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to hold a higher frequency, often through some type of interactive computer game which stops when beta frequencies are no longer maintained.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.

Does Lead Exposure Cause ADHD?

Many of these findings were based off of an original journal article regarding prenatal tobacco and lead exposure and the onset of ADHD by Braun and coworkers in the December 2006 issue of the journal Environmental Health Perspectives. For a quick synopsis of this article on lead and ADHD, please click here. Interestingly, this same group also published more recent papers on the effects of lead on conduct disorders, which are often comorbid to ADHD cases. This should be especially relevant for pregnant or nursing mothers. For more information on ADHD and pregnancy, please check out the collection of posts on this blog addressing the topic, which can be found here.

While the relevance of several studies regarding the effects of lead on ADHD and cognitive dysfunction is called into question, often because the lead-levels reflect a much higher exposure than what is often faced by the general population, a relatively large study done recently indicates that even moderately high blood lead levels show a strong correlation with ADHD. This suggests either one of two things:

• Other unknown or "hidden" factors were present in the lead-based studies which were the major contributors to impaired mental function and disorders such as ADHD. Even with lower lead levels, these under riding factors were still present, and therefore the major contributing causes to the disorder were still present.

OR

• The sensitivity to lead exposure in children is even higher than previously thought.

An important question we should be asking ourselves is "Does lead exposure beyond a certain point trigger specific ADHD symptoms, or is there an increase in ADHD behavior across the board?".

ADHD is often defined by two major components, the hyperactive/impulsive component and the inattentive component. Based on a recent publication by Nigg and coworkers in the February 2008 Journal of Biological Psychiatry, it appears that the hyperactive/impulsive component of ADHD predominates based on exposure to lead.

Interestingly, the children investigated in the study above were of the inattentive subtype or the combined subtype (both inattentive and hyperactive/impulsive) of ADHD. Based on these results, it is my personal opinion that a child who, under other circumstances may otherwise be of the ADHD inattentive subtype, could instead fall into the ADHD Combined Subtype if he/she is exposed to a specific quantity of lead during the prenatal or early childhood stages of development. Furthermore, I propose that, had the individuals in the study have been of the predominantly Hyperactive/Impulsive Subtype of ADHD, the results would have shown that lead exposure beyond a critical thresh hold would have exacerbated the already-negative hyperactive behaviors for this particular subtype.

In addition to the negative effects surrounding the hyperactive elements of ADHD, the study also found a correlation between low-level lead exposure and child IQ's. This, of course, has been a hotly debated topic for years. While other factors may clearly be at work (lead exposure is often higher in areas with lower socioeconomic status, which is also a factor often correlated with lower IQ scores), the results of numerous studies, many of them recent, still support a strong possible connection.

Theoretically, then, by significantly reducing the prenatal or early-developmental exposure to lead, a child may be at least partially shielded from negative symptoms such as a lower IQ and hyperactive behavior. However, for individuals with the predominantly inattentive form of ADHD, these lead-restrictive measures would be less effective in addressing their inattentive behaviors. Therefore, it is my opinion that reducing lead exposure due to prenatal intervention, iron therapy, or, even possibly chelation methods (both of which will be discussed in future posts), would be most effective for treating the Hyperactive/Impulsive and Combined subtypes of ADHD and less effective for the Predominantly Inattentive ADHD Subtype.

While we should be careful not to overplay or overhype the lead/ADHD connection (especially given the fact that overall lead exposure risks have gone down throughout most of the world in recent years due to the uses of unleaded gasoline and lead-based paint, among other things), it is important to recognize that there is still a statistically significant connection between the two, at least according to a number of recent studies. The Nigg paper, mentioned above, found a strong correlation with hyperactive ADHD-like behavior at much lower lead levels (much closer to the average levels found in much of the United States) than those in most previous studies. This information is particularly important to pregnant mothers, since it has been demonstrated that the negative effects of lead, and other heavy metals and toxins are more harmful on developing brains and nervous systems than to mature ones. The protective effects of reducing lead exposure to mitigate the negative symptoms of ADHD, should not, in this blogger's opinion, be overlooked.

In the next post, we will be discussing how treatment or supplementation with iron may be able to offset some of these harmful effects of early lead exposure on ADHD, should they occur.

