ADHD, Gender, and the SLC6A2 gene

We are currently plowing through the four candidate ADHD genes listed below which have been investigated for gender dependence based on an article by Biederman and coworkers. The four genes are:

• SLC6A4 Gene
  
• COMT Gene
• SLC6A2 Gene
• MAOA Gene

We have seen in previous posts that both the COMT gene, and to a lesser extent, the SLC6A4 gene have exhibited a gender dependent behavior with regards to the disorder of ADHD. In other words, certain forms of these genes tend to turn up at a higher frequency in males with ADHD than in females with ADHD. While both SLC6A4 (which is often referred to as a Serotonin Transporter Gene or SERT), and the COMT (short Catechol Methyltransferase, an important enzyme of relevance to ADHD and related disorders) gene effects on ADHD are suggestively greater in boys, the SLC6A2 and MAOA genes are believed to have a greater impact on ADHD in girls. We will be investigating the SLC6A2 gene here:

Location of the SLC6A2 gene:
SLC6A2 is a gene located on the 16th human chromosome. It is responsible for coding the important protein Norepinephrine Transporter Protein 1, and hence, the gene (as well as the protein that it codes for) frequently go by the abbreviation NET.

Clinical relevance of this SLC6A2 gene:
Norepinephrine is an important signaling agent in the nervous system, and deficiencies of this important chemical are often seen in various brain regions of individuals with ADHD. The protein is analogous to other proteins we've previously discussed, such as the Serotonin Transporter Protein, which is often abbreviated as SERT (which is coded by the SLC6A4 gene which was previously mentioned), and the the Dopamine Transporter Protein (DAT), which we've discussed in other previous posts. The NET, SERT, and DAT proteins are responsible for clearing Norepinephrine, Serotonin and Dopamine from the areas in between nerve cells and into the surrounding cells themselves, which aims at establishing an optimal balance of these three signaling chemicals in and out of the cells.

This is especially important and clinically relevant to ADHD, where the signaling chemicals (especially Norepinephrine and Dopamine) are often out of balance, often exhibiting a sub-optimal concentration of these signaling agents on the outside of the cells. Many stimulants and other ADHD medications work by correcting this imbalance by targeting these protein transporters which shuttle the signaling chemicals in and out of the cells and surrounding areas.

However, different gene forms can actually affect the activity of these shuttling transporters as well, which can disrupt the balance of these important neuro-signaling chemicals Norepinephrine, Dopamine, and Serotonin. As a result, different forms of the genes that code for these transporter proteins may actually play a role of how great the imbalance of these signaling chemicals is, which can affect how much of a particular medication is actually needed to correct these imbalances. In other words, the amount of stimulant medication one may need for ADHD may ride, at least in part, on which form of COMT, NET and DAT genes that particular person has. For a more visual and detailed look at this gene-medication relationship, please see this earlier blog post on titled ADHD genes influence medication dosage.

Other disorders associated with the SLC6A2 gene:
Anorexia:
There is widespread discussion as to the overall prevalence of eating disorders in individuals with ADHD compared to the general population. However, several studies have linked ADHD to significantly higher rates of eating disorders. If this holds true for the population, another study of potential interest may involve the SLC6A2 gene. A particular form of this gene (referred to by the alternate term norepinephrine transporter gene in the paper) was associated with doubling the risk of developing anorexia nervosa.

Orthostatic Intolerance:
Orthostatic intolerance is a disorder in which noticeable physiological differences (heart rate, lightheadedness, fainting, etc.) occur as a result of postural changes (i.e. going from laying down or sitting to standing). Of course, some of these signs occasionally affect everyone, but for some individuals, the differences are much more pronounced and much more severe.

According to a study done by Shannon and coworkers, it is believed that the SLC6A2 gene (again, called norepinephrine transporter in this paper) may play a role in the effects of orthostatic intolerance. A mutant form of this norepinephrine transporter gene resulted in around a 50-fold reduction in functional ability of the norepinephrine transporter protein coded for by this mutant form of the SLC6A2 gene and was susceptible to major changes in norephinephrine levels and pronounced physiological changes upon changing postural positions (to the standing position). As a result, a fully functional SLC6A2 gene is apparently critical in regulating stable physiological functions in individuals.


