Retrospectacle: A Neuroscience Blog

[I figured that some of you may be new to Retrospectacle due to the blog scholarship contest. I am also writing a manuscript and about to leave to give a talk in Antwerp. So, I thought I might repost a few of my more thought-provoking neuroscience posts today. I hope you enjoy them. -Shelley]

Attention deficit hyperactivity disorder (ADHD), currently the most common childhood-onset behavioral disorder, is nothing if not controversial. Nearly every aspect of ADHD from diagnosis to prevalence to medication, and even its mere existence, is disputed by at least one ‘concerned’ group. And honestly, who could blame parents for being hesitant to medicate their young children, especially since medications come with risks? However, ADHD is a very real (and prevalent) disorder which has discrete neurochemical and, as more and more research is suggesting, genetic causes. It has been linked with one neurochemical in particular.

What neural structures are theorized to underly the symptoms of ADHD? How is ADHD treated, and how does the most popular drug for it, Ritalin, work?

(Continued below the fold…)

Reduced Brain Activity in ADHD Patients

ADHD affects from 5-10% of children and adolescents, with boys 8 times more likely than girls to have it. The disorder is marked by an inability to focus attention and hyperactive/impulsive behavior. Often these symptoms are paired with poor social skills and difficulties at school, which makes for a very complex situation. One early study in 1990 discovered that brain activity was 8.1% lower in 30 of 60 brain region in adults who suffered from ADHD (measured by global glucose metabolism). The regions with the most significant decreases in activity were the premotor cortex and the superior prefrontal cortex (shown below, circled), which are regions which (among other things) mediate impulse control. That same year Biederman et al. reported that 28.6% of parents who are diagnosed with ADHD have a child who also has the disorder; the cautious suggestion was made that ADHD may have some genetic underpinnings. The next 17 years would lend much evidence to that effect.

So far over 10 genes have been suspected to be involved in the manifestation of ADHD, and many of these genes center around dopamine receptors or dopamine transporting molecules. Also, there seems to be no one gene which guarantees ADHD, but rather certain genes have been identified as denoting susceptibility to ADHD. (For the specific genes and there locations, go here.) Some of the genes may increase dopamine receptors in certain parts of the brain which may have the effect of depleting dopamine–which, as you will see, is an important player in ADHD.

Dopamine and Norepinephrine

ADHD was found to be the result of a deficiency of a specific neurotransmitter — here, norepinephrine. Like all neurotransmitters, norepinephrine is synthesized within the brain; however norepinephrine synthesis requires dopamine as an intermediate step. Specifically, the basic building block of each norepinephrine molecule is dopa; this molecule is converted into dopamine, which is then converted into norepinephrine. This is the normal process. Theoretically, if this dopa-to-norepinephrine synthesis is altered (say by certain genes), low levels of norepinephrine and ADHD-like symptoms could occur. Conversely, drugs which provide extra levels of norepinephrine relieve the symptoms of ADHD.

Its likely that the full spectrum of ADHD symptoms is not solely attributed to the prefrontal cortex, but rather entire pathways which interact together. These pathways do include the frontal/prefrontal areas (attention, impulse control) but also the limbic system (regulates emotions), the basal ganglia (this is the brain’s “router,” directing information), and the reticular activating system (affects attention and impulses, motivation). Since these areas communicate with each other, its likely that neurochemical problems in one area may affect others.

Drugs for ADHD

Ritalin and many other popular ADHD drugs (ie, Adderal) are stimulants: they make the brain produce more norepinephrine, relieving the symptoms of ADHD for as long as the drug is in the person’s system. About 4 million Americans are currently on Ritalin or a similar stimulant, and about 70% of those diagnosed with ADHD respond to this class of drug. Like any drug, there are costs and benefits to treatment which should be weighed with a health provider. According to the graph below, the United States and Canada have seen sharp increases in Ritalin prescriptions over the past few years.

Other ADHD drugs (like Strattera) are selective norepinephrine re-uptake inhibitors, which means it prevents norepinephrine from being degraded in the synapse. A potentially promising new ADHD drug (modafinil) was recently abandoned during clinical trails just this month when one of 933 children taking the drug developed a serious skin condition. This drug would have been an alternative to the stimulant variety, and focused more on producing states of wakefulness.

