ADHD and Alcoholism: The Corpus Callosum (part 1)

In our last post, we discussed some of the ties between ADHD and eating disorders such as bulimia. In this post, we will begin the first of a multi-part investigation on the connection between ADHD and alcoholism. In this session, we will see how these two disorders are both tied to improper function in a key brain region known as the corpus callosum.

Note the relative position of the corpus callosum in the diagram below (source of image here):

A quick aside: Note the proximity of this corpus callosum brain region to the cingulate gyrus (labeled "Gyrus cinguli" in the diagram above), a region which we discussed in a recent post on attentional control. The cingulate region can be thought of as the brain's "gear shifter". If underactive, it leads to consistent lack of focus on one thought or task (a hallmark characteristic of ADHD), if overactive, the cingulate can result in overfocus (a characteristic of obsessive compulsive disorder, or OCD).

Returning to the corpus callosum area of the brain, which is layered inside the cingulate gyrus, we can see some sub-regions of note. These include the genu and the splenium. There is also a small region (not listed on the diagram above), called the isthmus, which is just to the left of the splenium. Of these regions, pay close attention to the isthmus, genu, and corpus callosum.

Note: the classification of these brain region sometimes varies, some methods classify the isthmus and genu as part of the corpus callosum, while others group them as seperate elements. No need to get any further into specifics, but when I refer to "corpus callosum" in the context of this post, I am referring to the region distinct from the isthmus, genu and splenium.

The corpus callosum is primarily responsible for connecting and integrating information from the left and right hemispheres of the brain. It is composed of millions of individual fibers and is necessary for the integration and processing of sensory information and expressing this information through verbal language. This is one of the later-developing regions of the brain, and continues to develop and become more efficient during adolescence (and even into early adulthood). Studies have shown that this prolonged developmental process leaves brain regions like the corpus callosum more prone to improper development. One of the reasons young children have trouble expressing visual images verbally is because speech control is typically on the left side of the brain and visual imaging and imagination is typically on the right.

Improper development of this corpus callosum region can lead to quirks such as split brain. Additionally, it has been reported that development of this brain region can be impeded by prenatal alcohol exposure and is entirely missing in around seven percent of children with fetal alcohol syndrome. Additionally, chronic alcohol abuse can result in thinning in the corpus callosum region.

In addition to the inhibition of this key brain region due to alcohol exposure listed above, it appears that there may be an underlying factor at play for this region for both ADHD and alcoholism. A reduction in size in the corpus callosum, genu and isthmus has been associated with ADHD in both children and adults. A study done by Venkatasubramanian and coworkers found a connection between smaller volumes in these same three regions of the brain and an increased risk of developing alcoholism.

Note that a reduction in size of the corpus callosum has been linked with a decreased functional ability in this region as well. This includes the processing of information between the left and right hemispheres of the brain in processes such as integrating information of visual images obtained from both eyes.

In addition to its role in expressing and processing ideas and thoughts from both sides of the brain, the corpus callosum is also integral in coordinating movements in different parts of the body. This includes governing motor inhibition (restricting unwanted or inappropriate movements) across the body. Interestingly, individuals with ADHD have been shown to have a decreased ability in utilizing the corpus callosum to control movements, which is often tied to the impulsive behavior of ADHD individuals with their actions (such as constantly grabbing or playing with objects at inappropriate times).

The corpus callosum is not the only brain region thought to be involved with both ADHD and alcoholism. For example, the prefrontal cortex (the brain region behind the forehead), which we have discussed extensively in other posts, has repeatedly been found to be underactive for individuals with ADHD. Additionally, Schweinsburg and coworkers found a decrease in activation of the prefrontal cortex correlates with a higher risk in suffering from alcoholism.

In the next few posts, we will examine some of the genes thought to be underlying factors in both ADHD and alcohol abuse. Additionally, we will examine some of the numbers to get a better understanding of the magnitude of overlap between the two disorders. Finally, we will examine some of the "warning sign" behaviors which youngsters might display before the onset of alcoholism occurs.

