Monday, March 30, 2009

Daytrana Absorption and Metabolism Patterns Compared to Ritalin and Concerta

In the previous post, we introduced the relatively new ADHD medication Daytrana. Composed of the same chemical compound as Ritalin and Concerta (methylphenidate), Daytrana offers the distinct advantage of existing in the patch form, which is typically worn on the hip. At the present moment, this medication is used exclusively for children with ADHD and related disorders, although it can also be used off-label for adults with the disorder.

Given the entirely different delivery system of the patch form of Daytrana vs. the conventional pill form of Ritalin and Concerta, the question arises on how the rates and patterns of drug delivery compare between the two forms of the medication. A copy of a table from the previous post, titled Daytrana Dosing Equivalents to Ritalin and Concerta is given below:



Patch size refers to the size of the Daytrana patch worn by the individual. The total content of drug per Daytrana patch (in milligrams methylphenidate) and rate of delivery (per hour) of the different patch sizes are also listed above. The standard wear-time for the patch is 9 hours, so a comparison in total drug dosage for a 9-hour period is also listed. Finally, equivalents to Ritalin (Immediate release, abbreviated "MPH-IR", the dosage listed is given 3 times per day, in milligrams), as well as Concerta (given once per day, also in milligrams) are also listed.

As far as total methylphenidate content delivered, the three methods of comparison are all similar. However there are some differences in rates of delivery, drug absorption patterns, and drug metabolism between the three different methods. A comparison, based on a report from Pierce and coworkers on the pharmacokinetics of the methylphenidate transdermal system (a technical term for Daytrana) is highlighted below. Please note that some of the data are supplemented from other similar studies on children with ADHD, so don't take these numbers as absolute. There is still a large amount of variation between the different studies. Nevertheless, these values are, to the best of this blogger's knowledge and current research, a good representation of values typically found in the literature (sometimes numerical ranges are given in lieu of exact numbers to reflect this). In other words, look at the numbers for comparative purposes instead of absolute values. The important thing to note below are some of the trends and comparative differences between the different forms of methylphenidate.


About the table above:

The columns going across include Immediate Release methylphenidate ("MPH-IR", similar to short-acting Ritalin and the like), Osmotically released methylphenidate (MPH-OROS, which is the drug form used by Concerta) and the four different patch sizes of Daytrana currently available ("DT" 10, 15, 20 and 30, which reflect the amount of methylphenidate delivered in milligrams to the body over the standard 9 hour patch-wear time of the 4 different patch sizes, listed in our first table).

For the first column, Max Concentration reflects the highest concentrations of the drug methylphenidate which are typically seen (again, don't scrutinize the exact numbers too closely, just look for trends across the chart). The next entry, Time to Reach Cmax, reflects the approximate amount of time after first taking the methylphenidate capsule or putting on the Daytrana patch for this maximal concentration to occur (in hours, again, an approximation).

Effectiveness is a more relative term, but it is based on how long the desired effects typically last (in hours) of each drug formulation. Again, experts and studies disagree, so just use these as relative guidelines. Finally, the term half-life is used as a measuring tool for how fast the drug is eliminated or cleared from the body. For example, a drug with a half life of 3 hours means that every three hours, the amount of drug remaining in the system is cut in half (used in a similar matter to how radioactive decay is measured).

4 important trends to note from the table:

For convenience, the same table is listed again below.

  1. Higher drug concentrations from the patch form: Note that much higher plasma concentrations are typically seen with the Daytrana patch form of the drug than the other delivery system. This is likely due to the route of administration which bypasses several enzymes and other metabolic factors in the digestive system reserved for oral delivery routes. As a result, higher plasma concentrations can more easily occur. This is especially apparent in the two largest Daytrana patch sizes, where maximum plasma concentrations are close to double the levels attained via the traditional oral delivery methylphenidate medications for ADHD.

  2. Greater time to reach high concentrations: The time to reach these high concentrations is greater as well. This is often an advantage, given the fact that stimulant medications which exhibit the greatest abuse potential typically enter the bloodstream (and, subsequently the brain), extremely quickly (often in 15 minutes or less), and then leave the brain and body quickly. As a result, while this more drawn out process (relatively similar to that of Concerta, but slightly longer), is good news for lower abuse potentials. However, the relatively long time to reach maximum concentration can be difficult for seeing the desired effects shortly after medication. However, given the higher apparent "ceiling" for these patch-style delivery systems, adequate drug concentrations are typically seen within 2 hours (data not shown). In other words, medication effects can be felt long before these high maximal concentrations occur.