Environmental Effects?

Interestingly, the mystery of ADHD doesn’t end with genes and neurotransmitters, as there is a well-documented environmental effect. For example, babies born prematurely face a significantly greater risk of developing ADHD than full-term babies (socioeconomic status was controlled for). Infants born at “34 to 36 weeks’ gestation had a 70% greater risk of developing ADHD. And babies born before 34 weeks were nearly three times as likely to develop the disorder as those born at term.” However one theory states that premature babies are a higher risk for hypoxia in the womb, which in animal models led to increased dopamine receptors in the brain. More dopamine receptors would, in turn, mean less norepinephrine in the brain as the required substrate (dopamine) would have a higher likelihood of being bound or degraded before it could be synthesized into norepinephrine.

One last mention: an interesting study conducted at Chicago Medical School suggests that children diagnosed with ADHD who do receive Ritalin have a reduced likelihood of developing a drug or alcohol problem in adulthood. It is thought that the stimulants actually reduce the pleasurable effect that the drug elicits from the brain, making drug-seeking behavior and addiction more unlikely. Another explanation is that the stimulant conveys improved impulse control which reduces the likelihood of partaking in risky behaviors like drug abuse, and increases the likelihood of performing well in school and developing positive social skills which would deter drug abuse.

Comments

#1 Ed Yong
October 10, 2007

Wasn’t there a reasonably-sized study that came out just a few months ago on food additives and ADHD and found a significant association between the two? Anyone care to tell me if it was any good?
#2 Jeremy E
October 10, 2007

Thanks for the repost! It was truly fascinating for me, especially since both my brother and dad have ADD.

By the way, I’m a new reader to your blog (added to my RSS about a week ago). Keep up the great work, I love it so far.
#3 Walter Sear
October 10, 2007

Another explanation for the reduced drug use that has been suggest is self-medication – both directly for the ADHD (ie- stimulants), and as a coping mechanism for an overly distractable world (in the case of alcohol and other nonstimulant drugs).
#4 Tom B
October 11, 2007

Perhaps the tendency towards ADD is heritable– and biochemical– but I’ve always felt ADD might be connected to behaviors, like too much TV. Am I dead wrong? Has this been the subject of a well-controlled study?
#5 Terrance
October 11, 2007

Thanks for this. I was diagnosed with ADD (inattentive type, no hyperactivity) as an adult, five years ago. I spent 30+ years undiagnosed, struggled through college, got fired from job after job, and then the veil was lifted. I only wish I’d gotten treatment as a child, instead of having decades of lost time. I’d give anything to have even 10 years back.
#6 Jonathan
October 12, 2007

Dopamine is strongly associated with basically all forms of addiction and compulsive behavior. The increased numbers of dopamine receptors in the ADHD child’s brain would leave them more susceptible to the addictive effects of any drug that released dopamine, i.e. stimulants and depressants. Considering that Ritalin is a kissing cousin to crystal meth, it is not unreasonable to conjecture that the frequent use of Ritalin would burn out the pleasure-sensing dopamine receptors in the brain. This is seen with meth an cocaine addicts, in that they require drugs in order to reach orgasm. In the case of ADHD patients, any new drug attempted would not feel good enough initially to trigger the first stages of an addiction.
#7 KirkT
October 12, 2007

I’m diagnosed ADHD and, although my wife was never diagnosed, we are pretty sure she is as well. My 5 year old son is showing big-time symptoms but then again, he’s 5 so….

I also have a 1 year old daughter and another girl on the way so I figure we’ll see about this genetic thing (at least as far as we’re concerned).

I’m anxious to see where my son is going with this behavior, as I don’t want him to suffer through life as I did, however, as you mentioned, putting him (and possibly my other children) on lifelong medication is a concern.

I’ve been on a few of the meds, and the only one that seemed to show any benefit to me was Ritalin, however, not enough to say on it as I’ve already built, over the years, a system of compensation that addressed most of my issues.
#8 DuWayne
October 13, 2007

Thanks Shelley, for the repost, you are so the neuroscience queen!!!