However, in the next entry, we will examine whether there is a hereditary factor in place surrounding brain volume, as well the prevalence of expressed outward symptoms of ADHD, and how these are both associated with an increased risk in developing alcoholism later in life.

The ADHD and Bulimia Connection

ADHD is a disorder that has numerous comorbids ("comorbids" refer to disorders that often accompany or are seen alongside of ADHD). These include, but are not limited to: Depression, Tourette's, Conduct Disorders, Sleep Disturbances, Restless Legs Syndrome, Body mass and obesity issues, dysgraphia (poor writing skills and abilities), processing disorders, sensory integration disorders as well as several others.

In the midst of all of these co-occurring disorders, there are a few that often evade the attention of both researchers and the general public. One of these is the disorder bulimia nervosa. Bulimia nervosa (which is often simply referred to as bulimia), which is often characterized by eating (and often binging) followed by purging, is a major issue in many industrialized nations, especially among teens and young women. Based on a study by Surman and co-workers, it appears that there is a relatively high correlation and prevalence of bulima and ADHD. A link to a quick synopsis of the study can be found here, but for sake of time, I will summarize a few key findings from the article:

• Impulsive behavior is a hallmark characteristic of ADHD, and impulsivity is also thought to be a major factor in bulimia as well. It is even hypothesized that some type of underlying factor may be responsible for governing both disorders.

• Given the fact that the disorder of bulimia is expressed at much higher frequencies in young females in late adolescence and early adulthood, it is interesting to note that correlations between the two disorders were relatively weak for men and non-adult women. Additionally, this is worth mentioning because the percentage of individuals with ADHD is heavily skewed towards the male side. That being said, the fact that there was not more of a correlation between ADHD and bulimia in males could be a reflection of either a poor sample size or representation of t he general population, or a relatively weak connection between the two disorders (i.e., one this is unable to override the so-called gender bias of bulimia favoring women and ADHD favoring men).

• These results were tallied from 4 relatively large sample pools previously constructed to evaluate the effects of ADHD over an extended, longitudinal, multi-year period of time. This suggests that some of these relatively strong bulimia/ADHD correlations did not appear simply due to random statistical chance.

• Like ADHD, bulimia has been tied to functional imbalances involving several systems of neurotransmitters, which include serotonin and norepinephrine. It is also possible that hormonal surges during puberty may increase imbalances of neurotransmitters like serotonin, especially in females. Since serotonin levels are tied to feelings of satiation or fullness, imbalanced in this key neurotransmitter can interfere with the feedback of normal eating patterns. In addition to social and environmental pressures, this neurotransmitter imbalance may be another contributing factor to the prevalence of bulimia, anorexia and other eating disorders in females of this age.

• Stimulant medications, such as methylphenidate, which are often the first line of treatment for individuals with ADHD, especially those showing pronounced signs of impulsivity and hyperactivity, have shown potential in the treatment of bulimia, albeit through studies with very small sample sizes.

Taking this one step further, it appears that genetics may be an additional overlapping factor involved in stimulant medication treatment for ADHD. For example, some research suggests that different forms of DAT1 may be responsible for the effects of methylphenidate on appetite and eating behaviors including purging (DAT is short for "Dopamine Transporter Gene"). We have seen previously that there is a connection between the DAT gene and ADHD. Located on human chromosome #5, DAT1 has been linked to Parkinson's, Tourette's and substance abuse.

Additionally, proteins coded for by the DAT gene are expressed in high concentrations in the basal ganglia region of the brain. The basal ganglia is essentially responsible, among other things, for determining how fast a person's brain "idles" For example, "type A" individuals, who are often workaholics, easily stressed, and always on the go at 100 miles per hour often have overactive basal ganglia, while the more relaxed, easy-going, "type B" personalities typically have less activity in this critical brain region. While there also appears to be a significant overlap between bulimia and depression, individuals with bulimia typically display higher basal ganglia activities than those with isolated depressive symptoms.

