Sep 10 2009

ADHD and Brain Chemistry

ADHD (attention deficit and hyperactivity disorder) is somewhat of a beleaguered and misunderstood disorder. The key controversy (and it is mainly a public, not a scientific, controversy) is whether ADHD is an actual brain disorder, a product of environmental factors (bad parenting, too much TV), or a cultural fiction. As is often sadly the case, I find the public debate largely disconnected from the scientific research.

I have no particular bias toward any kind of explanation – whether ADHD is a hardware or software problem, or an observational artifact. I believe all three kinds of entities exist. My only interest is to understand what the science says about ADHD. My reading of the literature is that the evidence strongly supports the conclusion that ADHD is a brain disorder. Of course it is modified by the environment – but at its core, it’s a problem of brain function.

A new study supports this conclusion, but before I get to that let me go over some background. The clinical definition of ADHD, like all behavioral diagnoses, is based upon having a minimum number of a list of characteristic symptoms. This kind of “squishy” diagnosis often fuels the fire of ADHD denial – but in reality many medical diagnoses are made this way. Migraine, which is not a controversial disorder, is diagnosed the same way.

The diagnostic criteria for inattention includes things like the inability to sustain attention to a task and an unwillingness to engage in a task that requires sustained mental effort. The criteria for hyperactivity include things like being very fidgity, blurting out answers before questions are finished, and difficulty awaiting one’s turn. But in addition, these symptoms must cause demonstrable impairment in school or social function.

The challenge in making a diagnosis is that all kids exhibit some of these symptoms to some degree – so some judgment and experience is required in determining if a feature is present to an excessive degree for that child’s age. This subjective aspect to the diagnosis does make it reasonable to ask the question – how do we know this is a real disorder and not just normal variation. Here we get into the difficulty of definition.

To clarify, no one says that ADHD is a disease, or that there is some pathological process going on. It may be just one end of the Bell curve of typical human variation. But the definition of a disorder only requires that there are identifiable features that deviate significantly from the mean and which cause demonstrable problems. In fact, for practical purposes it is not necessary to obsess about whether an individual meets criteria for the diagnosis (are they fidgity enough) but rather to focus on whether they are having identifiable problems, and then address those problems. The concept of ADHD is useful in understanding why certain kids may be having problems and how to address them.

That’s my practical clinician’s approach to many situation. However, in reality, school systems and other institutions need labels and allocate resources accordingly. So even though labels are imperfect and are not strictly necessary to address a problem, the system often demands them.

So what kind of disorder is ADHD? The current concept is that it is a disorder primarily of executive function. The neocortex in the frontal lobes – that part of our brains that most recently evolved, is involved with master decision-making. The frontal lobes are at the top of the hierarchy – it is here that we override our desire to eat cheesecake, we consider the long term consequences of our actions, inhibit our impulses, and focus our attention. And, like all biological functions, there is extensive variation in the degree of executive function in the population. Those with ADHD are at the low end of the Bell curve of executive function.

The last 20 years of research has strongly supported this position. Brain activity levels in suspected brain areas are consistently lower in people with clinical symptoms of ADHD. Stimulants that increase brain activity relieve symptoms and improve outcomes. There is evidence for a genetic predisposition and about 10 genes have been linked to ADHD. Low dopamine in particular has been linked to ADHD.

This brings us to the new study – published in this week’s JAMA, a study by Nora Volkow et al. shows that untreated adults (to rule out the effects of medication) had lower dopamine transporter and receptor activity in key brain regions when compared to typical controls. The results seem fairly robust and confirm what we would predict from our current model of ADHD. So yes, Tom Cruise, ADHD is a problem with brain chemistry.

Dopamine is involved (among other things) with the reward system in the brain. Animals with central nervous systems have a very basic reward system in the brain that makes us feel good when we do something that evolution wants us to do (because it enhances our survival and the spread of our genes). Eating calorie-rich food and having sex feel good and give us a dose of dopamine to our reward centers.

Those with ADHD have been observed to have some behaviors, like overeating and drug addiction, that could be explained on the basis of decreased reward response. Therefore, they need to do more to get the same reward as the average person, so they engage more in reward-seeking behavior. This study, showing lower dopamine activity in the reward centers (like the nucleus acumbens) strongly supports that conclusion.