Tom B -

As with most neurological disorders, certain stimuli can definitely cause an increase or help manifest the symptoms. But it has no more to do with causing ADHD/ADD, than having a few drinks, causes alcoholism.

I have rather severe ADHD and believe me, I was not allowed to watch much of the television. I have also spent much of my life without a television at all, much preferring to read instead. I also don’t play video games as a rule, since I played them for the first time several years ago and went on a binge.

I should also note that my biological father and nearly every child he produced (they are legion) have ADHd. All of them had drastic variance in their upbringing, as their father was quite the philanderer (blessedly, he never laid eyes on me, until I was eighteen). In contrast, my maternal brother, raised in much the same way as myself, does not have ADHD.

I will try to find links, but yes, studies have been done. There is no evidence of causality, some evidence of triggering, or more accurately, aggravation of existing symptoms. (Anecdotally, when I went on my relatively short video game binge, my symptoms got really bad.)

Terrence -

I’m with you on that. What bothers me the most, is that I was diagnosed as a child, but my parents didn’t buy it. So I was raised to think it was a load of poo and if I just tried harder, it would all work out. Finally decided to screw it all, when I failed pre-algebra for the third time, in spite of the fact that I could answer all the questions and get every one right, because when I showed my “work” it wasn’t done the way I was told it had to be done. Never mind that that way made no sense to me. Never mind that I was perfectly capable of doing elementary calc. I got abysmal grades, in spite of near perfect test scores, because I literally could not manage to do homework. So I dropped out of school and decided to start hitchhiking around the country (a little in Europe too). Sixteen years later, with a five year old and one coming in December, I am finally trying to get a college education.
#9 Ichthyic
October 15, 2007

there was a very interesting site where an adult with ADD talks about using the only available NRI (Strattera), and has some very interesting commentary (pro and con) about initial dosages and whatnot.

sounds promising, if a bit on the expensive side if you don’t have health insurance.

http://www.crazymeds.org/strattera.html
#10 Ichthyic
October 15, 2007

…clarification:

only available NRI for ADD, that is.
#11 Nathaniel
October 15, 2007

I have been diagnosed with ADD and have eventually come to the conclusion that the so called “symptoms” are little more than boredom. A child with ADD can concentrate, they just don’t want to concentrate on the boring stuff the teachers and parents are suggesting they do. For instance, I would ignore my homework to play games. I could remember stats, names, moves, etc… of any and all characters of a given game I was interested in at the time. That involves quite a bit of concentration.

Now, this isn’t to say that there isn’t a different between “normal” and ADD kids. I have noticed one interesting chemical difference: Stimulants and depressants seem to work backwards on us. For instance, antihistamines make most people drowsy, they amp me up. If I drink ANY caffeine, I will loose consciousness father quickly. A good example is the difference between giving a kid with and without ADD aderol. The one with will become more calm, the one without will become more hyper. This is the only difference I’ve noticed. The odd part is that I’ve never seen any studies that mentioned this.

One interesting thing is that many people with ADD self-medicate with stimulants like caffeine or nicotine both of which do help with this supposed disorder.

I’ve found that being taught discipline and learning how to learn is all that is really needed to cope with ADD. I’ve been unmedicated for a very long time now (quit in high school). It was tough but I just couldn’t stand the pills anymore. In the end it came down to interest and desire. If you are interested in it and you want it bad enough, you’ll pay attention (as evidenced by the video game example).
#12 Ichthyic
October 15, 2007

I’ve been unmedicated for a very long time now (quit in high school). It was tough but I just couldn’t stand the pills anymore. In the end it came down to interest and desire. If you are interested in it and you want it bad enough, you’ll pay attention (as evidenced by the video game example).

what you’ve basically just said is that you’ve managed to overcome a handicap with hard work.

how much less effort do you think you might have had to muster to maintain focus if you had continued to take norepinephrine boosters or uptake inhibitors, I wonder?

if we compare to any other handicap, say poor vision, how much easier is life with a pair of glasses as opposed to squinting to see clearly?