Given the prevalent distribution of this gene's expressed proteins in key brain regions like the basal ganglia, and the role of involvement of these brain regions in eating disorders, the DAT gene may be an important determining and regulating factor for bulimia and other eating disorders, especially in the context of comorbid ADHD.

Please note: These final remarks are simply this blogger's opinion on the subject:
I personally find this connection between ADHD and bulimia to be interesting. However, I do believe that we should be cautious when investigating ADHD comorbid disorders. It is tempting sometimes to fall into the trap of falsely assuming that correlation always implies causation, and trying to find underlying causes for disorders and attempting to link ADHD to every other disorder under the sun.

However, the role of the DAT genes, which have been tied to ADHD, do offer at least some credence to at least some degree of genetic predisposition to both ADHD and bulimia. This claim is further strengthened by the degree of overlap involving medication treatments of the two disorders, namely stimulants. However, there have been several documented cases of the disappearance of bulimia symptoms following treatment with methylphenidate (Ritalin, Concerta, Daytrana, etc.) for comorbid ADHD.

As a result, we may be faced with a "chicken and egg" question: "Does bulimia increase the risk of ADHD or does ADHD increase the risk of bulimia?" (or even "Are they both side effects of an even larger underlying cause?"). Another plausible explanation is that ADHD is a culmination of secondary effects involving bulimia and other eating disorders. Constant purging will typically wreak havoc on the digestive system and lead to improper food and nutrient absorption. I have hinted in previous posts that digestive disorders such as celiac disease can often manifest symptoms which closely approximate those of ADHD. Given the mounting evidence connecting ADHD (or other disorders which exhibit closely related symptoms which could potentially lead to a "false" diagnosis of ADHD if one is not careful) to nutrient deficiencies, it is quite possible that ADHD and its symptoms are secondary effects of nutritional deficits caused by eating disorders such as bulimia.

Gene Variations Which Affect Attention Control

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

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

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

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




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

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

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


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

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

What does this all mean?

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


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

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


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


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


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

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


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

While the two studies of the two different brain regions and their respective tasks (the prefrontal cortex and working memory tasks vs. the cingulate region and attention control tasks) shared a high degree of overlap in their results, there were some key differences:

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



• When it comes to task performance requiring attention and working memory, it appears that differences in dopamine-governed signaling processes (such as those arising from "Val" or "Met" forms of the COMT gene), it appears that accuracy differences in performing tasks is more pronounced in cingulate regions of the brain, where differences in speed, reaction time and even premature decision-making are more evident in the prefrontal cortex region of the brain.
  
  
• Within the context of this post, it suggests that "Val" individuals are more prone to slower processing, poor reaction timing and impulse control on tasks involving the prefrontal cortex (such as tapping into working memory in tasks such as recalling and utilizing stored information such as math formulas or physics equations), and more likely to be error-prone with regards to tasks involving the cingulate region (such as discriminating between multiple conflicting stimuli and maintaining attention to the "correct" one).
  
  
• Taking the above one step further, this possibly suggests that if an untreated ADHD individual who has the "Val" version of both genes was taking a physics test, he or she could likely perform in a comparable manner to that of a similar individual with the "Met" form, if he or she had extra test time. This is because this type of test would likely involve working memory (i.e. recalling and then using an appropriate formula for a particular physics problem). However, if a continuous external distraction was present (such as a loud air conditioner or a flickering light or an attractive member of the opposite sex seated nearby), having extra test time would be less likely to even the playing field for our poor "Val" individual. This of course, may be stretching and over-simplifying quite a bit (of course we know that there are way more factors involved than just this), but these somewhat subtle genetic differences could possibly have some implications when it comes to discerning and providing accommodations for individuals with learning disabilities, especially in an academic or work environment.
  