Male vs. Female Differences of SLC6A2 and ADHD:
Like the SLC6A4 gene (and unlike the COMT gene) mentioned previously, the SLC6A2 gene showed statistically significant gender-based differences in preliminary tests, but failed to reach statistical significance upon a more detailed analysis. However, the authors of the study were quick to point out that there were gender-based differences in a specific sub region of this gene. Nevertheless, we must keep in mind that this gene, should it actually influence gender-based differences in ADHD patients, would play a much more minor role in the process than would other genes such as the previously-discussed COMT gene and the soon-to-be discussed MAOA gene.

As a note of potential interest, animal studies have actually shown differences based on analogous forms of this gene. For example, a study on rats (which, in general, shows a surprisingly high degree of overlap with human psychological disorders), showed that there was a gender-different responses to stress, even after gender-based hormonal differences had been taken into account. In addition, another analogous rat-based anxiety study (note that we previously discussed how females with ADHD exhibit more comorbid anxiety disorders than do ADHD males) showed that female rats without the SLC6A2 gene were much more prone to exhibiting behaviors of fear and anxiety than were male rats without the gene.

This possibly suggests a greater gender dependence of this gene, that is a greater "need" for a fully functioning SLC6A2 gene in females than in males. This may have potential implications in ADHD individuals, (many of whom exhibit some sort of anxiety-related disorder alongside their ADHD) by demonstrating a gender-based genetic influence into the mix. In this blogger's opinion, it is possible that genetic and clinical screenings for the SLC6A2 gene may be potentially useful factors in predicting one's likelihood of developing ADHD with a co-occurring anxiety disorder in the near future.

In the next post, we will finish our discussion of the four gender-based ADHD genes by going over the last gene of the series, the MAOA gene.

ADHD, Gender and the COMT gene

We have previously introduced a list of four ADHD genes which are being investigated for gender-specific effects. A list of the four can be found below:

• SLC6A4 gene
• COMT gene
• SLC6A2 gene
• MAOA gene

In the previous post, we investigated the SLC6A4 gene, which is located on the 17th human chromosome, and has a possible (but, at the current time a statistically questionable) preference towards being expressed in ADHD males than in ADHD females.

The second gene on the list, the COMT gene, is also believed to have a male-favoring genetic effect with regards to ADHD individuals. The COMT gene is located on the 22nd human chromosome. "COMT" is actually an abbreviation for catechol methyltransferase, which is an important enzyme involved in a number of neurological functions which have numerous ADHD-like implications. This important enzyme is coded for by the COMT gene (many genes share a name with the proteins which they encode). Unlike the SLC6A4 gene, this COMT gene has more grounds for statistical significance, both in gender-dependent and overall studies of genes believed to be associated with ADHD.

We have discussed the COMT gene and its role in ADHD in previous posts. We have also explored the possibility that COMT gene variations may affect attention control. Additionally, the presence of a specific form of the COMT gene, combined with a low birth weight, may be correlated to a higher prevalence of conduct disorders (aggressive, violent, oppositional and even criminal behaviors), which are sometimes seen at higher-than-normal levels within a subset of the ADHD population. Finally, different variations of the COMT gene may influence medication dosage levels for stimulants and other ADHD drugs.

Gender specific effects of the COMT gene and ADHD:

It is important to note that there is a fair amount of diversity in individual genes among the human (as well as other species) populations. Many of these genetic variations do not exhibit direct effects or physiological differences. However, in some cases, variations caused by a single bit of DNA in a key region of a gene can have significant effects. Such is the apparent case with the COMT gene.

Individual pieces of DNA (or nucleotides), are numbered for reference purposes. For the COMT gene, the Val158Met variation (also known as a polymorphism, which is another word for a variable form of the same gene), has been studied relatively extensively. "Val158Met" essentially refers to a DNA sequence change at the 158th position in the COMT gene which results in either a Valine (Val) or Methionine (Met) amino acid at a specific location in the COMT enzyme. This single DNA change in the COMT gene (and subsequent single amino acid change in the COMT enzyme) can result in drastic changes in the COMT enzyme effectiveness. This slight change can have effects on executive brain functions, response to morphine and other pain medications (as well as other drugs, as mentioned in a previous blog post titled ADHD genes influence medication dosage), differences in the overall pain response (among many other factors) and may even play a role into one's predisposition towards cannabis use.

Out of the "Val" and "Met" forms of the COMT gene (and resulting enzyme), there are believed to be gender-related differences. According to a publication on gender-based gene effects in ADHD, Biederman and coworkers found that males with ADHD had a greater likelihood of carrying the "Met version" (or allele) of the COMT gene than did females with the disorder. Another study by Qian and coworkers saw similar results. In addition, the Qian study found that the "Val "form of the COMT gene showed up at higher frequencies in females with ADHD than in males with the disorder.