This study adds to our understanding of ADHD and our confidence in the neuroscience models of what ADHD is. But most importantly, the more we understand the disorder the better we will be able to identify and treat it. Perhaps this may lead to treatments that target dopamine more specifically, for example.

ADHD is a highly emotionally charged diagnosis. The controversy stems partly from the fact that there is much confusion about how such diagnoses are made, the role of treatment trials, and the correlation between clinical criteria and objective measures of brain function. For cost and practical reasons we rely more on clinical criteria and treatment trials than PET scans and function MRIs to make the diagnosis – and the same is true of many entities in medicine.

But often ADHD is dismissed as an excuse for lazy parenting or schooling, as a quick fix to a complex problem, or the “medicalizing” of normal behavior. In my opinion such dismissive attitudes are not well-informed and largely stem from misconceptions about how diagnoses are made in medicine. I also think that emotions run particularly high when kids are involved, and I understand this.

But as is often the case, a thorough and sober assessment of the science is our best guide.

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21 responses so far

21 Responses to “ADHD and Brain Chemistry”

  1. medmonkeyon 10 Sep 2009 at 9:36 am

    Have there been twin studies for ADHD? I know the clinical risk assessment puts a lot of weight on first degree relatives with the diagnosis. As someone with a parent and 2 siblings with ADHD, I am acutely aware that the degree is disability varies GREATLY among individuals with the disorder, but is almost always debilitating to some degree. Ideally we would develop behavioral modifications to cope with inadequacies, but this is sometimes an unrealistic goal.

    I would also say that a major public concern with the diagnosis of ADHD is that all the drugs used to treat it are Schedule 2. The habit-forming nature of methylphenidate and the amphetamines requires a scrutinizing eye be kept on the application of this diagnosis to avoid abuse.

  2. Zelockaon 10 Sep 2009 at 12:13 pm

    Frankly I don’t see that we know enough about ADHD to start shoving drugs at it and especially not drugs at children who are still in the major time of brain development. I also consider it to be one of the most mis-diagnosed conditions out there since the symptoms are so flexible you could easily place 95% of the kids as having it. (BTW pulled 95% out of my butt. Not a really study number)

  3. Steven Novellaon 10 Sep 2009 at 2:17 pm

    The evidence suggests that 5-10% of children have the diagnosis. Like all diagnoses – there is under and overdiagnosis. There is no evidence to suggest that it is being largely overdiagnosed, and in fact studies show that diagnostic validity is pretty good:

    http://www.ncbi.nlm.nih.gov/pubmed/18983672?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

    There are lots of studies showing safety and efficacy of medical treatment for ADHD, and the mechanism accords well with what we currently understand about it.

    But of course it’s easy to emotionalize an issue by using phrases like “shoving drugs at kids.”

  4. Ribozymeon 10 Sep 2009 at 2:31 pm

    Besides having Asperger’s syndrome (something I found out only in my late 30s), I’ve had a significant degree of ADHD all my life, which was specially problematic during my childhood and early teens. I wish my parents had been brave enough to give me Ritalin (I remember seeing the medication at home but I don’t remember ever taking it). During my primary education years (6 in México) I didn’t have learning problems because I understood and memorized everything at a glance, although I had real difficulties solving math problems that required sitting for a while. I got very easily distracted. My teachers either loved me or hated me, because I understood everything very easily but was unable to sit still or being quiet during class. When I entered secondary education (grades 7-9), my ADHD seemed to synergize with my burgeoning hormones and I had serious lerning problems during those years. Stress was also a factor because as an Asperger (well, back then I was just considered weird) I didn’t fit among my peers at a stage of life when one most wants to fit in and socialize. Grades 10-12 were quite a bit easier either because my hormones were reaching a plateau or because I was more adjusted to the changes. College was really easy, but for the fact that I started having depression problems which still exist now in my mid forties. I can’t function for a very long time without taking SSRIs. I suppose that tendency for depression is due to the lower dopamine signaling. Some ten years ago I read that Ritalin is helpful also for adult sufferers of ADHD (I get distracted very easily and tend to lose things often; one develops tricks and rituals to cope with that) and got a physician friend to prescribe me Ritalin for a while. It was really helpful, I became a lot more focused. Alas, my friend got cold feet about prescribing Ritalin for an adult, which could easily be seen to be pandering to recreative use of drugs.

