Omega 3 Fatty Acids and ADHD: The Theory Behind the Practice

How Omega 3 Fatty Acids work and their influence on ADHD

In the past couple of posts, we have examined the connections between ADHD and alcoholism. We will continue this discussion shortly, when we begin to investigate specific genes of overlap between the two. One of these genes, whose products are thought to be affected by alcohol consumption, and appears to have some degree of influence on ADHD is called the Fatty Acid Desaturase 2 gene. We will be investigating this gene in the next post, but I want to preface it with a bit of a background information as to why fatty acids, especially the famous omega 3's, are believed to be so attractive as potential natural treatments for managing ADHD (as well as a host of other disorders).

Since ADHD is so strongly affiliated with the nervous system, the physical composition of this system is extremely important when considering some of the implications for this order. Keep in mind that the brain is over 60% fat in humans and other mammals.


Additionally, during the brain developmental stages, neurons are coated with an insulation of sorts, a fatty material called myelin. This whole process is called myelination. When this myelination process is complete, a neural connection can be up to 100's of times more efficient, and signaling through these connections can become exponentially faster. During the teen years, this myelination process often runs rampant, as the brain begins to hardwire itself for greater efficiency. That is why it is so crucial to develop these key connections early in life, before this myelination process begins.

Given the importance of fat in the myelination process, and the overall abundance of fat in the brain as a whole, the nervous system is extremely influenced by fat composition obtained from dietary means. Cell membranes, which are the outer protective layers of cells (in all parts of the body) are also comprised of fatty materials. Among these are omega-3 fatty acids and omega-6 fatty acids.

**Please note: the rest of this post deals primarily with the biochemistry of omega-3 fatty acids and their impact on cell structure and function, and their connection to disorders like ADHD. If you are just interested in general strategies on omega-3 supplementation, you can skip to the end of the post, where I have listed 6 tips to increase your chances of effective treatments. If you want a bit more background as to why I am giving these suggestions, please continue reading!

These two types of fatty acids each have unique structures, which means that their incorporation into the cell membrane also affects its structure. For example, omega 3's typically take on a more curvy shape, and omega 6's are often more "straight" and narrow. Because of these shape differences, the omega-3 rich regions of the cell membrane are more prone to forming "gaps" in the cell membrane, making this whole region more "fluid". However, the straighter, more rigid, omega-6 regions of cell membranes make for tighter and smaller gaps, making the cell membrane less flexible. Numerous studies have shown that fatty acid composition in cell membranes is directly affected by dietary intake of omega-3 fatty acids.

Among the omega 3-fatty acids, perhaps the most important is called alpha-linolenic acid (ALA). The human body is unable to produce this type of fat, so it must be obtained via dietary measures. The body can then convert ALA to two other types of omega-3 fatty acids, DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid). Both DHA and EPA can be incorporated into cell membranes, giving them a more flexible conformation. Not surprisingly, all three of these omega-3's (ALA, DHA and EPA) are currently popular supplements and health-food items. Supplementation with EPA and DHA-rich fish oil has been shown to boost levels of these omega-3's in the cell membrane.

Keep in mind that many of these studies of omega-3 incorporation into cell membranes typically involve blood cells as opposed to nerve cells. However, there have been a few recent findings supporting the incorporation of supplemented DHA into neuronal cells in mammalian systems. Additionally, dietary differences in omega-3 fatty acids has also been shown to influence the ratio of these to other fats in the brain in rat model studies of ADHD, and possibly influence learning behaviors.

The makeup and rigidity of the cell membrane is very important for proper functioning among cells in the nervous system. Gaps, such as those from omega 3 fatty acid regions, allow easier passage of key materials in and out of cells. Among these key openings are a type of passageway, made up of protein-based structures called ion channels. We will see in later posts that ion channels play a huge role in a number of diseases and disorders, including those which involve the nervous system (including ADHD). It is believed that these ion channels are not directly influenced by omega 3's and other fatty acids but rather by the tension on the cell membrane caused by these fats. Therefore, the right amount of tension, governed by the fatty acid composition is thought to regulate ion channel function is necessary for proper cell function.


Additionally, these ion channels are able to change shape, allowing the membranes of different cells to "fuse together" at specified times. This allows for adequate conductance of electrical signals and facilitates communication in-between cells. However, with a more rigid structure (i.e. from one that is deficient in omega 3 fatty acids), this lack of flexibility impairs the ability of these ion channels to change to the optimal conformations necessary for this fusion process. As a result, functional cell-cell communication is hampered. This too, is thought to be a factor in disorders such as ADHD (which will be discussed in future posts).