Taking this one step further, the Met allele of the COMT gene has been tied to impulsive behaviors and aggression, two behaviors more commonly associated with males. Interestingly, a recent study just came out, which found the Met form of COMT gene to be associated more with the inattentive subtype of ADHD, while the Val form of the COMT gene was more connected to oppositional defiant disorders (which are often connected to the hyperactive/impulsive or combined subtypes of ADHD). As a result, the specific allele one has of the COMT gene may be a potentially useful tool as far as predicting which subtype of ADHD a person would be predisposed to, should they actually be diagnosed with the disorder.

Given the numerous associations of COMT in areas related to (as well as unrelated to) ADHD, we should remain on the lookout for future studies regarding the gene. The Val158Met polymorphism of this gene continues to be a hot topic of discussion and study. Additionally, the fact that a number of these associations have gender-based implications, makes COMT potentially the strongest of the four ADHD genes previously mentioned which are believed to have gender-dependent effects and expressions.

In our next post, we will investigate the SLC6A2 gene and its role on the gender dependence of ADHD. Unlike the COMT and SLC6A4 genes we've just discussed, which both have a predilection towards males with the disorder, this SLC6A2 gene is believed to have more of an influence on females with ADHD.

ADHD gene SLC6A4 favors males over females

In our last post, which asked the question "Are ADHD genes Gender Dependent?" we introduced four genes believed to be associated with the disorder of ADHD:

• SLC6A4 gene
• COMT gene
• SLC6A2 gene
• MAOA gene
  

In the next four posts, we will investigate each of the 4 ADHD genes listed above.

SLC6A4 gene, gender effects, and ADHD:

Out of the four genes listed above, the SLC6A4 gene has the least gender-based effects. The authors of the original paper on gender effects of four genes actually concluded that the gender specific influence of SLCA4 gene was not statistically significant. Nevertheless, the authors briefly noted that there was a greater influence on males than females for this particular gene (in the summarizing abstract portion of the paper).

The particular region of investigation on the SLC6A4 gene, which is located on the 17th human chromosome, was at a specific marker rs2066713 (If you are not familiar with this terminology, this is not important, it is just a way of citing a specific region of DNA and can be used to pinpoint a more exact location on a gene for studies on genetic variations, mutations, etc.). According to the study, at this specific marker on the SLC6A4 gene there was a higher likelihood that ADHD boys would receive the DNA base thymine ("T" for short) at this particular location than did ADHD females. This suggests that this "T" form (or "allele", which is a particular form or variation of a gene) at this particular spot on the 17th human chromosome which contains the SLC6A4 gene is more likely to be passed on to males with ADHD than females with ADHD. In other words, this "T" form of the SLC6A4 gene may be more associated with ADHD in males than in females. Of course, we must reiterate, that although a gender difference was observed, it was not sharp enough to be considered statistically significant, according to the original study.

Some other thoughts about the SLC6A4 gene and potential relevance to ADHD symptoms and behaviors:

• The SLC6A4 gene is often referred to by other more common names: the serotonin transporter gene (also abbreviated as 5-HTT, Serotonin Transporter, and SERT) is believed to be associated with a number of depression-related mechanisms. Interestingly, the link between the serotonin transporter gene and depression may also be susceptible to stress and other environmental factors. This gene is responsible for coding for and ultimately producing a serotonin transporter protein, which is frequently implicated in depression-related illnesses and is the target of antidepressant medications, such as Paroxetine (Paxil), Imipramine (Tofranil) and Fluoxetine (Prozac). In addition, the products of the SLC6A4 gene are also affected by amphetamines, which among some of the most common types of ADHD stimulant medications. In other words, the different forms of this SLC6A4 gene may actually play a role as to how an individual acts to a particular antidepressant or amphetamine medication. Again, keep in mind that there is often a fair amount of overlap of depression with ADHD (some experts argue that a "Depressive" form of ADHD should actually warrant its own ADHD subtype), so it is possible that gender based differences in this gene may be related to this hypothetical subtype in particular.

• However, other evidence suggests that the SLC6A4 gene may not be exclusively labeled as a "depressive gene". A study done on multiple genes believed to affect aggression and impulsivity (the latter being a common trademark of ADHD, while the former is occasionally seen extreme cases, although much more rarely, and typically only in the presence of additional comorbid disorders to ADHD), and found a nominal association between this SLC6A4 gene and cognitive impulsivity. Cognitive impulsivity, in essence, is associated with an individual making hasty decisions without carefully considering the consequences of one's actions, which frequently leads to negative or even dangerous outcomes. Not surprisingly, this is seen at much higher rates in ADHD individuals. Similar features are seen in ADHD individuals who have underactive functioning in the right frontal lobe region of the brain (a diagram of this region is given in an earlier blog post on differences in ADHD kids' brain regions), as well as those who have low tryptophan levels (which often correlates with depression and depression-like symptoms).