  5. Zelockaon 10 Sep 2009 at 3:04 pm

    Sorry if I seem rude I just remember it from my time in school where they pushed to have me and a little over half the class on these types of drugs during elementary school. Then again I am 32 now so that was a while ago and it may be that my experience is an anomaly.

  6. fidodaon 10 Sep 2009 at 6:46 pm

    What’s funny with kids with ADD and ADHD is that they have no problems playing video games that require high level of attention. This is also true when they do things the like a lot.

  7. Scarybugon 10 Sep 2009 at 7:07 pm

    fiododa, that’s just not true. I am very close to someone with ADD who loves video games and playing the piano, but has trouble concentrating at either for long periods of time.

  8. Barrilon 10 Sep 2009 at 9:54 pm

    fidoda, wouldn’t that just fit with the description based on dopamine receptor and creation problems? With things that a person gets a large amount of enjoyment, it would seem that the dopamine levels could reach a point that grant a level of attention that isn’t present with other activities?

    Alternately, many video games output a great deal of information through many different senses. It could be a sufficient amount of information that when their attention waivers, there is something in the game world that can grab their attention. It would be more difficult for an external source of input to pull attention away, as the difficulty in changing attention from in-game to outside of game is more than just changing attention to different input within the game’s world.

    I could be way off on these guesses, though.

  9. mccorvicon 11 Sep 2009 at 9:58 am

    One problem that I ran into often as a middle school teacher was that nearly every parent of a child that was a bit restless in school claimed it was just ADD right away.

    I had a student that would come into class at 7:30am with a doughtnut and one of those extra-large energy drinks and, as you’d predict, be hyper as all get out. When I suggested to the parent that they try adjusting his morning diet first before anything else I was met with the dirtiest look.

  10. Calli Arcaleon 11 Sep 2009 at 12:11 pm

    Sorry if I seem rude I just remember it from my time in school where they pushed to have me and a little over half the class on these types of drugs during elementary school. Then again I am 32 now so that was a while ago and it may be that my experience is an anomaly.

    Zelocka, I’m close to your age (I’m 34) and have ADD myself, and was in fact medicated for it with Ritalin. So I come from a similar perspective. ;-)

    ADD was kind of a fad diagnosis for a while when we were kids. Almost the way that autism is now. I don’t think actual clinical diagnoses went up, but the *amateur* diagnoses did. I mean the teachers and school nurses saying “oh, this kid must be ADD” and then urging parents to consider medication. I doubt it ever got to where half the class actually *was* on drugs, but I could believe some teachers suggesting the possibility of drugs to the parents of a significant percentage of their students.

    But the drugs are actually pretty well studied. Ritalin has been around for about a half a century, and in addition to ADD, has also been prescribed for sleep disorders. That doesn’t mean it’s the best thing ever, but it does mean there’s a significant body of evidence that can be examined when deciding whether or not to try it.

  11. OdiousMemberon 11 Sep 2009 at 3:20 pm

    As an adult (and of course once a child) with ADHD, in my opinion the continued controversy over this disorder stems not from its scientific foundations but primarily from the stimulant medications used to treat it. I know I have faced skepticism to downright hostility from pharmacists when filling my monthly Adderall script.

  12. trrllon 11 Sep 2009 at 9:07 pm

    I feel like we probably dodged a bullet on stimulant therapy for ADHD, not out of any kind of wisdom, but out of sheer dumb luck. At the time we began treating kids by the hundreds of thousands with stimulants, we had no idea whatsoever whether chronic treatment of children, with a still-developing nervous system, with stimulants was safe. And considering what we now know about stimulants and neurotoxicity, it would not have been in the least surprising if they had all come down with early Parkinson’s or some other nasty neurodegenerative disease.

    The first generation that was treated heavily with these drugs must be well into their 40′s by now, and there’s been no evidence of a spike in neurodegenerative disease. I think we’re in the clear. I suppose that it could still go bad, I think we’d have seen more of a hint of it by now if things were going to be sour.

