Friday, January 2, 2009

Gene Variations Which Affect Attention Control

A couple weeks ago, I posted some information on a specific gene thought to be connected with ADHD called COMT (short for Catechol-O-Methyltransferase). This gene is located on the 22nd human chromosome, and can exist in different forms. What is important to note is that the amount of stimulant medication necessary for effective dosing for ADHD and related disorders is often dependent on which forms of this gene an individual possesses. To view this (somewhat lengthy) post on COMT, please click here.

In this previous post, I mentioned that the COMT gene codes for an enzyme which goes by the same name. This COMT enzyme has two forms of interest with regards to our discussion, the "Met" form and the "Val" form. "Met" and "Val" are short for Methionine and Valine, respectively, which are two different amino acids seen at the 158th spot on the COMT enzyme.

The reason that this is so important and relevant to the topic of ADHD is that this relatively small difference in enzyme composition can have a huge effect on how much of a stimulant medication is required to reach peak chemical efficiency in a region of the brain called the prefrontal cortex.

The prefrontal cortex is located in the brain behind the forehead, and is heavily associated with the disorder of ADHD. What a recent study found was that individuals with the "Met" form of the enzyme often require significantly less "assistance" from stimulant medications to reach peak efficiency in this critical brain region during cognitive tasks, than do individuals with the "Val" form of the enzyme. To illustrate this, please refer to the diagram below, which was seen in this previous post.:

Now it appears that, in addition to the prefrontal cortex region of the brain, these two variations in this COMT gene are responsible for what goes on in other brain regions as well. This region is called the cingulate cortex. The region of this brain section which we are most interested in for this discussion is about 2/3 of the way back, closer to the center of the brain. This region of interest is around area 31 on this brain map below, which is referred to as the dorsal cingulate. Here, the word "dorsal" means "back", and the word "cortex" refers to the outer layer. As a reference, the prefrontal cortex area of the previous discussion of interest is around region 9 of the brain map below:
There are a couple of differences worth mentioning between these two brain regions. The prefrontal cortex region mentioned in the previous post is responsible for functions such as working memory (which is explained in more detail here), as well as screening out unimportant information and inhibiting inappropriate responses. We can see how this is relevant to ADHD, as improper function on this region can lead to excessive distraction by unimportant stimuli and poor impulse control. To use the analogy of a car, we might think of this brain region as a type of "braking system" for the brain.

If the prefrontal cortex region acts as the brakes, the cingulate region of the brain can be thought of as a type of "gear shifter". In addition to being relevant to ADHD, this cingulate region of the brain can also be a major factor in disorders such as OCD (Obsessive Compulsive Disorder). In the case of OCD, the cingulate region is overactive. As an analogy, think of pushing on a gear shift with too much force that the vehicle gets "stuck" in a specific gear. In the same sense, individuals with OCD often get "stuck" on a certain fixation whether it be washing one's hands repeatedly, counting cracks on a sidewalk, or repeatedly checking to make sure the oven is off.

As an interesting aside, there has been some interesting discussions on the role of the cingulate region of the brain with regards to governing events involving motor control such as hand movements. This may be one of the reasons why individuals with ADHD often have poor handwriting and difficulty taking notes.

There are some differences in chemical function between these two brain regions (the cingulate and the prefrontal cortex) as well. For the prefrontal cortex region, there are relatively few receptors and transporters for the brain chemical dopamine. Dopamine is a key ingredient for proper signaling between neurons, and a specific balance of this chemical inside and outside of nerve cells is critical for proper function. For individuals with ADHD, there is often a shortage of dopamine in the areas in between nerve cells, so this inside-outside balance is off. Many stimulant medications work to "correct" this imbalance by blocking the transport of dopamine from the outside of cells to the inside of cells in specific regions of the brain. In contrast to the prefontal cortex region of the brain, where there are relatively few of these dopamine transporting and receiving agents, the cingulate region of the brain has a much higher concentration of these dopamine-regulating areas.

The reason that the COMT enzyme is so relevant to all of this, is that this enzyme is capable of metabolizing and breaking down the chemical dopamine. We have previously seen that the "Val" form of this enzyme is more effective at metabolizing dopamine than the "Met" form. As a result, individuals who exclusively have the "Val" form, are often more prone to a shortage of free dopamine than individuals with the "Met" version.

What does this all mean?

Several studies have indicated that the cingulate region is very important in monitoring conflict and regulating behavioral control as well as governing challenging decision making processes. With regards to our discussion here, if an individual is taking an online exam and a cricket is chirping outside, the cingulate region is in part responsible for which "stimulus" is more worthy of attention. Therefore, this cingulate region of the brain plays an important role with regards to attentional control.

A brief recap of the study on COMT gene variations on the cingulate brain region:

A comprehensive study was done by Blasi and coworkers to investigate the differences between the "Met" and "Val" forms of the COMT gene with regards to attentional control. They found that individuals who had both copies of the "Val" form of the COMT gene (remember that humans typically possess two copies of a gene, one coming from each parent) had much more difficulty maintaining attention than did individuals who had both copies of the "Met" form of the gene. Individuals who had one "Val" form and one "Met" form fell in between.

Blasi's group found that in order to maintain attention for a prolonged period of time (i.e. screening out distracting stimuli that interfere with the desired task at hand), the "Val" individuals had much more activity going on in this cingulate region of the brain. In other words, this cingulate brain region had to work harder (i.e. was less efficient) for the individuals who had both copies of the "Val" form of the COMT gene, than for those who had one copy of each. Individuals who were fortunate to have both copies of the COMT gene be of the "Met" form showed the most efficient (i.e. less work needed) cingulate region of the brain, and were more effective at maintaining attention to the desired task at hand.