• There is also a possible connection of this particular SLC6A4 gene and autism, although numerous other studies have shown conflicting results. Nevertheless, given the fact that there appears to be a notable (but incomplete) overlap of ADHD and autistic symptoms, and the fact that autistic disorders are much more prevalent in boys, it is possible that there may be a tie-in between this "male-dominated" SLC6A4 gene form and a possible ADHD-autism connection.

• Finally, studies have linked variations in this serotonin transporter gene to bipolar disorders. This is also of interest because ADHD and bipolar disorders can occur together frequently and can sometimes be difficult to differentiate, especially at the pediatric level.

In the next few posts, we will be investigating three other ADHD genes believed to have gender-specific effects, which each have a potentially greater sex-related differences than this SLC6A4 gene.

Are ADHD Genes Gender Dependent?

In the past, we have investigated a large number of ADHD genes (that is, specific genes who have one or more forms or alleles which correlate to the disorder ADHD at higher-than-normal frequencies). We have also previously looked at some of the roles of gender effects on ADHD. However, we have not dedicated much time to exploring the possibility that these two factors may, in fact, be related.

A 2008 paper by Biederman and colleagues on sexually dimorphic effects of ADHD genes may shed some light on this potential association. They highlighted a total of four different genes which may be of influence with regards to the onset of ADHD. Two of these four genes appear to exhibit more of an influence on males, and the other two may exhibit more of an effect on females.

These four gender-related ADHD genes are listed below:

• COMT gene
• SLC6A2 gene
• MAOA gene
• SLC6A4 gene

We will be exploring each of these four ADHD genes affected by gender in subsequent postings.

Do ADHD Kids Use Their Brain Regions Diffferently?

There is a fair amount of debate as to whether ADHD is a developmental delay type of disorder. We are seeing a growing body of research which supports this assertion. One of these supporting pieces of evidence is a recent study done by McAlonan and coworkers on the topic of how relative volumes of specific brain regions correlates to ADHD behaviors such as inhibiting certain responses (a deficiency marked by impulsivity, a key attribute of ADHD), as well as the ability to shift attention to another area and refocus (a deficiency which is especially pronounced in ADHD individuals who exhibit symptoms or diagnoses of comorbid Obsessive Compulsive Disorders or OCD). Additionally, a relatively mild (but still notable) association was seen between age and improvement in reaction times for inhibiting responses and shifting focus, which suggests that the increasing of brain volumes (for specific brain regions) during the childhood developmental process can result in subsequent improvements with regards to efficiency in the impulsive behavior inhibition process as well as in attentional shifting capabilities.

Overview of the methods used in the study:

These next few paragraphs outline the method used in the McAlonan study to measure the two key reaction times which would later correspond to certain brain volume differences. Although a bit lengthy, I felt it necessary to include the details for the sake of understanding what these reaction times and their values are actually measuring.

The McAlonan study involved a computer-simulated measure in which the children watched a computer screen for an airplane to appear on either the left or right hand side. Once one appeared, they were to press a button corresponding to the correct side of the screen in which the airplane appeared. However, in one fourth of the cases, an auditory "stop" signal was presented and the children were instructed to push a third button instead as soon as possible. The timing of these responses were recorded throughout the test. There were actually two measurable components to this exercise, the stop signal reaction time portion of the response (the amount of advanced warning time the auditory "stop" signal needed to appear before the airplane for the child to avoid pressing one of the two airplane direction buttons), and the "change signal reaction time" portion of the response (the amount of time it took for the child to push the third button during the quarter of the trials involving stop behaviors).

To clarify, let's assume that it takes a particular child 0.500 seconds to press the correct button once an airplane flashes on the screen. This is the child's typical response time. If the auditory stop signal is given 0.499 seconds after the airplane appears, it is doubtful that the child could stop from pressing one of the "airplane buttons", since they only had 0.001 seconds to respond to the auditory warning. However, if the auditory signal is given at 0.200 seconds after the airplane appears, the child would have 0.300 seconds to stop from pressing the airplane button. The "stop" reaction time is essentially the amount of time needed for the auditory stop cue to precede the normal reaction time (which, in this child's case, is 0.500 seconds) for the child to successfully avoid pressing one of the airplane buttons.