  3. Longer duration of effectiveness: The pharmacokinetics study of the methylphenidate patch for ADHD noted that detectable levels of the drug, when given in the patch form, were still seen in the blood the next day, up to 15 hours after the patch was removed (although only around 5% of the maximum concentration). Nevertheless, this 9-hour patch delivery method may prove useful in maintaining a constant presence of the medication throughout the day, and may extend the drug's effectiveness beyond even some of the longest-lasting oral methylphenidate forms. This may prove useful for individuals who still need to control for lack of focus and hyperactivity, such as a child with a big homework project. Of course, the flipside to this could be a greater potential for long term side effects, due to the constant persistence of the drug (keep in mind that this Daytrana system is only 2-3 years old, so long-term evaluations are still not available to any sufficient extent).

  4. Similar rates of clearance: Perhaps the most consistent parameter across the board, it appears that the clearance rates of the patch and oral systems of methylphenidate all seem to hover around the three hour mark. This suggests that once the drug is actually delivered (albeit by a different delivery system), the rest of the metabolic processes are pretty much the same for the different forms of methylphenidate.

The enantiomer effect of Daytrana:
Before going, I just wanted to mention another peculiarity of the transdermal (patch-based) form of the methylphenidate delivery system:

Most methylphenidate medications are actually a mixture of two compounds of the same formula that exist as mirror images of each other. These mirror images are called enantiomers. While they have the same chemical formula and structure, the two different mirror image forms of the drug can behave entirely differently. In some extreme cases, getting the wrong enantiomer or mirror image of a drug can even produce disastrous side effects. For example, for the drug thalidominde, which was prescribed for morning sickness in pregnant mothers was actually found to have one safe enantiomer, but the other enantiomer, or mirror image resulted in severe birth defects. As we can see, this one minor change in drug shape can have huge repercussions if we're not careful.

In the case of methylphenidate, however, the effects of the differnt mirror images of the drug are much less pronounced. However, one of the two enantiomers (called the "d form") of the drug is much more potent or active than the other form. As a result, new formulations containing only the more "active" form of the drug began to develop. The drug Focalin (dexmethylphenidate) is an example of this. It has been demonstrated that Focalin can produce similar effects to regular methylphenidate at half of the methylphenidate dosage. We will save further discussion on this topic for later posts.

The reason I mention this enantiomer effect is that the two mirror images of the methylphenidate are metabolized and cleared at different rates. What is interesting is that the actual form of delivery for the drug (i.e. the patch for Daytrana, or the oral form for Ritalin or Concerta) actually affects the ratio or balance of the two mirror images of the drug after short periods of time.

To illustrate, consider the following:

  • For Methylphenidate Immediate Release (Ritalin-IR), the "L" form (the less active form) is almost non-existent shortly after dosage is administered. That is, the "D" form (the more active form, or the mirror image which exists exclusively for Focalin), is the overwhelmingly predominant form of the drug remaining within a period of 1-2 hours.

  • For Concerta (a slower releasing form of the drug compared to the immediate release Ritalin form of methylphenidate), the ratio is still skewed shortly after administration of the drug, with the "D" form: "L" form exhibiting a ratio of around 40:1 (after a few hours). Once again, the more potent form of the drug predominates shortly after the drug is given, and the less active form is more quickly cleared.

  • However, with Daytrana, the "D" to "L" mirror image ratio of the drug is still in favor, but not by nearly the amount of the two oral delivery forms (Ritalin and Concerta). In the case of Daytrana, the "L" form stays around longer, sitting at about 55-60% of the more active "D" form of the drug. It is still unclear at the moment as to why this is, but some possibilities include the difference in enzymes and enzyme systems used to break down the drug between the skin and the digestive forms of delivery. Nevertheless, this blogger would not be surprised to see another patch form of delivery comprised exclusively of the more potent "D" form of the drug (as in a patch form of Focalin) on the horizon as an even more effective treatment for ADHD.
To summarize, Daytrana appears to be an effective alternative form of delivering methylphenidate for children with ADHD. Given the fact that the individual can now control two variables (patch size and wear time), it appears that this form of the medication may be easier to tailor to the individual than the oral form of methylphenidate.


We will continue our discussion about some of the other pluses and minuses of the Daytrana form of methylphenidate and how they relate to strategies of ADHD treatment in the next few posts.

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Friday, March 27, 2009

Daytrana Dosing Equivalents to Ritalin and Concerta

Methylphenidate remains one of the most popular choices of medications for individuals with ADHD. However, the combination of dosing difficulties and negative side effects connected with oral administration left room for an alternate form of delivery: the methylphenidate transdermal delivery system, more commonly known as Daytrana. Currently, this medication is prescribed for children with ADHD and not adults, although it is sometimes prescribed off-label for adults with ADHD and related disorders.