These findings have medication implications as well. Based on the Prefrontal Cortex / Working Memory studies with regards to the "Val" and "Met" forms of the COMT gene, we have seen that differences in ADHD medication dosage are affected, with "Val's" typically requiring more stimulant medications than "Met's" to achieve optimal dopamine balance. However, in the cingulate brain region, another key signaling chemical called serotonin also comes into play. As mentioned previously, the cingulate region is thought to play a role in OCD, and medications of the antidepressant variety (which often boost serotonin levels and can actually indirectly reduce dopamine production, as serotonin and dopamine can sometimes act in a "push-pull" manner, where an increase in one can decrease the other) are often utilized as a medication treatment option.

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

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

Genes and ADHD Brainwave Patterns

There is mounting evidence surrounding the genetic basis for ADHD. Some studies place the blame on genes, as heritability of ADHD may be as high as 75 percent. Some of the specific ADHD genes under investigation can be seen here.

EEG has been a hot topic of discussion as of late for individuals suffering from attentional difficulties. Short for electroencephalography, EEG is an electrical measuring device used to monitor brainwave patterns and frequencies. In general, the higher the frequencies, the more "alert" the individual is:

Some common states and their EEG ranges can be found below. Note that the numbers are in hertz or cycles/second

Delta: 1-4, sleep
Theta: 5-7, daydreaming
Alpha: 8-12, relaxation (watching TV)
SMR (Sensorimotor Rhythm): 12-15, Focused relaxation, live sporting events, easy video games
Beta: 13-24- concentration
High Beta: over 25-30, anxiety and related symptoms

Individuals with ADD or ADHD often (not surprisingly) have more difficulty staying in the Beta range and are seen excessively in the Theta state. EEG programs are available in which the individual attempts to remain in a beta state for as long as possible. Essentially, they "train" the brain to hold a higher frequency, often through some type of interactive computer game which stops when beta frequencies are no longer maintained.

To be perfectly honest, I know relatively little about the intricacies of this procedure. However, based on what I've gathered so far on the subject, this practice seems to have had a moderate amount of success. Some consider it to be too costly or over-prescribed, while others swear by the results. Based on what I've read, typical treatment is often comprised of weekly interactive EEG treatments for a period of 1-2 years. At this point, I am not in a position to give advice on this alternative treatment measure for ADHD and related disorders, but I do find at least the theory behind it to be highly plausible.

Returning to the genetic basis surrounding EEG measurements for a moment, we see that the degree of heritability is thought to be highest somewhere around the high alpha and low beta states (right around the Sensorimotor Rhythm region mentioned above) and begins to decrease at both higher (high Beta) and lower (Delta and Theta) states. Given the difficulties of achieving a consistent Beta state for ADHD'ers, we can see that these difficulties may fall right in the eye of this storm of heritability and genetic predisposition.

A comparative study was done examining EEG patterns of un-medicated children with ADHD who had siblings or parents with the disorder. This study measured baseline brainwave frequencies and brainwave patterns when the subjects underwent a Continuous Performance Task.

In a nutshell, Continuous Performance Task tests measure both inattention and impulsivity, both of which are landmark ADHD characteristics.

How the Continuous Performance Task test typically works:
An individual may be asked to press a computer button only after seeing a specific letter or shape. If that letter or shape is shown only rarely, then the individual enters a "bored" state (which is often connected to Theta activity, which is typically higher in ADHD individuals to begin with). As a result, he or she may space out and miss when the letter or shape is finally presented on the screen. This "miss" is called an error of omission, and is reflective of inattention.

On the flip side, if the letter or shape is constantly being shown, the individual may attempt to "guess" when it is next displayed and push the response button prematurely. This is an error of commission, and is more connected to impulsivity.

Correlations in EEG patterns between siblings was much higher for measures taken in a state of cognitive activation (i.e. when undergoing the continuous performance task listed above) than EEG baseline patterns. This suggests that ADHD genetic differences are much more pronounced during cognitively challenging situations, than during rest. In other words, similarities in brainwave patterns of ADHD siblings are greater during cognitive tasks than while at rest.

