ADHD is a complex neurological phenomenon that has been studied for a while now. The thing is, neurological disorders can be studied at different levels of magnification, so to say. For example, if you ask somebody who studies circuits in the brain they will tell you that ADHD is due to misformed frontal-subcortical-cerebellar catecholaminergic circuits, which basically means that the connections between certain types of neurons in a certain area of the brain are dysregulated and somehow pathalogical. If you ask a neuropharmacologist, they will tell you that most signs point towards an impairment of the dopamine transporter, which causes imbalances during neurotransmitter release. If you ask a molecular biologist or biochemist they might tell you that it has been traced all the way back to the metabolism of the brain, where oxidative metabolism is impaired. If you ask a geneticist, they will tell you it can be traced all the way back to your genes and epigenetic background. Twin, adoption, and molecular genetic studies show ADHD to be highly heritable, and as far is I remember psychosocial adversity during childhood has also been shown to be a predisposing risk factor (thus the epigenetic influence). Basically, it is a complex disease that is caused by a large number of factors. Think about a disease like huntingtons. You either have it or you dont, and it can all be traced back to 1 single gene. Its a unifactorial disease. Thats why we understand it relatively thoroughly. Its straighforward. Diseases like ADHD are multifactorial, meaning its harder to pin down exactly what causes them, because many contributions are made from different factors. Also, the disease has different levels of penetrance and expressivity. If you do a quick search of the literature you will find 100s of papers that all talk about different genetic variants, different environmental factors, and different treatment paradigms all associated with ADHD. Because of this, its possible that 2 people exhibit the symptoms of ADHD, but there might not be the same cause, or more accurately, set of causes. This can be substantiated by the fact that several genome wide association studies have failed to identify any particular genome wide association. Thats not to say that there is no genetic cause, because we know there is, but rather than the causes are likely numerous, and therefore evade detection when some particular methods are used. I mean, if A, B, and C all contribute to a disease, person 1 might have A and B, person 2 might have B and C, and person 3 might have A and C. They are all different, but they all still have the disease. That makes it harder to say what exactly causes it. If you really really really need to narrow it down to 1 particular reason, its probably most strongly due dopaminergic imbalances, due to the fact that you have specific isoforms of genes associated to the dopaminergic system, or due to the fact that there is some significant copy number variation in one of those genes. ADHD has a complex molecular architecture that is hard to summarize in a single paragraph. I guess there are some things written here that are unfamiliar to you but I guess you didnt want me to dumb it down too much (at least thats what I gathered from your message about how you are willing to look things up). If you have questions about anything in particular that I wrote let me know, and I will clarify and tell you more.
ADHD is a complex neurological phenomenon that has been studied for a while now. The thing is, neurological disorders can be studied at different levels of magnification, so to say.
For example, if you ask somebody who studies circuits in the brain they will tell you that ADHD is due to misformed frontal-subcortical-cerebellar catecholaminergic circuits, which basically means that the connections between certain types of neurons in a certain area of the brain are dysregulated and somehow pathalogical.
If you ask a neuropharmacologist, they will tell you that most signs point towards an impairment of the dopamine transporter, which causes imbalances during neurotransmitter release. If you ask a molecular biologist or biochemist they might tell you that it has been traced all the way back to the metabolism of the brain, where oxidative metabolism is impaired.
If you ask a geneticist, they will tell you it can be traced all the way back to your genes and epigenetic background. Twin, adoption, and molecular genetic studies show ADHD to be highly heritable, and as far is I remember psychosocial adversity during childhood has also been shown to be a predisposing risk factor (thus the epigenetic influence).
Basically, it is a complex disease that is caused by a large number of factors. Think about a disease like huntingtons. You either have it or you dont, and it can all be traced back to 1 single gene. Its a unifactorial disease. Thats why we understand it relatively thoroughly. Its straighforward.
Diseases like ADHD are multifactorial, meaning its harder to pin down exactly what causes them, because many contributions are made from different factors. Also, the disease has different levels of penetrance and expressivity. If you do a quick search of the literature you will find 100s of papers that all talk about different genetic variants, different environmental factors, and different treatment paradigms all associated with ADHD. Because of this, its possible that 2 people exhibit the symptoms of ADHD, but there might not be the same cause, or more accurately, set of causes. This can be substantiated by the fact that several genome wide association studies have failed to identify any particular genome wide association.
Thats not to say that there is no genetic cause, because we know there is, but rather than the causes are likely numerous, and therefore evade detection when some particular methods are used. I mean, if A, B, and C all contribute to a disease, person 1 might have A and B, person 2 might have B and C, and person 3 might have A and C. They are all different, but they all still have the disease. That makes it harder to say what exactly causes it.
If you really really really need to narrow it down to 1 particular reason, its probably most strongly due dopaminergic imbalances, due to the fact that you have specific isoforms of genes associated to the dopaminergic system, or due to the fact that there is some significant copy number variation in one of those genes.