If you are not familiar with Daytrana as a method of treatment for ADHD, you are not alone. It is a relatively new medication, introduced in 2006. It consists of the drug methylphenidate, the same chemical compound used in the more common ADHD medications Ritalin and Concerta. It is currently the only ADHD medication available in the patch form.

We will begin a series of posts exploring this new player in the world of ADHD, but I would like to start off with just providing a table of approximate dosing equivalents between Daytrana and the more common forms of methylphenidate, Ritalin and Concerta. A rough comparison, obtained from an article by Arnold and coworkers in the journal Pediatrics titled Treating Attention-Deficit/Hyperactivity Disorder with a Stimulant Transdermal Patch: The Clinical Art.

Please note that there are four different patch sizes of Daytrana currently available, which, based on the pharmacokinetics of a 6-12 year old child, correspond to four different doses of both the immediate release methylphenidate (note this 2nd-to last column corresponds to a Ritalin immediate release dose that given 3 times/day) and an osmotic-based release form of methylphenidate (Concerta). The patch is typically placed on the relatively inconspicuous location of the child's hip, and should be administered to the same site on a daily basis for consistency (different locations can actually affect the releasing dosage patterns of the patch)

Typical wear is for 9 hours, which is why the 9-hour dosing equivalents are given. However, the theoretical maximum dose per patch (which is the delivery rate times a 24-hour period) is also given. However, anything beyond a 9-hour dose is typically considered "off-label" use for Daytrana. These delivery rates of dosing for the different patch sizes are slower than the other forms of methylphenidate, as we will see in future posts. Nevertheless, I have included them to illustrate the patch size/dosing rate relationship for Daytrana. Note that the patch area and delivery rate follow a linear relationship, which is indicative of a uniform distribution of the drug across the surface of the patch which provides approximately 2.2 mg of methylphenidate content per square centimeter of patch area (over a 24 hour period).

We will be going into much more detail about the modes of action and functional differences of the Daytrana form of the drug methylphenidate (especially the differences between this patch form and the conventional "pill" form) as well as highlight some of the advantages and disadvantages of this new form of treatment for ADHD in the next few posts. Topics addressing the difficulties of an oral delivery system (we have hinted at some of the problems of food or drug metabolism and the ensuing consequences due to digestive issues such as celiac disease and ADHD symptoms) will also be discussed in the very-near future. In the meantime, a good overview of Daytrana, as evaluated by the FDA can be found here.

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Thursday, March 26, 2009

Methylphenidate vs. Atomoxetine ADHD Medications: Effects on Sleep

Stimulants are often the primary source of medication for ADHD and related disorders. Medications such as methylphenidate (Ritalin, Concerta, Daytrana), Adderall, Vyvanse and the like are often the first line of defense and choice of prescription for ADHD for many practicing physicians. However, certain drawbacks exist to these medications. Perhaps the three most common concerns are cardiovascular effects, stimulant induced sleep difficulties, and appetite suppression and resulting weight loss.


As a result, some parents and prescribing physicians choose a non-stimulant form of medication for treating ADHD such as Atomoxetine (Strattera). While some of the negative side effects mentioned above are less common for these non-stimulant options, the overall efficacy of reducing core ADHD symptoms is often less extensive than for the stimulant counterparts.

In this post, we will investigate one of the problem areas of stimulant medication by examining a handful of studies comparing and contrasting the different effects of methylphenidate and atomoxetine on sleep patterns in ADHD individuals. Sleep patterns are often analyzed via reports (either the patients themselves, or parents if the patient is a child), actigraphy (less invasive) or polysomnography (more details and quantitative data).


Methylphenidate:

Adult ADHD studies on methylphenidate and sleep quality:
While sleep difficulties are clearly evident in several studies, numerous others have actually shown overall positive effects of methylphenidate on sleep performance. For example, a study by Boonstra and colleagues on sleep activity patterns in adult ADHD showed that methylphenidate administration resulted in a delayed period of sleep onset. However, once subjects did fall asleep, the frequency of nighttime awakenings decreased significantly for the methylphenidate group (keep in mind that all of these individuals had ADHD), and that the overall duration of sleep for the night was less for the methylphenidate participants. These positive results were echoed in a study by Sobanski and coworkers, which found that methylphenidate administration improved efficiency and restorative quality in adults with ADHD compared to non-medicated individuals with the disorder. In other words, it appears that although methylphenidate can delay the onset of sleep, it appears to offer a positive effect in promoting a deeper pattern of less-interrupted sleep in ADHD adults.


ADHD, Methylphenidate and Sleep Quality in Children:

One of the difficulties in assessing the effects of ADHD medications on sleep deficits in children is that it relies heavily on parental reports and observations. Unfortunately, the overall accuracy of these parental (as well as teacher ratings) has been called in to question by several recent findings. More info on this is given at the bottom of the post.