Perhaps the biggest effect that cell membrane integrity has to do with ADHD is its influence on the signaling agent dopamine. It has repeatedly been shown that ADHD is intricately connected to dopamine-based signaling methods and systems. The role of dopamine on ADHD is especially pronounced in specific brain regions such as the prefrontal cortex, in which this key neurotransmitter is often deficient. Numerous animal studies have shown that a deficiency of omega-3 fatty acids can lead to reduced dopamine function in the prefrontal cortex.

Interestingly, there has been a reported increase in dopamine levels in omega-3 deficient animals in another brain region called the nucleus accumbens. The reason this is somewhat intriguing is that the prefrontal cortex and the nucleus accumbens are thought to work in different directions, in an oppositional sort of way. Some studies suggest that this "ADHD" brain region, the prefrontal cortex inhibits the nucleus accumbens. As a result, a dopamine deficiency in the prefrontal cortex could lead to less inhibition and higher dopamine levels in the nucleus accumbens brain region. This confers the idea that the prefrontal cortex is often deficient in free levels of the important neurotransmitter dopamine.

When addressing ways to "naturally" treat deficits with regards to any type of disease or disorder, it is often tempting to "supplement" the problem away. Because of the dopamine deficiency in the prefrontal cortex, combined with the fact that omega-3 fatty acid deficiencies have repeatedly been seen in ADHD brains, it is easy to jump to the conclusion that rampant supplementation with fish oils and other omega-3 rich sources can make negative symptoms of this disorder go away.

However, research has indicated that although individuals with ADHD have been shown to have plasma deficiencies of omega-3 fatty acids, the cause is not likely to be a dietary omega-3 deficiency. Only a few limited studies have actually suggested direct reduction of ADHD symptoms with omega-3 fatty acid supplementation. For example, based changes in teacher rating scores on ADHD symptoms, children who took EPA and DHA supplements did show noticeable reductions in ADHD symptoms. Interestingly, this same study found that the effects of antioxidant vitamin E were also a large factor.

Even if these studies above hold true for the general population, numerous others have shown omega-3 supplementation to be effective in reducing ADHD symptoms. What is confusing is that this method has proven successful in some instances, while doing little-to-nothing in other cases. As a result, we are left with the big question, why? It appears that the answer may lie in the genes of the individual.

Fatty acid desaturase genes are responsible for coding for a series of enzymes of the same name. These fatty acid desaturase enzymes are important for the metabolism of omega-3 fatty acids. Deficiencies in fatty acid desaturase enzymes are not limited exclusively to genes. We now know that external chemical factors such as maternal alcohol use can also reduce the activities of these key enzyme systems. As a result, omega-3 metabolism suffers. Our next post will deal almost exclusively with this topic.

Before we go, I would like to list a few strategies to follow if you're interested in exploring omega-3 fatty acids as a treatment option for ADHD. Of course there is no guarantee that this treatment method will work, but here are a few pointers to stack the deck in your favor:

***Please note: You may be wondering why I am not giving specific dosage recommendations for omega-3's. There are two main reasons: 1.) There are still no clear-cut established daily amounts, and with the information I currently have, I am not fully comfortable in recommending a numerical amount, and 2.) Due to so many other factors at work (such as age, gender, disease status, cardiovascular health, genetic background, total caloric intake, and other dietary choices), omega-3 recommendations do not follow a one-size-fits-all model. However, a better option is to keep a good balance between omega-3 levels and intake levels of other fats. Since dietary fat intake plays a huge role on hormonal functions, overall ratios and balance play as much of a role as total amounts. Nevertheless, if you're looking for a rough estimate, many of the sources out there generally suggest levels of around 1-2 grams (on the higher end of this for men and the lower end for women) total of omega-3 fatty acids per day.

