know, for a lack of a better term, sort of blank slates and they really haven’t decided what they’re going to be just yet, so they have the potential to be pretty much anything.

    13:27 So looking at this figure we have the stem cells.

    13:31 They can go on to differentiate and to becoming things like a neuron, an astrocyte, an oligodendrocyte, dendrocytes.

    13:37 So they can do a lot of different things is the idea.

    13:40 So neural stem cells have the capacity to differentiate into anything, yes.

    13:44 They could be put in the appropriate place and become what we call a progenitor cell and potentially migrate into the area of deficiency.

    13:52 So if we’re looking at, say, Parkinson’s disease and we’re seeing an issue with substantia nigra or the basal -- the other areas where you don’t have enough dopamine production, you could put in a stem cell and the stem cell would become a progenitor cell and realize that it needs to become a cell that producing dopamine.

    14:11 And so you could work in diseases where the deficiency is at the cellular level, so things like Alzheimer’s, Parkinson’s, and MS, where you need to reestablish the appropriate level of activity that’s being modulated by the neuron and you do that by looking at stem cells.

    14:28 So obviously, you have two base camps, those who believe that using stem cells is dangerous because of its potential to be used inappropriately.

    14:37 Some are against how they’re harvested because typically you get stem cells from -- or you can get stem cells from aborted fetuses, you can get them from excised tissue from young children.

    14:50 You could even get stem cells from yourself in appropriate key areas and reintroduce them to where you need them.

    14:57 But the whole process is barred with a lot of adversity, but I would say those that are scientifically inclined agree and say the general consensus these days that stem cells, especially if you can do something as impactful as addressing some of these disorders, is really, really useful.


    About the Lecture

    The lecture Biological Bases of Nervous System Disorders – Psychological Disorders (PSY) by Tarry Ahuja, MD is from the course Individual Influences on Behavior. It contains the following chapters:

    • Schizophrenia (PSY, BIO)
    • Depression (PSY, BIO)
    • Alzheimer's Disease (PSY, BIO)
    • Parkinson's Disease (PSY, BIO)

    Included Quiz Questions

    1. Decreased brain size
    2. Increased dopamine receptor sensitivity
    3. Increased dopamine
    4. Abnormal mesolimbic pathway
    5. Abnormal temporal lobe
    1. Increased dopamine levels
    2. Decreased frontal lobe function
    3. Decreased number of gyri and sulci
    4. Increased ventricular size
    5. Decreased brain mass
    1. Serotonin
    2. Histamine
    3. Acetylcholine
    4. Epinephrine
    5. GABA
    1. Formation of beta amyloid plaques
    2. Increased brain size
    3. Retrograde amnesia
    4. Loss of language and motor skills
    5. Abnormal parietal lobe
    1. Intention tremor
    2. Rigidity
    3. Flat face
    4. Change in handwriting
    5. Slow and shuffling gait
    1. Difficulty forming new memories
    2. Difficulty recalling childhood memories
    3. Dissociative memories
    4. Fugue state
    5. Difficulty performing previously learned tasks

    Author of lecture Biological Bases of Nervous System Disorders – Psychological Disorders (PSY)

     Tarry Ahuja, MD

    Tarry Ahuja, MD


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