Another key issue, is the relative lack of long-term controlled studies on methylphenidate in children due to a myriad of safety and practicality issues. As a result, obtaining clear-cut and accurate information on ADHD stimulant medications and sleep disorders in children is more tenuous than in the adult model, even though the overall number of studies on ADHD medication effectiveness is much higher in children. In other words, sleep disorders still hold a relatively remote corner amongst the sea of information on pediatric ADHD.

Nevertheless, several studies on the matter have been done in the past few years. I will highlight some of them below:

An investigation by O'Brien and coworkers found a significant increase in sleep disturbances for ADHD children regardless of medication status. These findings suggest a neutral effect of stimulant medications such as methylphenidate for children with ADHD, but cite an often-overlooked characteristic: ADHD children typically exhibit more sleep difficulties than non-ADHD children. Therefore, some of the bad rap attributed to ADHD stimulant medications such as methylphenidate for inducing sleep disorders may simply be due to the nature of the individual's ADHD and not to the medication. This is an important observation to keep in mind, especially when investigating sleep medication studies.

There is even some evidence that the assertion of methylphenidate administration later in the day (afternoon) may negatively impact sleep performance is less pronounced than popularly believed. Many physicians fear that a third daily dose of methylphenidate may cause sleep difficulties and omit the afternoon dosage. However, a study by Kent indicates that this may not be the case. Of course this is just one study, and should be regarded as such, but this may at least open the possibility that a number of these afternoon medication/sleep impairment fears may be less grounded than previously believed. Nevertheless, sleep disturbances are still a concern with ADHD medications such as methylphenidate, but, according to recent findings, the effects are relatively small.


"Do genetics play a role on sleep disorders and the ADHD medication response?"

This is an intriguing question which needs to be investigated further. We have had several previous discussions on the COMT gene and its effects on ADHD. Now it appears that sleep disorders and potential medication response may actually be impacted by an individual variation in this hotbed region of the human genome. A study done by Gruber and coworkers suggests that ADHD children with the Val form of the COMT gene may be more prone to sleep difficulties while on methylphenidate compared to the Met form of the COMT gene (if you are unfamilar with this "Val", "Met" and "COMT" terminology, a good explanation of these terms and how they relate to ADHD and ADHD medications can be found here).

ADHD, Sleep Quality and Strattera (Atomoxetine) in children:

In contrast to methylphenidate, which seems to delay the onset of sleep, individuals on atomoxetine have a much smaller delay in sleep onset. These differences were highlighted in an article by Sangal and coworkers titled Effects of Atomoxetine and methylphenidate on sleep in children with ADHD. Other advantages of atomoxetine over methylphenidate include less irritability, less difficulty getting ready for bed, less difficulty waking up in the morning, and less of an appetite suppression. However, the postive effects of fewer nighttime awakenings seen in methylphenidate were not observed in atomoxetine.

Methylphenidate vs. Atomoxetine: Comparative Effects on Sleep

Here are some of the highlights obtained from the Sangal study. A number of parameters and categories were investigated, but I have only included ones which were either statistically significant or ones which I personally found to be noteworthy:

A comparison of differences between Atomoxetine (Atom) and Methylphenidate (MPH), as well as the effects of both medications compared to unmedicated ADHD individuals are shown above. Quantitative measurements were performed using both polysomnography (polysom) and actigraphy. Some key trends of note:

  • A delayed onset of sleep was seen in Methylphenidate.
  • However, REM sleep (an important factor in overall sleep quality) was reached faster with Methylphenidate and slower with Atomoxetine.
  • Additionally, a slight increase in the percentage of sleep time spent in REM was seen with methylphenidate treatment.
  • Fewer sleep disruptions (partial or full, as in awakenings) were seen with both medications, but the effects were even greater in the methylphenidate group.
  • When a child did awaken during the sleep cycle, the children medicated with methylphenidate were able to fall back asleep much faster. Note this contrast to the increased time to fall asleep initially for the methylphenidate group.
Overall, it appears that while methylphenidate does slow the onset of sleep initially at a significant level, it appears that once a child does fall asleep, the overall sleep quality is actually improved if the child is medicated with methylphenidate. This data runs against the grain as far as prescription medications for ADHD are concerned, in which nonstimulants such as Strattera (Atomoxetine) are often given in favor of stimulants such as methylphenidate if sleep disorders are a concern. This is likely due to the most obvious parameter (initial difficulty falling asleep), which favors Strattera, while the other parameters, which favor methylphenidate and are more numerous, are less intrinsically obvious.

Why the pronounced difference between the two ADHD medications?