The change response reaction time is measured by the amount additional time it takes for the child to press the correct third button beyond the stop time. In other words, it addresses how long it takes the child to re-engage in the behavior of choosing the correct button once he or she has successfully stopped the "wrong" behavior.

I realize that the test description above might not make intrinsic sense, but the two main things we should take home from these measurements from the article:

1. Stop signal reaction time (SSRT): The time it takes for a child to inhibit a particular behavior (i.e. the amount of warning time a child needs to avoid pressing an airplane button after receiving a stop signal in the process described above). For a frame of reference, the average stop signal reaction time was around 0.45 seconds for the ADHD children and 0.36 seconds for the non-ADHD children. Interestingly, in addition to their slower stop signal reaction times, there was a much higher degree of variability within the ADHD group. We have seen this trend of higher variability with response times in ADHD individuals before, in an earlier post on nicotine withdrawal effects in ADHD smokers. Additionally, there was a much greater improvement in stop signal reaction times with the ADHD group compared to the non-ADHD group, and that, around the age of 12, the ADHD kids often "caught up" to their peers with regards to reaction times. This may support the idea that ADHD children may suffer from functional delays in development early on, but can catch up over time.
   
   
2. Change response reaction time (CRRT): This is the amount of time it takes to shift gears and execute an appropriate response (pushing the correct third button in the airplane task described above). The average change response reaction times were around 0.188 seconds for the non-ADHD kids and 0.263 seconds for the ADHD kids. Once again, there was a much greater variability in reaction times for this category for the ADHD children than the non-ADHD children, and the differences between the ADHD and non-ADHD groups diminished with age.
   

As a quick aside, errors (i.e. pushing the wrong button after an auditory stop signal was presented) were, not surprisingly, significantly higher in the ADHD group than the non-ADHD group.

Relevance and applications of the study:
For comparison purposes, the association between volumes of specific brain regions and reaction times for inhibition and attention shifting tasks was carried out in both ADHD and non-ADHD children. Interestingly, there was a fair amount of difference between the specific brain regions involved for the ADHD children vs. the specific brain regions involved in the non-ADHD children for inhibition of response and attention-shifting behaviors. This may at least suggest that ADHD children may be using different parts of their brains to elicit certain responses than their non-ADHD counterparts.

Given the fact that specific brain regions develop at different rates (some are mostly developed by early childhood, while others continue on into late adolescence and even into one's 20's), it is entirely possible that ADHD individuals may use slower-developing brain regions for certain tasks than their non-ADHD counterparts to control certain behaviors. This combined with the fact that an overall delay in brain maturation is often evident in ADHD individuals, may provide clues as to why ADHD children (and even adults) are less likely to elicit age-appropriate control of certain behaviors.

Reaction Timing vs. Brain Region Volumes:
To elucidate this possible connection, I have constructed a chart which highlights the brain regions whose volumes were connected to faster response times for inhibiting for inhibiting responses and shifting attention in both ADHD and non-ADHD children according to the McAlonan study. These assertions were based on the premise that larger volumes in the following specific brain regions are connected to improvements in stop signal reaction times (related to impulsivity, a key factor in ADHD) and change response reaction times (related in the ability to shift topics, which is often a difficulty in obsessive compulsive disorders, which can also co-occur alongside ADHD) described above.

The top half of the chart entitled "Stop and Inhibitory Behaviors" refers to the brain regions whose relative volumes corresponds to stop signal reaction times (for both ADHD and non-ADHD children) and the bottom half, entitled "Response Changing Behaviors" deals with the brain regions whose relative volumes correspond to change response reaction times.

I have attached a handful of diagrams showing the approximate locations of several of the key brain regions listed above in the chart. These three diagrams (with brief descriptions) are shown below:
Above: The reddish region in the center part of the brain in the image above (the individual is facing to the left, and we're looking at a side view) is the basal ganglia (for original image source, click here). It is comprised of several parts, which are labeled above (don't worry about these sub-components for this article, it is possible we may explore them in further detail in later postings). Actually, a sub-region of the basal ganglia which has been cited by the McAlonan as the major player in response timing for ADHD individuals is called the lentiform nucleus. It is comprised of the Putamen region and globus pallidus, both of which are shown above. Again, don't worry about the exact locations or functions of these subregions, just realize that they show a connection to reaction response timing in ADHD individuals, in addition to their many other functions.