What is interesting to note is that this group tested the subjects on different tasks which required varying degrees of attentional control. This was done by asking the individuals to analyze the relative orientation of different sized arrows on a computer screen (see here for the the diagrams used in the study). Notice that there are three different sizes of arrows, in which seven small arrows make up a medium sized arrow and six medium sized arrows comprise a large arrow. Subjects were asked to answer which direction a given-sized arrow (either "small", "medium" or "large") was facing. Note that for the "easy" attention tasks, all 3 sizes of arrows were pointing in the same direction, while in the "medium" and "hard" attention-based tasks, the different-sized arrows were pointing in different directions.

Results of the attention-based study: The study found that the genetic effects were much more pronounced for the difficult attention control tasks than for the easier tasks. In other words, individuals with the "Met" forms of the COMT gene had a much less difficult time with this task than did individuals with the "Val" forms of the COMT gene (that is the cingulate region of the "Met" individuals required less brain activity to complete the task than the cingulate region of the "Val" individuals).

This is analogous to the results from a brain activity study involving the differences in the "Val" and "Met" gene forms on a working memory task, which utilized the prefrontal cortex region of the brain (you can find the blog post on this study here). Based on this prefrontal cortex study, the more difficult the working memory task, the more pronounced the difference between the "Met" and "Val" individuals (like in the cingulate study, the "Val" individuals' brains had to work harder). Brain activity in both studies was determined by measuring changes in blood flow to these brain regions required to complete the task, using an oxygen-detecting system (larger increases in blood and oxygen flow to a specific brain region signify harder work by that portion of the brain).

Key differences between the two brain regions regarding Val and Met differences:

While the two studies of the two different brain regions and their respective tasks (the prefrontal cortex and working memory tasks vs. the cingulate region and attention control tasks) shared a high degree of overlap in their results, there were some key differences:
  • While individuals with the "Val" form of the COMT gene required greater effort in their prefrontal cortex region of their brains (as detected by blood oxygen sensors) than those with the "Met form", this overall increase in effort did not correspond to worse performances in the tests by the "Val" individuals. In other words, for tasks involving working memory, it appears that while "Val" individuals have to work harder, they can still perform at comparable levels of accuracy to "Met" individuals. However, "Val" individuals may have a more difficult time when it comes to the cingulate region, as there was a connection between an increase in required brain activity and actual performance on these tasks. In other words, "Val" individuals could be out of luck when it comes to matching performances with their "Met" counterparts when it comes to functioning during very difficult attention-maintaining tasks. Of course this is not to say that practice, training and medication treatment cannot overcome at least some of this inherent genetic disadvantage.

  • When it comes to task performance requiring attention and working memory, it appears that differences in dopamine-governed signaling processes (such as those arising from "Val" or "Met" forms of the COMT gene), it appears that accuracy differences in performing tasks is more pronounced in cingulate regions of the brain, where differences in speed, reaction time and even premature decision-making are more evident in the prefrontal cortex region of the brain.

  • Within the context of this post, it suggests that "Val" individuals are more prone to slower processing, poor reaction timing and impulse control on tasks involving the prefrontal cortex (such as tapping into working memory in tasks such as recalling and utilizing stored information such as math formulas or physics equations), and more likely to be error-prone with regards to tasks involving the cingulate region (such as discriminating between multiple conflicting stimuli and maintaining attention to the "correct" one).

  • Taking the above one step further, this possibly suggests that if an untreated ADHD individual who has the "Val" version of both genes was taking a physics test, he or she could likely perform in a comparable manner to that of a similar individual with the "Met" form, if he or she had extra test time. This is because this type of test would likely involve working memory (i.e. recalling and then using an appropriate formula for a particular physics problem). However, if a continuous external distraction was present (such as a loud air conditioner or a flickering light or an attractive member of the opposite sex seated nearby), having extra test time would be less likely to even the playing field for our poor "Val" individual. This of course, may be stretching and over-simplifying quite a bit (of course we know that there are way more factors involved than just this), but these somewhat subtle genetic differences could possibly have some implications when it comes to discerning and providing accommodations for individuals with learning disabilities, especially in an academic or work environment.
These findings have medication implications as well. Based on the Prefrontal Cortex / Working Memory studies with regards to the "Val" and "Met" forms of the COMT gene, we have seen that differences in ADHD medication dosage are affected, with "Val's" typically requiring more stimulant medications than "Met's" to achieve optimal dopamine balance. However, in the cingulate brain region, another key signaling chemical called serotonin also comes into play. As mentioned previously, the cingulate region is thought to play a role in OCD, and medications of the antidepressant variety (which often boost serotonin levels and can actually indirectly reduce dopamine production, as serotonin and dopamine can sometimes act in a "push-pull" manner, where an increase in one can decrease the other) are often utilized as a medication treatment option.

This is why medication treatment strategies, can get hairy with regards to this cingulate region. On one hand, we want to tune down the dopamine-destroying effects of the "Val" form of the COMT gene in an attempt to regulate attentional control, while at the same time keep this cingulate region in check so a chemical imbalance of serotonin doesn't force this region into overdrive and result in or exacerbate OCD behavior. That is why some of these studies tying down the effects of variations of specific genes to specific brain regions can be such useful tools in determining medication levels.

I am personally convinced that in the future, individual genetic screens will become more commonplace and will play much more of a role in governing the selection and dosage of specific ADHD medications. As we begin to pin down more and more gene forms to specific regions of the brain, we will certainly be armed with more tools to fine-tune individual treatments for ADHD and related disorders and eliminate some of the guess-work in selecting medications and other treatment options.