While there is still a fair amount of debate surrounding the exact cause of different impacts of these ADHD medications on sleep, the different biological targets and modes of action may offer some clues. For example, while methylphenidate primarily targets the neuro-signaling agent dopamine in brain regions such as the striatum and nucleus accumbens, Strattera (atomoxetine) instead targets another neurotransmitter called norepinephrine.

It appears that the different neurochemical targets and specific brain regions impacted by the two medications are responsible for the differences. For example, we have previously mentioned in another post on gene variations and attention control that the cingulate region of the brain, which essentially acts as the brain's gear shifter, has a high density of receptors for dopamine, the very chemical that methylphenidate targets. It is possible that changes in dopamine levels from methylphenidate may indirectly impact the "gear shifting" ability of the key brain region of the cingulate. We have previously discussed that an overactive cingulate region can lead to difficulties changing focus or transitioning between topics or activities, while an underactive cingulate can lead to difficulty maintaining focus on a particular thought or state.

Putting this into context of our sleep and ADHD medication discussion, it is also worth noting that the Sangal paper mentioned that children who took the methylphenidate had a more difficult time getting up in the morning and settling down into a pre-bedtime routine than the Strattera group. In other words, it seems like the methylphenidate group had trouble with transitions. As a result, this blogger hypothesizes that the transitions may be caused, at least in part, by the increased activity of the cingulate region of the brain and it's high density of dopamine targets, which see increased activities driven by a boost in free dopamine levels from the methylphenidate. In other words, I suggest the possibility that methylphenidate induces a state of the cingulate "gear" shifter becoming overactive and getting stuck in one routine (either the waking or sleeping state) and having trouble moving to another (getting out of bed or falling asleep). Further supporting this hypothesis is the data from the table above showing that the methylphenidate treatment group appears to be more inert (i.e. fewer sleep interruptions, and a quicker return to a previous sleeping state).

Inconsistencies between parent and teacher reports and actigraphic studies for sleep in ADHD children:

Finally, it is worth noting that the different methods of sleep data acquistion are far from perfect. It appears that there is at least some discord between the methods of measurement.

Compounding the problem of sleep disorders in children is the relative inconsistency between parental reports of sleep disturbances and disorders and results derived from actigraphic studies. This appears to be a recurring problem in the literature, and is confirmed by several other studies of observation. Additionally, teacher evaluations may also be flawed with regards to sleep disorders and ADHD-like behaviors.

Final notes on the methylphenidate vs. atomoxetine debate on ADHD and sleep:

While the current trends in medication prescription still shy away from stimulants such as methylphenidate for fear of insomnia, the findings of some of the recent studies show that overall sleep quality in ADHD individuals may actually improve (in spite of the initial sleep delays) with methylphenidate treatments instead of non-stimulant medications such as Strattera. I personally anticipate further sleep studies in the near future which will confirm several of these findings.

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Wednesday, March 18, 2009

2 Key Brain Regions Which Are Smaller in ADHD Individuals

We have previously held several different discussions about brain regions and ADHD. Some have hinted at reduced activity, often measured by lower bloodflow patterns either during resting states or mental challenge, while others have examined different patterns in brain waves and food allergy-induced changes in brain electrical activity. Still others have pointed towards gene-based lowering of chemical signals in key brain regions of ADHD individuals. Additionally, we have looked at articles dealing with alcoholism and the relative size of specific brain regions with regards to ADHD.

Adding to this growing body of evidence on the differences between brains of ADHD'ers and non-ADHD individuals is recent article by Ellison-Wright and coworkers on structural brain differences in ADHD individuals. We will be extracting some of the key findings of this meta-analysis (a review which combines and analyzes bodies of data amassed from a number of previous findings and publications and compiling it into a larger set of data to look for underlying trends and relationships). Here are 10 key points to take home from Ellison-Wright's findings (as well as from some of the other articles he cites in the analysis study):

  1. An overall reduction in gray matter in the right putamen (shown in red) and globus pallidus (shown in blue) regions of the brain has observed in ADHD patients compared to controls. This is an underlying theme among multiple previous studies. The image below is of the human brain with the approximate regions of the putamen and right portion of the globus pallidus regions (the view is from the top down on a subject with the front part of the brain at the top and the back part of the brain at the bottom of the image).




  2. Brain volume changes in two other regions, the frontal lobe and the caudate nucleus have been associated with genes related to processes of the key neurotransmitter dopamine. Please note that the frontal lobe has often been tied to ADHD, both through a decrease in size (in the prefrontal cortex region part of the frontal lobe, see below for details). Additionally, the caudate nucleus, actually combines with the putamen and globus pallidus to form a larger brain region called the corpus striatum (see diagram below). The approximate locations of the prefrontal cortex (brown), globus pallidus (blue), caudate nucleus (green) and right putamen (red) are shown in the image below. As in the image above, we are looking from the top down on an individual who is facing forward towards the top of this page.