A child with ADD can concentrate, they just don’t want to concentrate

this is not correct. You might have been misdiagnosed (it happens), but there is a real chemical imbalance here that is diagnosable and treatable, and results are obtained.

ergo, it isn’t just a mater of material and concentration level.

I understand the drive against the idea of “overmedication”, but there is also the issue of straddling someone with an unnecessary handicap that might have been easily treated, as well.
#13 Nathaniel
October 17, 2007

Nah, I know I’ve got it specifically because the medication works. I know it helps. But I began to develop a resistance to it and eventually the dosage was so high that it gave me migraines. I also didn’t like the way it made me feel… like a zombie.

My point is that kids with ADD can concentrate on things like video games because the kid is interested in them. School is boring, games are fun. The kids are simply going to abandon boring activities for more interesting activities. When they can’t find something fun to do, they’ll make their own fun.

I know the medication works, I’m just one of the people who believes that ADD/ADHD is actually a natural deviation in human brain chemistry. I prefer not to think of it as a handicap. In fact, thinking about it as a handicap gives kids with ADD/ADHD an inferiority complex. “here, there’s something wrong with your brain, you have to take pills to fix it, and we’ll give you special help in school.” Man it took me ages before I was able to admit to myself that I was a perfectly intelligent person.

Alright, I’ll contend that ADD is real. That there is something wrong with our brains and that it can be treated with medication. However, I believe that the current treatment for ADD/ADHD is… lazy at best, and psychologically damaging at worst. What is helpful, is “overcoming the handicap” as you put it. Now I don’t need the medication, I just have to apply myself. That being said, this isn’t what this post was about, so I’ll stop there for the sake of keeping things relatively on topic.

back on topic:
I am fascinated by the fact that certain areas of the brain show decreased activity. I wonder if the comparison is made against adult brains or against brains of kids with and without ADD. Naturally, kids will have decreased levels of activity in the regions of their brain that govern impulse control and decision making. If it is true that kids with ADD have even lower levels of activity in these regions of the brain, then that is HUGE news. Essentially the cause of decreased attention span would be a “no-brainer” (terrible pun intended).

I also can’t help but wonder what impact ADD has on rates of teenage depression. Obviously if neurotransmitters involved in pleasure are effected, it would have at least some effect on a child’s mood. That would be an interesting study.

In any case, I’m not bashing anyone. I’ve always been fascinated with the subject, mostly because research in this field could directly effect me… and my kids, because I know it can be hereditary. I am also fascinated by neuroscience. I’ll certainly keep coming back and reading more as it comes. Keep up the good work.
#14 Ichthyic
October 20, 2007

I believe that the current treatment for ADD/ADHD is… lazy at best, and psychologically damaging at worst.

this being a science blog, you might want to actually support that with something other than personal anecdotes. There is a LARGE body of literature looking at the effects of even the older drugs like ritalin, and the long term side effects seem pretty minor comparatively.

I too grew up with ADHD, took ritallin for 8 years, and never had a problem with “boring” subjects; I don’t agree that school is/was boring when I was younger at all. However, I did go on to get a graduate degree in Zoology, for whatever that’s worth.

Moreover, I don’t think you would find a large difference between ADD sufferers and those who don’t as to whether things like vid games are more appealing than schoolwork. Watching TV was far more popular than schoolwork even before computer games.

they’re DESIGNED to stimulate interest in ways that schoolwork simply can’t.

I don’t doubt (considering I spend a bit of time playing them NOW – and I’m over 40), that if they were around when I was younger, I also would have spent a lot of time playing them. got nothing to do with ADD.

Bottom line, I think you might have some issues with having been treated for ADD; harbor some resentments, maybe. While exploring those, I wouldn’t recommend you overgeneralize about the usefulness of treatment for others.

I’ve always been fascinated with the subject, mostly because research in this field could directly effect me… and my kids, because I know it can be hereditary.

there is some suggestion that epigenetics might be involved (like with Autism), which complicates the “heritable” aspect of it. If you are really interested in the subject, you might want to look at that.