• The only statistically significant EEG pattern seen between siblings at the resting or baseline state was that of the theta state in the frontal region of the brain. This is interesting to note, because this region, which includes a brain domain called the prefrontal cortex, which is thought to be one of the major "hot spots" for chemical imbalances in an ADHD brain.

• During these performance tasks, which involve periods of concentration, it was noted that correlations between sibling brain wave patterns were extremely high; higher than a cause which was purely genetic would indicate (since non-identical twin siblings only share half of the same genetic material). This suggests that among these siblings, both genetics and overlapping environmental factors are both at work.

• While all brain wave states during concentration tasks were thought to be genetically connected, it appears that changes in the alpha state (and somewhat with the theta state)were the most pronounced. This was believed to be due to an overall decrease in these overall frequency states during concentration tasks, which suggests that in order to maintain concentration for a cognitive tasks, the brains of these individuals were forced to work "harder" by operating at a higher frequency (Beta) state. To overstate the obvious, this supports the idea that ADHD brains must work harder to maintain an attention span by bumping up to a higher state.

• One note of particular interest: It appears that genetics (i.e. having at least one parent with the disorder) plays a much greater role in errors of omission (see description near the top of this post) than in errors of commission. Since errors of omission are more associated with inattentive behavior and errors of commission are more associated with impulsive behavior, it suggests that genes are more likely involved in individuals who are more of the predominantly inattentive ADHD subtype than they are for the hyperactive-impulsive ADHD subytpe.

• While genetics appeared to be connected to overlaps in brain wave states and how hard the brains of ADHD siblings had to work to maintain attention, there was little statistical evidence linking actual cognitive task performance to family-based genetic heritability. In other words, while the brains of these children with ADHD had to work harder to complete the cognitive task, the overall abilities to actually perform the task were not thought to be tied to familial inheritance (such as from the parents).

• This above point suggests two things: 1.) Individuals with ADHD are able to over-ride genetic predispositions and maintain an attention span, albeit at a higher cost, and 2.) EEG is a powerful diagnostic tool that is a more accurate predictor of genetic heritability of ADHD than are physically detectable symptoms (such as observed bouts of inattention, hyperactivity or distractibility).

While these findings are encouraging, it is important to note that EEG-based treatment of ADHD is still in a period of relative infancy. However, like the experience of watching a duck on the water (who appears to be calmly floating along while his legs are thrashing below the water's surface) EEG offers the unique ability to detect the "thrashing below the surface" of an ADHD brain. The studies above strongly suggest that there may be a much greater genetic component to this thrashing than we previously expected.

Reboxetine for ADHD Treatment

In previous blog posts, I have mentioned some unconventional and lesser-known medications used to treat ADHD. Many are either new to the market or have primary uses not designated as ADHD drugs, such as anti-depressants, mood-stabilizers, anti-convulsants, etc. Unfortunately, these results are often obscured or hidden from the general public. The medical community (somewhat understandably) often initially shies away from these studies because they are often done on a small scale, have less-rigorous built-in-controls, are not done by big-name researchers, are studied in foreign countries, and are published in less-prominent journals. What is often surprising is that the results of treatment with these less-publicized medication choices, is that, although small and somewhat isolated in nature, a number these studies have displayed eye-opening levels of success, and should warrant further investigation.

The beauty of being a blog-writer, as opposed to a highly-publicized journalist, is that one can take more of a "chance" by reporting some of these findings, without feeling pressured to stick to the more "mainstream" findings.

Without further ado, the drug of topic for today is Reboxetine.

Like many ADHD drugs, Reboxetine (also marketed under labels such as Solvex, Prolex, Vestra, Davedax, Edronax or Norebox). It's main line of treatment is for depressive and panic disorders, but has also shown solvency in the treatment of ADHD on a small-scale. Like many other ADHD medications, Reboxetine exists as a mixture of two compounds, which are mirror-images (also called enantiomers), of each other. It is used in a number of European countries, but is yet to be approved in the United States.