  3. Adding to this discussion, the article refers to a process in which the globus pallidus acts like a type of highway (the article uses the term "circuitry", but a highway or series of highways may be easier to visualize) between other brain regions, including the caudate and putamen regions. Therefore, the size and shape of this globus pallidus may play an even more crucial role with regards to ADHD and other related disorders, as multiple other brain regions can be critically dependent on it.

  4. Many previous publications frequently study brain regions which are easier to study (i.e., ones that are less complex and easier to map and analyze than the smaller and more elaborately dense brain regions), often out of necessity. However, this selection process for sake of convenience can leave out several critical brain regions and sub regions which may actually play a critical role in the brain volume/ attentional disorders connection. At this point, it appears that we are just scratching the surface with regards to studies involving these key brain regions and ADHD.

  5. ADHD seems to be more correlated brain volume imbalances due to decreases of specific brain regions, namely the putamen and globus pallidus (see diagram above), rather than relative increases in other brain regions. In other words, ADHD appears to be more of a "brain volume decrease-based" type of disorder, at least at the moment.

  6. Further adding to the idea that the striatum region of the brain as a whole is another study done by Bush and coworkers, which have pinpointed this brain region as one bearing a significant role on the disorder of ADHD. The striatum is comprised of the putamen and caudate nucleus (on both left and right halves of the brain), and is shown in green in the diagram below:




  7. Studies involving brain damage (such as those caused by impact or injuries to the brain) found a strong association between ADHD symptoms and lesions for both the right and back parts of the putamen region of the brain. It appears that reductions in these sub regions either due to lack of size or damage can elicit similar results which include an increase in ADHD or ADHD-like behaviors.

  8. The basal ganglia (the odd "snail-shaped" region in the diagram below, which includes the aforementioned putamen, globus pallidus and caudate nucleus, as well as a few other sub regions we haven't yet discussed) is another key brain region which is believed to be involved in ADHD and other related disorders. The basal ganglia region of the brain essentially determine how fast a person's brain "idles". This region has often been found to be underactive in ADHD and similar disorders and overactive in obsessive compulsive or anxiety-related disorders. Thus the basal ganglia function can have some far-reaching implications. Not surprisingly, then, is the fact that mis-development in the "wiring process" of the basal ganglia (such as seen in the formative years), may play a crucial role on the onset of ADHD both directly, and indirectly (via interaction with other key "ADHD" brain regions).



  9. Returning to the two main brain regions of investigation (the globus pallidus and the right putamen) for a moment, we see that these brain regions may also play a key role in governing the response to and effectiveness of potential ADHD medications.

    For example, a positive response to the ADHD stimulant methylphenidate (Ritalin, Concerta, Daytrana) may be influenced, at least in part, to the function of the right putamen region of the brain. According to this study, a higher level of bloodflow to the right putamen region (among a few others listed in the study), was significantly correlated to a positive response to the methylphenidate medication. In other words, a functionally active right putamen brain region may increase the odds of a child being able to tolerate their Concerta, while children with reductions or abnormally slow developments of the right putamen might be prone to less success with this type of medication. As of now, it is unclear if this brain region exhibits the same effects on other ADHD stimulants as well.

  10. It is also likely that metabolic differences in the globus pallidus play a role in ADHD. A metabolic study involving the ratio of two types of "fuel" (creatine and N-acetylaspartate or NAA), which is often a good indicator of neuronal health in several key brain regions, found that individuals with ADHD had an abnormally low ratio of NAA to creatine. Taking this one step further is the topic of supplementation. Creatine supplements, often used by exercise enthusiasts, have been shown to boost levels of this nutrient to the brain as well, which can decrease the NAA to Creatine ratio (i.e., more creatine and less NAA). This brings up the hypothetical question as to whether creatine supplementation can actually exacerbate some of negative effects of ADHD by tampering with this desired ratio. We will actually be exploring the topic of creatine supplementation and its effects on the brain in another blog post in the near future.

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Saturday, March 14, 2009

ADHD, Gender and the MAOA gene

The MAOA gene will be the last of the four-part series on genes believed to be connected to ADHD that exhibit a gender effect. The four genes, which were discussed in an article by Biederman and coworkers are listed below:

  • SLC6A4 gene (also referred to as SERT or Serotonin Transporter Gene)
  • COMT gene (also referred to as Catechol Methyltransferase Gene)
  • SLC6A2 gene (also referred to as NET or Norepinephrine Transporter Gene)
  • MAOA gene (short for Monamine Oxidase)

The first two genes on the list above are believed to exhibit a greater influence on males with ADHD than on females with the disorder. In other words, specific "ADHD" forms of these two genes often show up at significantly higher relative frequencies in males with the disorder than in females with ADHD.