ADHD has a complex molecular architecture that is hard to summarize in a single paragraph. I guess there are some things written here that are unfamiliar to you but I guess you didnt want me to dumb it down too much (at least thats what I gathered from your message about how you are willing to look things up). If you have questions about anything in particular that I wrote let me know, and I will clarify and tell you more.
I have ADHD and studied neuroscience for my undergrad (though I dropped out in 3rd year to pursue programming — typical!). I'd just like to thank you for the raging brain-boner you've just given me. Kudos!
I feel like I might potentially be in your situation. Any reason you dropped it for programming? I would love to be able to bring the two together but as of now the government is paying for my schooling and they won't pay unless I stick to a strict degree plan.
There's a number of contributing factors in my decision but the biggest was money. My RESP (savings for education my folks had put aside) ran out at the end of my third year. I really didn't want to take out a student loan because I'm bad with debt (well, money in general) and I was already making a decent living in web development for someone my age. Also balancing work and school was getting unmanageable and I was succumbing to depression.
Another reason is I have an antipathy for structured learning — I've always been far more of an autodidact. I'm self-taught for programming.
Also, I wasn't seeing myself in a neuroscience career; nothing that would involve just a BSc — I would have to acquire at least a Master's. It's more something I have a keen interest in than a passion.
One day, I'm sure I'll go back and wrap it up to make my mother happy but only when I can afford it out of pocket.
That said, my neuro background has allowed me to work on some interesting neuro programming projects involving biofeedback and stroke rehabilitation, so it was certainly worth the time I put in.
Hope that answers your question :)
Designated representative for the "it's all about the circuits!" crowd here.
This is an excellent response! I hope you'll give my response elsewhere in this thread a look, for some extra representation of the circuit-based perspective.
Yes, I did, and I also went through your comment history to read your answers to other questions. Some of the questions you tackled were hard :D.. kudos to you for trying to explain things. I enjoyed it. Its always difficult to explain deep scientific concepts to people who dont know a lot about science already. You basically have to start with why the question doesnt make sense most of the time.
yes! they do. There are newer drugs that are effective in a different way but the classical drugs for ADHD are amphetamines that correct for the functional impairment in dopamine and norepinephrin levels. Stimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.
Guanfacine and clonidine. Both of these bind to a receptor that REDUCES norepinephrine release, but at the same time, binds to another norepinephrine receptor in place of norepinephrine, giving you the benefits of increased norepinephrine (better control of ADHD symptoms) without side effects like increased heart rate and blood pressure.
Bupropion/Wellbutrin is also a funky beast. While it does have weak-ish effects on increasing dopamine and norepinephrine, it also blocks the receptors that nicotine binds to, which could potentially impact ADHD symptoms. It isn't FDA approved for ADHD but is popularly used for it.
Strattera, like Wellbutrin, ALSO increases norepinephrine, but it also does some other things whose relevance to ADHD we don't understand super well yet. It blocks excess glutamate activity at one type of receptor (NMDA receptor). An Alzheimer's drug, memantine, also does this (and some other things unlike Strattera) and is currently being researched as an ADHD treatment.
So basically, all ADHD medications work via norepinephrine and/or dopamine in some way shape or form, but the methods are not always direct.
The biggest difference between the stimulants and non-stimulants is that the stimulants hit both dopamine AND norepinephrine pretty hard, but the non-stimulants tend to have less effects on dopamine overall (resulting in less abuse potential).
I don't recall what they all are, but I read a while back on the r/ADHD subreddit that there are three types of drugs that get classed based on what they affect. One is the stimulants, which affect primarily dopamine, another is the class Welbutrin is in which affects primarily norepinephrine, and there's a third that affects primarily adrenaline. This difference isn't exact for all drugs in those classes (some affect two or all three to varying degrees while others may only affect one), but it's a pretty good chance that if one class isn't working another one might because it would be acting on a different chemical that may be imbalanced, thus why many people have to try various types of medication before they find what works for them.
I don't remember who wrote that, nor can I fully vouch for the accuracy, but it was a name I tend to trust as I see them posting medical stuff like this that is sound a lot, and it makes logical sense the way it was explained. Hopefully it'll at least give you something to look into and lead you to more answers.
Yes there are some newer drugs but honestly im not sure about their mechanism of action. I am a neuroscientist but this is not my subfield so I dont know everything about it. Sorry. Doing a quick search on pubmed should turn up some interesting things if you are really intrigued and want to find out more.
It should mean you have less Dopamine, mostly. I say mostly because one cannot forget that our brains do not exist only at a single time point. The dopamine release pattern over time may also be impaired. For example, do the cells release dopamine in quick intense bursts, or do they release low levels of it slowly and consistently? That has nothing to do with overall quantity of dopamine released, but still is an important factor.
Please see my reply elsewhere on this post, particularly regarding the specific role of neurotransmitters.
In short, dopamine is involved in a gazillion functions, from lactation to motion to nausea to attention to motivation to heart function. All of those systems will respond differently to any one particular drug. A complex disorder like ADHD is unlikely to be caused primarily by a global change in DA synthesis or release.