Functionally, and to a lesser-degree, chemically, Reboxetine resembles another common ADHD medication, Strattera (Atomoxetine). Unlike many types of anti-depressant medications, which often target the key neuro-signaling agent serotonin, Reboxetine's primary target is another major signaling compound known as norepinephrine. Norepinephrine, a chemical "cousin" to adrenaline, is often found to be at lower-than-normal levels in the surrounding environment outside neuronal cells in individuals with attentional and depressive (in addition to other related) disorders. Essentially, there is an imbalance in the amount norepinephrine inside and outside the cells on the nervous system. Reboxetine functions as a "blocker" of the process of taking norepinephrine up into neuron cells, which helps restore the balance of this neurotransmitting agent inside and outside cells in the nervous system.

This selective restoration of balance concerning levels of norepinephrine serves other benefits as well. For example, disorders such as fibromyalgia and chronic pain are associated with norepinephrine level imbalances. Based on multiple case studies, it appears that reboxetine can help alleviate at least some of these pain-related symptoms. Attentional deficits are often (perhaps, not surprisingly) a secondary symptom of pain-related disorders, so this is of some therapeutic value already. Additionally, migraine headache pain is also a common comorbid symptom of ADHD. However, there is more...

One of the most difficult issues surrounding drug design is specificity. We naturally want the drug to reach its desired target in the body. However, it is often difficult for a drug to reach only its specific target and avoid all other undesired ones. Unfortunately, this is not always possible, and one of the main consequences of a drug's lack of selectivity is unwanted side effects. In the case of Reboxetine, however, it appears that its overall degree of affinity for unwanted targets (often referred to as receptors in biological terms) is less than many other comparable medications. In other words, Reboxetine is less "promiscuous"; it has minimal interaction with target receptors for other neurotrasmitters such as acetylcholine (which can lead to digestive dysfunction, and is partly responsible for the dry-mouth and constipation symptoms found in many drugs) and serotonin (which can lead to drowsiness and other sedative effects).

Returning to the specific topic of ADHD, however, Reboxetine has shown to have some other advantages over other ADHD medications.

• Reboxetine is long-lasting. Reboxetine's plasma half-life is around 13 hours (that is, it takes around 13 hours for half of the drug to be cleared and eliminated in the body). In comparison, atomoxetine (Strattera) has a plasma half-life of around 4 hours.

• It serves as a good "back-up" treatment for ADHD as a medication. While stimulants remain the drug class of choice for ADHD, roughly 30% of children with ADHD show little response to stimulant medications. Based on findings from a recent study, children with previous adverse effects to methylphenidate were able to handle Reboxetine. In addition, based on a side-by-side comparison study of Reboxetine and methylphenidate, the Reboxetine performed equally well with its counterpart as far as reducing ADHD symptoms.

• While some medications have shown to be effective in treating the predominantly inattentive symptoms of ADHD or the hyperactive-impulsive symptoms of the disorder, Reboxetine appears to improve symptoms of both. Based on a study of boys ages 6-16 of the Combined subtype (that is, they show significant levels of inattentive as well as hyperactive and impulsive symptoms), treatment with Reboxetine showed significant improvements based on parent ratings in as little as 2 weeks.

• In addition, Reboxetine has shown some success in treating conduct disorders, which are often comorbid to (or occur alongside of) ADHD. In this case, the disorder was called hyperkinetic conduct disorder, which is very similar to ADHD, but with more severe behavioral issues and a greater probable genetic component.

• While specificity in choice of biological targets appears to be an advantage of Reboxetine, it also appears that Reboxetine can also boost free dopamine levels in the prefrontal cortex region of the brain (which is a region thought to be highly-connected to ADHD). Dopamine is another highly important agent used in signaling throughout the nervous system and its cells, and is intricately connected with ADHD in the prefrontal cortex region of the brain (which is located behind the forehead). Reduced levels of dopamine in between nerve cells in this important region of the brain (like the lower levels of norepinephrine described above), typically results in an increased onset of negative ADHD symptoms. These effects are thought to be more indirect, as norepinephrine carriers can also transport and clear dopamine from the areas in between neuron cells. However, if these carriers are tied down or "busy" handling the Reboxetine, then these carriers are less available to shuttle away the free levels of dopamine in this critical brain region. As a result, a gradual build-up to more "normal" levels of dopamine are seen, which often results in a reduction of ADHD symptoms.