In contrast, however, the SLC6A2 gene, which codes for the critically-important norepinephrine transporter protein, seems to have some type of genetic predisposition to ADHD females. We discussed this in the previous post on SLC6A2.

Location of the MAOA gene in the human genome:

Unlike the other three genes we've discussed, which appear on the first 22 chromosomes, the MAOA is unique in that it is located on the X chromosome (which is a sex-linked chromosome). Because of this, it is, perhaps without surprise, a possible gender-linked difference in ADHD connected to different forms of this gene.

The relevance of the MAOA gene to dosage levels of ADHD medications:

In a previous post, we covered extensively the different forms of the COMT gene and the implications on medication dosage levels. For MAOA, there is apparently an analogous gene-medication dosage connection as well.

Monoamine Oxidase inhibitors (MAOIs) are a class of drugs often used for treatment of depression and related disorders. This class of antidepressants have a mechanism of action that targets the enzyme Monoamine Oxidase, which is coded for by this ADHD gene MAOA. Given the fact that depressive disorders often occur more often and with greater severity makes the gender-based difference of the MAOA gene even more intriguing.

Blogger's personal note (feel free to skip this section, which reflects my personal opinions as to the direction that the ADHD medication battle may soon be heading in the near future):

I have mentioned in previous postings that I believe that analyzing specific genes believed to be associated with ADHD and screening individuals for which forms of the gene they have can be an immensely useful tool in the very near future. Given the fact that even slight variations in a specific gene can result in huge differences in the level of expression enzymes and other proteins encoded by these genes, having one of the "underactive" forms of a certain ADHD gene may play a huge role as to what level of medication dosage one must take.

Since many ADHD medications (as well as medications for many other types of disorders) are initially tailored by the individual's size and weight (in addition to the severity of the symptoms, of course), one's genetic makeup may be an equally important determining factor. For example, let's assume that an individual is exhibiting a number of depression-like symptoms, and is placed on a monoamine oxidase inhibitor drug (Which is actually unlikely, at least initially, since MAOI drugs are typically more dangerous than most other antidepressants, and are often used only as a last line of defense. Nevertheless, for the sake of example, let's consider it.).

Monoamine Oxidase Inhibitor (MAOI) drugs, as their name suggests, reduce the activity levels or expression of the monoamine oxidase enzyme (which is coded for by the MAOA enzyme). Now let's assume that an individual has a relatively rare genetic form of the MAOA gene, which produces an enzyme with only one percent of the activity of the more common MAOA gene forms. Because much less enzyme is produced or expressed compared to a normal case, this particular individual would likely need less of the MAOI drug to do the trick than would someone who expressed a much higher level of the enzyme. As a result, instead of giving a 30 mg dose of the drug (determined by the patient's size and symptom severity), the prescribing physician might want to initially start with a lower dosage. For a similar argument with regards genes and medication dosages dealing with the COMT gene ("COMT" is short for Catechol Methyltransferase) please see an earlier blog entry titled ADHD Genes Influence Medication Dosage.

Other diseases and disorders affiliated with the MAOA gene:

Anxiety: As previously mentioned, girls with ADHD are typically more prone to comorbid anxiety disorders than are boys with ADHD. There is some evidence, based on the mouse model (which is often a surprisingly good approximation of human behaviors with regards to psychological disorders, a topic which will be reserved for later posts) that mutations in the MAOA gene that reduce its function may be related to higher anxiety levels.

Aggressive, antisocial and criminal behaviors and MAOA:

Deficiencies of the enzyme Monoamine Oxidase, which is coded for by the MAOA gene, have been linked to impulsive aggression and related behaviors in mildly retarded individuals. Keep in mind, however, that this was obtained from a small study and that the disorder, known as Brunner Syndrome, is relatively uncommon.

A more focused study found that the MAOA gene may actually play a role in the "nature/nurture" debate as to why some individuals exhibit violent and aggressive behavior and why others do not. This study focused on children who had been mistreated and analyzed which of the mistreated children were prone to aggressive, violent or criminal behavior. According to the study, children who had "high levels of MAOA expression" (that is, children who had genetic variations of the MAOA gene which produced higher levels of the enzyme monoamine oxidase) were less prone to violent behavior, while those who had lower activity forms of the MAOA gene were more prone to criminal behavior.

As a result, screening individuals who have unfortunately endured a history of abuse for specific genetic variations, may actually help predict (and get a leg up on early treatment options for) the likelihood of that particular individual of developing violent, criminal or abusive behaviors themself. While we must guard against the tendency to put too much emphasis into one particular gene (or even group of genes) for predicted a complex and multi-faceted behavior pattern, I personally believe that we should try to take advantage of every little point of potentially valuable information at our disposal.