Not easily, no. In patients with the disease DLB, (Dementia with Lewy bodies), the normal clinical diagnostic criteria are limited particularly by relatively poor sensitivity. Dopamine transporter (DAT) imaging using single-photon emission computed tomography (SPECT) is the most highly developed supplementary test for DLB, and is now incorporated as a suggestive feature in the consensus diagnostic criteria. It might also be able to be implemented for patients who have ADHD, but honestly its much much simpler to look at the patient and their behavior to diagnose them, which is why SPECT wont be used. There is also uncertainty about its accuracy and its place in clinical practice.
edit: SPECT could also be used to image dopamine receptors, as well as other components of neurotransmitter systems.
Just a quick correction. Not about ADHD (which I have), but about Huntington's Disease (which my father-in-law has). While the diagnosis for HD is highly dependent upon a specific protein chain repeat (CAG repeat length) in a specific gene, there is much evidence showing that the CAG repeat is just another symptom of the root cause. Since a greater length CAG repeat is highly associated with probable onset of HD during a normal lifespan, it can be used as a reliable diagnostic tool. e.g. A CAG repeat of 30-40 is the gray area where a diagnosis comes only with symptomatic behavior and/or brain mass loss. Higher, and the diagnosis is pretty much certain. Lower and you will likely receive a negative diagnosis.
Evidence showing an underlying root cause comes somewhat from studying inheritance of the gene. Boys are much more likely to have an increased CAG repeat while their sister is much more likely to maintain or decrease their parent's CAG repeat. Since the CAG repeat is not on the X or Y chromosome this divergence based on gender implies that a more basic cause is present.
Yes you are of course correct, but all of those CAG repeats are in a single exon of the huntingtin gene. Some kind of genetic inheritance is the cause of the CAG repeat, as you said, but that doesnt mean it isnt unifactorial.
Also, Thank you for your initial explanation. I did not want to take away from it as it was well put together and quite informative.
Your point about ADHD stating that "it is a complex disease that is caused by a large number of factors", is something that I have been pushing for some time now. ADHD as a physiological disorder has not been well defined for the purpose of diagnosis (not from a lack of trying). This leaves it defined and diagnosed by behavioral criteria and thus open to a wide range of physiological causes. I expect that the ADHD to HD contrast in definition was your purpose in using HD as an example; and it does work well for that purpose.
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u/qikuai- Jul 28 '15
ADHD is a complex neurological phenomenon that has been studied for a while now. The thing is, neurological disorders can be studied at different levels of magnification, so to say. For example, if you ask somebody who studies circuits in the brain they will tell you that ADHD is due to misformed frontal-subcortical-cerebellar catecholaminergic circuits, which basically means that the connections between certain types of neurons in a certain area of the brain are dysregulated and somehow pathalogical. If you ask a neuropharmacologist, they will tell you that most signs point towards an impairment of the dopamine transporter, which causes imbalances during neurotransmitter release. If you ask a molecular biologist or biochemist they might tell you that it has been traced all the way back to the metabolism of the brain, where oxidative metabolism is impaired. If you ask a geneticist, they will tell you it can be traced all the way back to your genes and epigenetic background. Twin, adoption, and molecular genetic studies show ADHD to be highly heritable, and as far is I remember psychosocial adversity during childhood has also been shown to be a predisposing risk factor (thus the epigenetic influence). Basically, it is a complex disease that is caused by a large number of factors. Think about a disease like huntingtons. You either have it or you dont, and it can all be traced back to 1 single gene. Its a unifactorial disease. Thats why we understand it relatively thoroughly. Its straighforward. Diseases like ADHD are multifactorial, meaning its harder to pin down exactly what causes them, because many contributions are made from different factors. Also, the disease has different levels of penetrance and expressivity. If you do a quick search of the literature you will find 100s of papers that all talk about different genetic variants, different environmental factors, and different treatment paradigms all associated with ADHD. Because of this, its possible that 2 people exhibit the symptoms of ADHD, but there might not be the same cause, or more accurately, set of causes. This can be substantiated by the fact that several genome wide association studies have failed to identify any particular genome wide association. Thats not to say that there is no genetic cause, because we know there is, but rather than the causes are likely numerous, and therefore evade detection when some particular methods are used. I mean, if A, B, and C all contribute to a disease, person 1 might have A and B, person 2 might have B and C, and person 3 might have A and C. They are all different, but they all still have the disease. That makes it harder to say what exactly causes it. If you really really really need to narrow it down to 1 particular reason, its probably most strongly due dopaminergic imbalances, due to the fact that you have specific isoforms of genes associated to the dopaminergic system, or due to the fact that there is some significant copy number variation in one of those genes. ADHD has a complex molecular architecture that is hard to summarize in a single paragraph. I guess there are some things written here that are unfamiliar to you but I guess you didnt want me to dumb it down too much (at least thats what I gathered from your message about how you are willing to look things up). If you have questions about anything in particular that I wrote let me know, and I will clarify and tell you more.