Other interesting points of note regarding Reboxetine:

• As mentioned above, Reboxetine was rejected by the FDA in the United States, although it has been used widely in over 50 other countries. The reasons for its rejection by the FDA have not been disclosed in full to the general public.

• While the study mentioned above cited the effectiveness of Reboxetine treatment for some children who had experienced adverse side effects with methylphenidate, around half of the children in the study who showed negative side effects to methylphenidate also saw similar effects to Reboxetine (although many were more mild than for methylphenidate).

• While Reboxetine does not target serotonin receptors like many other antidepressant medications (which can cause sedative effects), drowsiness is still one of the more common side effects of the drug. Additionally, treatment with Reboxetine can also lead to appetite suppression, which is a common side effect of stimulant medications used to treat ADHD.
  

• While dopamine is the main agent of concern in the prefrontal cortex region of the brain with regards to the disorder ADHD, norepinephrine levels in this brain region are thought to be connected to oppositional behavior. While this study used atomoxetine for treating these symptoms (albeit in a rat model), it leaves the door open for investigation of treatment with atomoxetine or reboxetine for both ADHD along with comorbid conduct disorders such as Oppositional Defiant Disorder (ODD, which is actually quite common in ADHD individuals).
  

• Reboxetine is metabolized mainly in the liver, using an enzyme called CYP3A4. Several other drugs and food compounds also utilize this enzyme system. This is important because when two or more drugs or food-substances share a similar pathway, there is a much greater potential for these substances to interfere with each other. The result is often impairments or drug-drug interactions. For a comprehensive list of other types of drugs and compounds which also use this enzyme system, please click here. Although not emphasized in the previous link, I personally found it interesting that the compound quercetin was a strong inhibitor of this enzyme system. Quercetin is found in high concentrations in foods such as onions, teas, apples, and berries, many of which are touted for their numerous health benefits such as cardiovascular health and antioxidant properties. While no significant studies (at least to the best of this writer's knowledge), have been done on the effects of quercetin and the drug Reboxetine, there is a strong possibility that high levels of consumption of these healthy antioxidant-rich foods may actually interfere with the metabolism of Reboxetine and potentially alter its effectiveness in treating ADHD or related disorders.

In spite of a number of positive findings surrounding the drug, there is still a shroud of mystery (much of which is due to the FDA rejection of the drug in the U.S.) over the effectiveness of Reboxetine for treating ADHD on a large scale. Given the fact that its main function is that of an antidepressant, it would appear that functionally, Reboxetine would be useful for treating individuals with ADHD and comorbid depression (in a way somewhat analogous to drugs such as Wellbutrin).

Nevertheless, some of the promising results surrounding the drug suggest a potential for treatment of comorbid conduct disorders. This may serve as a potential all-in-one approach, as opposed to being prescribed multiple drugs for multiple co-existing symptoms. The versatility of this drug is intriguing, especially when we consider the relative specificity that Reboxetine has almost exclusively for the signaling agent norepinephrine.

Given the fact that this class of antidepressants appears to bypass the serotonin-dependent pathways, it is possible that this drug could be used in conjunction with other anti-depressant drugs as well, with a reduced potential for negative drug-drug interference.

Finally, due to its comparatively long half-life, and potential interference from foodstuffs such as quercetin, there is an increased risk of unwanted buildup and possible side effects associated with toxicity issues surrounding the drug. Nevertheless, there is room for further exploration, especially in the context of approaching ADHD treatment from a different angle than most stimulant medications. This is definitely a drug to keep on the radar for the near future.