MAOA and Bipolar disorders:

One note of potential interest, however, is the fact that Brunner Syndrome (mentioned earlier) carries with it relatively high degree of overlap with bipolar disorders. Bipolar disorders may both occur alongside ADHD or exhibit such a similarity of symptoms (especially in younger children) that misdiagnoses between the two can occur. A study by Lim and coworkers found an association between the MAOA gene and bipolar disorders. However, while some other studies have supported this connection between bipolar disorders and the MAOA gene, other studies have brought in to question or refuted the findings. Also, please note that the study was done in males, which, according to the Biederman study are less susceptible to genetic difference-based ADHD than are females with the disorder.

Restless Legs Syndrome:

We have previously discussed some of the connections between ADHD and Restless Legs Syndrome. We have hinted at an underlying iron deficiency, which may affect levels of the important signaling chemical dopamine. A study was done on the MAOA gene and restless legs sydrome and concluded that for individuals with a "high activity" form of the MAOA gene were significantly more prone to developing restless legs syndrome. A note of further interest is that the same study saw an assocation in the MAOA gene variant and restless legs syndrome in females but not in males, lending credence to the possibility that girls may be more susceptible to MAOA gene differences in disorders besides ADHD.

The MAOA gene and disorders associated with specific brain regions:

Attention span: The MAOA gene (like most genes) does not express itself uniformly throughout the body. Instead, certain regions appear to be more targeted more than others. The cingulate is a region of the brain which we've discussed on more than one occasion in previous posts, and essentially acts as the brain's gear shifter. If this brain region is overactive, the individual can become overly focused on one particular topic or action (obsessive compulsive disorders or OCD-like behaviors can ensue), while underactivity in the cingulate region of the brain can result in someone's attention being scattered all over the place, like in most ADHD cases.

A study by Fan and coworkers found that different alleles (different versions of the same gene, which vary from individual to individual) of the MAOA gene corresponded to different levels of activity in the cingulate portion of the brain. These genetic variations and different levels of cingulate activity corresponded to differences in reaction timing to certain attention-based tests. The actual test used in the study was an "arrow test", which is described in more detail in an earlier blog post titled Gene Variations Which Affect Attention Control.

MAOA Gene, Brain Size and Tendency Towards Impulsive Behavior and Violence:

The different forms of the ADHD gene MAOA may affect more than just activity level in the cingulate region of the brain. A 2006 publication by Meyer-Lindenberg and coworkers titled Neural mechanisms of genetic risk for impulsivity and violence in humans found that individuals who had "lower activity" forms of the MAOA gene (and protein which it encodes) actually had smaller volumes in specific brain regions, including the cingulate (as well as larger volumes in other brain regions, some of which are believed to be affiliated with specific forms of ADHD).

There was at least somewhat of a gender-based difference with regards to this MAOA gene/brain size association, which was higher in males, according to this particular study. Thus it appears that while the MAOA gene may play a greater role in ADHD, anxiety and a handful of other disorders in females, it may have more of male-based effect in other disorders (some of which frequently occur alongside of ADHD themselves).

MAOA and Autism:

The gender based differences of the effects felt by different forms of the gene MAOA can also be seen in autism (which is a predominantly "male" disorder), at least based on the findings of some studies. Cohen and colleagues found that male children who had a lower-activity version of the MAOA gene displayed more severe autistic behaviors than those with higher-activity forms of the gene MAOA.

I realize that this has been a long and extensive post on the MAOA gene. To quickly summarize:

  • The MAOA gene is located on the X chromosome, which makes it more susceptible to sex-linked differences (since females have two copies of this chromosome and males only have one).
  • For ADHD and some other disorders which can often occur alongside of ADHD, such as anxiety, the MAOA gene has shown a tendency to have more pronounced effects in females.
  • For other disorders, such Bipolar Disorders, Autism, and Violent/Aggressive behaviors, the MAOA connection appears to be stronger in males. Environmental factors (such as a previous history of abuse) may have a greater interaction with genes such as MAOA than we previously thought.
  • The specific allele or form of the MAOA gene that a particular indivual has may play a role in governing the type of and optimal dosage levels of that individual's medication needs.

This concludes our four-part series on ADHD genes thought to exhibit gender-specific effects. However, we will continue to re-visit some of these topics in future posts on this blog.

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Friday, March 13, 2009

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:

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.

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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:

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.

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Tuesday, March 10, 2009

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:

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).

  • 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.

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Saturday, March 7, 2009

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:

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

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Friday, March 6, 2009

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.

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