  13. HHCon 12 Sep 2009 at 12:42 am

    Based on the dopamine theory, sexual promiscuity is a natural result of ADHD. Was the hippie movement useful for American life?

  14. Tyron 12 Sep 2009 at 3:45 am

    There is also the study from Vanderbilt http://www.biopsychiatry.com/dopamine/adhd.html

    The study found the dopamine “running backwards”:

    “We believe that this is important evidence that ADHD can be caused by a functional deficit in the brain’s dopamine signaling pathway,” said Randy Blakely, Ph.D., director of the Center for Molecular Neuroscience.

    The researchers propose that because the altered transporter runs backward and pushes dopamine out into the space between neurons — like normal transporters do when amphetamine, or ‘speed,’ is present — it alters dopamine signaling and contributes to the symptoms of ADHD.

    Turning to a sensitive technology called amperometry that uses a small carbon fiber to “listen in” on how single cells release or transport dopamine, the Galli and Blakely laboratories discovered that the altered transporters were running backward at an exaggerated rate, literally pushing dopamine out of the cell.

    “We think this activity would short circuit the normal synaptic transmission process,” Blakely said. “Instead of the precise ‘pop-pop-pop’ of dopamine being released from vesicles (tiny packets of neurotransmitter), there’s a cloud of dopamine bleeding out, and the dopamine signaling system is not as sharp as it should be.”

    To their surprise, the investigators also found that amphetamine blocks the leak of dopamine through variant transporter. Normally, amphetamine does just what the mutation does — it causes the dopamine transporter to run in the reverse direction.

    The findings offer a new perspective on a conundrum in the ADHD field — the fact that two of the medications that successfully treat the disease have opposing effects on their molecular target, the dopamine transporter. With the normal dopamine transporter, methylphenidate (Ritalin) blocks the ability of amphetamine (Adderall) to make the transporter run backward, yet both drugs are equally beneficial to patients with ADHD.

    But when the transporter runs backward of its own accord — as it does with this rare mutant version — both agents act as blockers and stop the leak of dopamine.

  15. Mark_in_Seattleon 12 Sep 2009 at 4:31 pm

    I agree with Fidoda about the video games. My son is dx with ADD. As far as school subjects, he has the hardest time with phonics and learning reading/writing. And in general, you just can’t get him to focus and pay attention, whether it’s in school, on the soccer field, or whatever. But if he is in his zone, with something like video games or legos or his bakugan toys that he loves so dearly, well then it’s another story – he’s amazing. So I think a different part of the brain must be at work for those activities that he loves so dearly. Or perhaps those activities provide enough stimualation that they override the dopamine problem or whatever. Personally, I’m trying to research natural alternatives – such as magnesium, zinc, omega 3′s and carnitine. Regards – Mark.

  16. pious fraudon 13 Sep 2009 at 9:11 am

    I have a friend who is studying to get her Ph.D and is definitely in the mental illness denial camp, she brings up all the points Dr. Novella warns about in his 5 part series on mental illness denial – she’s of the Szasz variety, not scientology – and I wrote her to read this blog and get her response. She didn’t comment in this section, but I know she won’t mind me pasting her arguments here. this is a perfect example of the denialist strategy:
    “Here are my initial thoughts. And I only read the abstract of the article he cited so I can’t really critique their methods or anything.
    So he says, “My reading of the literature is that the evidence strongly supports the conclusion that ADHD is a brain disorder. Of course it is modified by the environment – but at its core, it’s a problem of brain function.” Then he says,“To clarify, no one says that ADHD is a disease, or that there is some pathological process going on. It may be just one end of the Bell curve of typical human variation.”

    It may just be my reading of it, but those two statements sound a bit conflicting. But besides that, first, the definition of disease and disorder need to be worked out. Lots of things are on the far end of the bell curve, like having your heart in the right side of your chest (but it retains function), being left-handed, and murdering your family, but those are not considered diseases. But I think he is arguing the “harmful dysfunction” idea, which holds 2 criteria for “mental disorder”: 1) there is a dysfunction, generally based on an evolutionary model of natural function, and 2) the dysfunction is deemed harmful by the standards of the person’s culture. So, for example, without understanding how a hallucination works, you can infer it is a disorder with the explanation that it represents something gone wrong with how our perceptual mechanisms are designed to function. One problem with this idea is in determining what is “natural function”. For example, drapetomania – the disease of runaway slaves – was based on the idea that black people were naturally designed to be submissive and to serve,…of course a false idea of what is “natural”. But it illustrates that the whole harmful dysfunction framework is limited by our current cultural understandings of what is “natural”, as well as what is “harmful”. Using the bell curve as the basis for determining what is natural (i.e., most people don’t hallucinate – or don’t claim to hallucinate – so hallucinating is not natural or normal) has similar and other flaws.