Above: The Cerebellum, Temporal Lobe and Frontal Lobe (which includes the Prefrontal Cortex, which is listed in the chart above in its outer layer) are all shown above (for orignal image source, please click here). We should note that individuals with ADHD generally exhibit lower activity in the prefrontal cortex (in most cases) and the temporal lobe (in several cases).

Above: The Anterior Cingulate region of the brain is approximated by the numbers "24" , "32" and "33" in the brain region chart listed above (for original file source, click here). Note that we are looking from the side at a brain diagram of a person facing to the left. The cingulate acts as a "gear shifter" in the brain. Obsessive behaviors and constant worrying are indicative of an overactive cingulate (think of a car whose gear shift gets "stuck" in a particular gear), while an underactive cingulate region often results in a constant shifting of thoughts and behaviors. Not surprisingly, individuals with ADHD show underactivity in the cingulate (note the similarities between over and underactivity of the cingulate and basal ganglia in OCD and ADHD individuals, respectively).

From the brain region chart listed above, we should note a few of the overall trends:

1. In general (as mentioned earlier in this post), the correlation between age and volume of specific brain regions was more pronounced in the ADHD children than the non-ADHD children. This refers to the "Age dependent" column in the chart listed above, and may suggest that these brain regions mentioned above may experienced delayed growth patterns in ADHD children but are more likely to be "full-grown" in non-ADHD children. This would explain the age-related effects of brain volume, and possibly (again, assuming that volume of these specific brain regions is connected to faster response times) the resulting differences in response times between ADHD and non-ADHD children.
   
   
2. * The stop response reaction time and change response reaction time utilized different brain regions, with the exception of the right basal ganglia (which was present in both reaction times, but only in the cases of ADHD children). It is interesting to note that the basal ganglia region of the brain essentially governs how fast "idle" is for a specific individual. Individuals with ADHD typically have underactive basal ganglia, while individuals with Obsessive Compulsive Tendencies and workaholics typically have overactive basal ganglia. In addition, symptoms such as poor concentration, poor handwriting and poor fine motor skills, all of which commonly exist in ADHD individuals, are often indicative of underactive basal ganglia.
   
   
3. **There was a tremendous amount of difference with regards to the brain regions associated with reaction times between the ADHD and non-ADHD groups. Of all the brain regions listed above, only the left cerebellum had a correlation between its relative volume and improved reaction time (change response reaction time to be more specific) for both ADHD and non-ADHD cases.

**There are a number of direct implications here. For those of us who parent or work with ADHD children, we often find ourselves directing the child to stop a certain negative behavior and restart an appropriate one such as: "Billy, stop spinning in circles and pick up your truck!". We may often find ourselves frustrated by the length of time it takes for the child to follow both portions of the directions, but we should keep in mind that at least part Billy's slow response may be due to innate delays in stop and change reaction times highlighted in the McAlonan article. Thus, there may be practical implications to the findings of this study beyond the general overview of brain regions at work here.

One last thing to note (which was not brought up by the study):
In the computerized airplane task mentioned above to test for "stop" and "change" signal reaction times, the authors used an audible stop signal to get the child to stop. However, we have recently investigated the co-occurrence of ADHD and auditory processing disorders. Given the relatively high prevalence of this association, it is entirely possible that part of the delay in reaction times for the ADHD group may, in fact be attributed to an underlying comorbid auditory processing disorder (which often goes undetected as a side disorder in a number of cases involving ADHD children).

In fact, the temporal lobes of the brain (see diagrams above) play a critical role in auditory processing. From the chart of brain regions listed above, we see that both the left temporal lobe (whose volume is associated with stop signal reaction times in ADHD children) and the right temporal lobe (whose volume correlates to change response reaction times in non-ADHD children) are both key components with regards to reaction timing, at least based on the McAlonan paper. It would be interesting to see if there was much of a difference in reaction times had the "stop" signal been a visual instead of auditory cue instead, and whether the correlation between temporal lobe size and reaction times would still exist in either the ADHD or non-ADHD cases.

Summary:
To summarize, we have seen that multiple brain regions have been implicated in both the reaction times related to impulse control/stop behaviors as well as change response time/shifting behaviors. We should also note that the two processes often utilize completely different brain regions, whose rates of development can differ significantly. Furthermore, the correlation of specific brain region volumes to these two types of reaction times was significantly different in ADHD vs. non-ADHD children. This may indicate either a developmental delay in some of these brain regions for ADHD children, or an entirely different set of functioning of specific brain regions in ADHD vs. non-ADHD children.