1. Take a mixture of omega-3 fatty acids, not just one kind. Since ALA is the omega-3 precursor (mentioned above) to EFA and DHA, it might be tempting to just take ALA and let it convert to these other omega-3's in the body. However, this conversion process is slow and inefficient, as the enzyme system involved results in less than 1% of the ALA being converted to EPA and even less (since EPA goes through a series of steps using other enzymes to convert itself to DHA) to DHA.
2. Don't omega-3 overload. This is extremely important. Many well-meaning treatment methods for ADHD and related disorders often try to force down high levels of these seemingly benign substances to "cure" these disorders. However, an omega-3 overdose can also cause problems. These enzymes (which are the same desaturase enzymes will will be discussing in the next post), operate by a mechanism called negative feedback. This means that if omega-3 levels are too high, the activity of these enzymes is significantly reduced, and the conversion processes listed in suggestion #1 are greatly impaired.
3. On the other hand, keep a good balance between omega-3 fatty acids and omega-6 fatty acids. Recommendations may vary, but most sources recommend between a 1:1 and 2:1 ratio of omega-6's to omega-3's. Unfortunately, most Western industrialized diets have a much more skewed ratio, often upwards of 10:1 or even 50:1 in favor of the omega-6's. This imbalance, too, will affect enzyme activity in the omega-3 conversion process. As mentioned above, a balance of these dietary fats is essential for maintaining proper structure and integrity of cell membranes. While this is a bit of oversimplification, fats from marine sources are typically much greater in omega-3's and fats from land animals is higher in omega-6's (and another class of fats called omega-9's, which the body can actually produce from the other 2).
4. Keep your vitamin E levels up to speed. Since the brain is comprised of high levels of fat, it is one of the most oxidation-prone organs in the entire body. A number of neurodegenerative diseases such as Alzheimer's are thought to be products of this oxidation process. While all antioxidants have some benefits, vitamin E appears to be one of the best with regards to brain health. This is in part because it is a fat-soluble vitamin (unlike vitamin C, which, in its most common form, is not). I mentioned in the study above on a reduction of ADHD symptoms based on teacher evaluations after omega-3 supplementation that vitamin E levels were also a major factor in the study.
5. On the other hand, don't go overboard on the vitamin E. General daily amount recommendations and upper limits (a bit high in my opinion for the upper limits, try to stay well under these upper boundaries), and food and supplement sources of vitamin E can be found here. While a number of antioxidants are water-soluble, like vitamin C (which can easily be flushed out of the system and much tougher to overdose on), vitamin E can build up to toxic levels in the body much more easily. An alternative strategy is to take sufficient levels of vitamin C, which can help "recycle" vitamin E and enhance it's positive antioxidant effects while reducing the likelihood of toxicity.
6. This should go without saying, but eliminate alcohol intake if you are pregnant. We will spend our next entire post on the negative effects of maternal alcohol consumption on these desaturase enzymes which are needed to convert dietary omega-3's to ones which can be used by the cells. This is another possible link between alcohol and ADHD, a topic which we have been exploring in quite a bit of depth as of late.

ADHD: A Precursor to Alcoholism? (Corpus Callosum part 2)

In the previous blog post on ADHD and alcoholism, we investigated some of the signs of overlap between the two disorders. One factor which both disorders appear to share in common is a reduction in volume of specific brain regions, including the corpus callosum, the genu, and the isthmus, when compared to similar individuals who do not exhibit either of the symptoms of ADHD or alcoholism. For a generalized location of these brain regions, please see the diagram below (which is a reprint of the figure from the last blog entry):

The corpus callosum is the tan band located inside of the gyrus cinguli, also known as the cingulate gyrus, a brain region whose role in ADHD we have discussed previously. The isthmus region is relatively small and is not labeled on this diagram. It is located to the right of the label "corpus callosum", and is just to the left of the area labeled "splenium".

**Please note my use of nomenclature here, I am continuing to use the same labeling as I did in the previous post. Here, we are considering the "genu" and "isthmus" as separate, distinct regions from the corpus callosum due, in part, to how they were classified in the studies I have been reviewing. However, many professionals label them all as one entity, with the genu and isthmus serving as sub-sections of the corpus callosum as a whole.

In today's blog, we will discuss the answers to two key questions:

1. Is there a hereditary factor at play for the size abnormalities for these three brain regions?


2. Does the outward expression of symptoms for one of these two disorders predate the other? In other words, is the appearance of ADHD symptoms a warning sign of impending alcohol abuse (or vice versa)?

For the answer to the first question, we turn to a journal article by Venkatasubramanian and coworkers in the journal Psychiatry Research: Neuroimaging. This group found that the relative size of the corpus callosum, genu and isthmus regions of the brain were correlated to an individual being at "high-risk" or "low-risk" for alcohol abuse. In this study, the "high-risk" group had a statistically significant reduction in size of multiple brain regions when compared to the "low-risk" group.

For comparison purposes, the "high-risk" group had approximately:

• a 9% reduction in corpus callosum volume
• a 13% reduction in the volume of the genu, and
• a 17% reduction in isthmus volume when compared to the low-risk group for these brain regions.