    Second, his first statement I quoted underestimates the bi-directionality between biology and experience. There are many examples demonstrating that behavior, experience, and function can alter and determine brain structure – just as the other way around.

    He also makes the comparison between diagnosing ADHD and diagnosing a migraine, as we wouldn’t question the existence or reality of a migraine even though we have no objective markers (in other words, the diagnosis is based on subjective symptoms). But, in the words of Thomas Szasz, behaviors are not and can never be diseases. So, yes, I believe labeling and treating a person’s behavior is very different from labeling and treating a person’s physical complaint of pain. There is a moral component involved in the former that is not involved in the latter.

    He further states, “For cost and practical reasons we rely more on clinical criteria and treatment trials than PET scans and function MRIs to make the diagnosis – and the same is true of many entities in medicine.”
    To clarify, regardless of “cost and practical reasons,” there is no test that is diagnostic of ADHD. That is why we don’t take brain scans to diagnose – because there have been no consistent differences in “ADHD brains” vs. “normal brains” that would allow us to make a diagnosis.

    I’ve got an article that critiques ADHD brain imaging studies. Don’t know if I can attach that through FB or if I’d have to email it to you. But, if you’re interested, it’s only 4 pages and I can send it to you.

    Ok, well that’s my initial take. There’s really a lot to be said in response to his post. I’m sure I just scratched the surface. But thanks for sending me that. It was actually kind of fun”

    Any thoughts?

  17. son 13 Sep 2009 at 11:47 am

    Interesting questions. Nature vs nurture as usual. A “geographic analysis of ADHD in children” done in Milwaukee County shows a surprisingly non-random distribution. Which may indicate environmental causes. See map at http://www.fammed.wisc.edu/our-department/newsletter/fall-2007/geographic-analysis-adhd-children-milwaukee-county.

  18. M. Davieson 15 Sep 2009 at 12:16 pm

    Actually, even though children with ADHD can play video games for a long time (no surprise, since the stimulation is immediate and intense) they are still worse at those games than children without ADHD – they appear to sit still, but their in-game activity is impaired:

    Lawrence, V., Houghton, S., Douglas, G., Durkin, K., Whiting, K., & Tannock, R. (2004). Executive function and ADHD: A comparison of children’s performance during neuropsychological testing and real-world activities. Journal of Attention Disorders, 7(3), 137-149.

  19. Hyperionon 29 Sep 2009 at 11:31 am

    Sorry for the late comment, but I must agree with M.Davies remark above regarding ADHD and video games. I have ADHD, and like many of my (non-ADHD) friends, I love the “Grand Theft Auto” series of video games. The difference between me and my friends is that my friends actually accomplish missions and advance in the game. Me, I start playing, I might even try to complete a mission, but then “oooh look, I can steal a helicopter!”

    But with video games in general, many game feature short missions with clear objectives, multiple attempts allowed with often little or no penalty for mistakes, and frequent rewards (in terms of flashy graphics or movies) after the completion of short tasks. This is of course the sort of situation that someone with ADHD will find attractive.

    It is, however, a major fallacy to conclude that this merely represents a “learning style” for people with ADHD. While this approach may be quite fine for teaching someone with ADHD to push buttons in the correct order, such a strategy is completely useless for teaching most life skills. Further, it should be noted that the expected immediate reward is a large part of the appeal for someone with ADHD. Most life tasks do not come with flashing lights and a cutscene where you save the princess, nor could we expect a college seminar to play cool music and offer prizes every time a student correctly takes notes for each section of a lecture.