**Note: it worth mentioning that the comparative differences in relative brain sizes followed some sort of age-dependent trend. The subjects of study were boys and young men between the ages of 9 and 23. For the age 9-15 group, all three of the above brain regions were smaller. However, for the older group (over 15), only the isthmus region had a statistical size difference between the "high-risk" and "low-risk" groups. This suggests that either the isthmus region follows a much greater developmental delay in individuals identified as being "high-risk" for alcohol dependence than do the corpus callosum or the isthmus region never does fully "catch up" in size to the "low-risk group"

So what exactly constitutes "high" and "low" risk? In this study, the researchers studied males between the ages of 9 and 23 (sampling a relatively even distribution across this age range) who had male parents who both:

1. Developed an alcohol dependence before the age of 25 (average age of dependence around 20)
2. At least two relatives (first-degree), who also had alcohol dependence (average was 3 relatives).

The "low-risk" control group of children and young adults consisted of individuals whose parents were not diagnosed with alcoholism or any other psychological disorders. To ensure that maternal genetic influences were not a factor, none of the mothers of the children (the 9 to 23 year-old group) in the study were diagnosed with alcohol abuse.

This study is of potential interest. While the sample size was small (only 20 "high-risk" and 20 "low-risk"), the choice of following only male parents and male children offered some clear-cut advantages over other similar studies. Among them were:

• It eliminated gender effects. While debatable, some studies have found brain regions like the corpus callosum to be larger in males than in females. Having an all-male study eliminated this potential factor.


• The ages of the two groups (high and low risk) followed similar distribution patterns, to rule out size increases in these brain regions due to aging.


• Since the alcoholism was restricted to the paternal side, physiological effects during pregnancy were eliminated. This is important, as several studies have shown that maternal alcohol consumption during pregnancy can affect the development process including relative sizes of these brain regions. In other words, confounding effects, such as fetal alcohol syndrome were significantly reduced, since none of the mothers in the study suffered from clinical alcohol abuse.


• None of the 9 to 23 year-old test subjects had already developed an alcohol dependence. This eliminates the effects that chronic alcoholism has on reducing the size of the corpus callosum, as reported in recent studies.


• Other than alcoholism for fathers of the "high risk" group, none of the parents of the study participants had any other psychological disorder. This is important, especially due to the effects of comorbidity (disorders or symptoms occurring alongside alcoholism, such as conduct disorders or abuse of other substances) on worsening the symptoms of alcoholism.

So how does ADHD tie in to all of this?

Based on this study's findings, it appears that the expression of ADHD (as well as other "externalizing symptoms", which are symptoms that can be seen outwardly, such as hyper-excitability, conduct disorders, substance abuse, etc.) may be a warning sign of impending alcohol abuse.

For example, it has been postulated that hyperexcitability, which is often seen in individuals with ADHD (especially of the hyperactive-impulsive or combined subtypes) is a genetic precursor to alcohol dependence. In this case, and ADHD-like trait predates alcohol abuse. In other cases, symptoms such as substance abuse, conduct disorders, impulse control problems and other antisocial behaviors have grouped under the umbrella term generalized disinhibitory complex. Here, these numerous symptoms are essentially "clumped together" as one generalized behavior.

Regardless of the "model" one subscribes to, please keep in mind that a reduction in size the corpus callosum, genu and isthmus regions of the brain have been associated with ADHD.

Additionally, the degree of overlap between the two disorders was definitely worth mentioning. Out of the 20 children and young adults of the "high-risk" group, 17 of them were diagnosed with ADHD. Out of the 20 "low-risk" children? Zero.

Keep in mind that the fathers of the high-risk group were not diagnosed with any other disorders, just alcoholism. Additionally, keep in mind that none of the high-risk children had developed an alcohol dependence as of yet. These facts give compelling evidence that fathers who suffer from early-onset alcohol dependence who are not even ADHD themselves, are much more likely to have male children with ADHD, with an onset which precedes alcohol dependence itself.

In essence, this study established a degree of linkage (but not necessarily a direct cause) between the expressed behaviors of ADHD and alcoholism and the physiological features of relative sizes of the isthmus, corpus callosum and genu.

Hopefully this provides evidence that there is in fact a strong underlying hereditary component surrounding both disorders of ADHD and alcoholism. In the next couple of posts, we will investigate some of the individual genes thought to be involved in both of these disorders.

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.