    On a related note:

    I’m glad to finally see a science blog that covers ADHD, including rebuttals to many of the common misconceptions out there. The level of misinformation available in popular media is mind-blowing. Part of this may be because the C-II status of most ADHD drugs puts major handicaps on the drug companies’ ability to advertise, and part of it may be due to scientologist and anti-psychiatry movement propaganda (which is often “washed” through more reputable sources first). And there’s the lack of organized ADHD advocacy, for obvious reasons.

    But a lot of it probably stems from the simple problem that accepting the validity of ADHD, and its neuropathophysiology, makes a LOT of people very uncomfortable about the implications with regard to self-control and the extent to which our behavior really is just the interaction of various neurological functions. For someone with ADHD who takes medication, this is easy to accept: on medication, I have a set of neurological functions that most of you take for granted. Off medication, I do not. Being on medication does not really cause any change in who I am, it simply switches on certain neurological abilities. It really does function like an on/off switch, and the subjective effect is quite fascinating from a neuroscience standpoint.

    But I can see why ADHD causes such a visceral reaction from some people. After all, if things like impulse control and sustained attention to detail, which many lay people regard as matters of discipline, are really just a set of executive functions that result from activity in certain regions of the brain…

    And so we get various armchair philosophising (as I have seen repeatedly in the comment sections on other posts here) that attempts essentially to wish away the realities of ADHD, or to pretend that it is merely a personality trait. This makes some people more comfortable, allowing them to continue to live in a world where there is a “mind” and “consciousness” that they control and are separate from “involuntary” neural activity.

    At its heart, it stems from the instinctive, visceral idea that the human mind must be something that sets us apart from those “lower” animals. Reminding people that ADHD is just a problem with a specific set of neurological functions is to remind people that most of their behavior is just the result of interaction of several discrete neurological functions, all using the same neurochemical transmissions found in almost all other animals.

    So it is actually not surprising that people wish to keep the “mind” as the last haven of that which keeps us separate from animals. It is thus difficult to convince deniers to give up this last vestige of humanity and accept that what they see as making us “human” is an organ just like any other, and that our human behavior results from the same sort of neural transmissions found in anything from jellyfish to slugs to dogs to chimps.

    And thus, deniers must claim that ADHD, mental illness, and behavioral problems in general must stem from this mysterious “mind,” because they cannot and likely will never accept that their behavior might be every bit as much a “choice” as when salmon swim upstream to spawn.

    In the end, though, the theory that ADHD is caused by neurological malfunction offers treatment and the ability to lead a more productive life. The theory that ADHD is just a mindset of bad behaviors and lack of motivation that can be cured by just trying harder only offered me (and many others) the option of a lifetime of stocking shelves…or far worse. Deniers, armchair philosophers, anti-medication crusaders and others are probably ignorant of the consequences of their actions. Then again, a few of them are probably quite aware of this. Their motivation eludes me, perhaps fodder for another post from you, or another comment from me.

  20. Hector Moraleson 08 Jan 2010 at 3:18 am

    I can’t speak for anyone else. For me, it was the money. Okay. Here goes.

    I am the guy. I created the “disease” ADHD. [I had to think of something to put on paper as my business plan to get a loan.]
    I figured I would create a disease. Then, I’d create the cure.

    Voilà! Soon, I would earn one quarter trillion dollars selling nothing helpful to fix nothing at all.

    It wasn’t that hard, either, especially for someone who can’t pay attention, constantly fidgets, speaks out-of-turn, daydreams endlessly and craves highly stimulating, often dangerous, thrill-seeking adventures.

    Wish there was a pill I could take.

  21. Hector Moraleson 08 Jan 2010 at 3:52 am

    [One problem with this idea is in determining what is “natural function”... drapetomania – the disease of runaway slaves – was based on the idea that black people were naturally designed to be submissive and to serve,…of course a false idea of what is “natural”]

    Baby you’ve got it. Old Sammy Cartwright knew normalcy if anybody did. His massive, double-blind, controlled tests of slaves vs. non-slaves and their compulsion or lack thereof to bolt, was a rare achievement in the highly regarded, antebellum field of scientific research.

    And what a cure. “If any one or more of them…are inclined to raise their heads to a level with their master or overseer…they should be punished until they fall into that submissive state which was intended for them…”

    “of course a false idea of what is “natural”. Pious, your friend said it all in this little, off the cuff statement, didn’t she?
    OF COURSE.

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