Magnesium Deficiency and Childhood ADHD

Magnesium Levels and the Connection to ADHD
In the last blog post, we talked about how an iodine deficiency in pregnant women can lead to ADHD and other cognitive dysfunctions in children. Iodine is just one of the many key nutrients that have been correlated with a worsening of ADHD-like symptoms. The effects of deficiencies for more well-known minerals such as iron and zinc are widely published. Low levels of both of these minerals have been associated with the onset of ADHD, and will be discussed in later posts. However, a lesser-known but equally important mineral relevant to ADHD and overall brain function is magnesium. There have been multiple studies linking low levels this key nutrient to an increased onset of ADHD.

Signs and Symptoms of Inadequate Magnesium Intake
Magnesium actually shares a functional overlap with iodine as far as proper bodily function is concerned. It plays a crucial role in maintaining function in a number of enzymes and other essential proteins. Additionally, like iodine, magnesium is essential for adequate bone health as well as maintaining adequate body temperature and energy levels. There are a number of signs of magnesium deficiencies which actually mask symptoms of other diseases, but some of the most distinctive signs of low magnesium levels are unexplained ulcers in the mouth area. Additionally, while allergies and asthma occur at higher levels in individuals with ADHD as comorbid disorders, the presence of ADHD, allergies, asthma and fibromyalgia (high levels of constant pain and sensitivity to touch) can be due to inadequate magnesium levels in the body.

Frequency of Magnesium Deficiencies and Recommended Daily Amounts
Like iodine, magnesium deficiencies are relatively common in industrialized countries. In children, these trends are even more ominous, with some estimates placing up to 90% of children in the magnesium deficient category. Recommended amounts typically fall within 280 to 400 mg per day, with men requiring slightly higher amounts than women. Seeds and nuts are among the best sources of this vital nutrient, with one of the best options being pumpkin and squash seeds (1 ounce provides about a third of the recommended daily amount).

**Please keep in mind that the recommended magnesium levels of 280 to 400 mg are for adults and older children. For newborns (around 30 mg/day) to children under 9 (130 mg/day), the requirements are lower. While there are no "food-based" upper limits for magnesium, there are for supplements. This is due to in part to different absorption patterns of the different magnesium forms in supplements as opposed to foods. Please click here to see some tables for recommended and upper limits of magnesium for children. Also, keep in mind that certain antacids and laxatives contain high levels of magnesium already, so please follow the upper limit max for supplements.

Treating ADHD with Magnesium Supplementation
Given the relatively low consumption of these foods by individuals in westernized countries, as well as the prevalence of nut allergies, supplementation with magnesium is another good option.
While both of the main components of ADHD (inattention and impulsivity/hyperactivity) are both associated with low levels of magesium, it appears that the hyperactivity factor is even more pronounced. The effectiveness of magnesium treatment is boosted by another key nutrient in the family of B vitamins, namely Vitamin B6. My next blog post will go into more detail about this treatment combination for ADHD.

Increasing Concerta Medication Dosage: Benefits and Risks

In the last post, we introduced the concept of dosage windows for ADHD medications. In other words, we see that the dosage level of an ADHD medication can be of equal importance to the type of medication used. For more info on this topic, please check out the blog site of Dr. Charles Parker called CorePsychBlog. It is extremely well-organized, concise, and easy to follow, in my humble opinion. This is where I was first introduced to the "window" concept of medications, the term which I have borrowed for the last couple of posts.

This post is meant to expound on the dosage principle in the context of on of the more popular ADHD stimulant medications currently on the market, Concerta (slow-release methylphenidate). We will be drawing information from a few key articles, including one from the 2003 Journal of Pediatrics by Mark A. Stein and coworkers. A copy of the original online journal containing a summary of this article can be found here.

If you do not have time to read all of this post, feel free to skip to the last paragraph at the bottom of the page to get the overall message of this blog entry. If you are looking for more detail, I have addressed the key points made in this article in the major points below:

• The drug Concerta releases the active methylphenidate ingredient into the system at slowly increasing levels over roughly a 12-hour period. The overall effect is similar to that of the traditional tri-daily methylphenidate medication.

• The article studied the positive and negative effects of this medication in 5 to 16 year-old children under three different common prescription doses, 18, 36 and 54 milligram doses. These children were of average or above-average IQ, with about 1/3 being diagnosed as Learning Disabled. About two-thirds of the children had never taken any type of stimulant medication for ADHD before the study.

• Noticeable differences were seen between different ADHD subtypes. For the Inattentive subtype, lower levels doses were optimal, while for the Combined subtype (inattention plus impulsive behavior plus hyperactivity), higher amounts were typically optimal. When the effects of co-occuring disorders such as oppositional defiance (ODD) and learning disabilities were factored out to focus in the ADHD itself, the subtype differences were even greater. This underscores the need for proper subtype diagnosis as opposed to just labeling an individual ADHD.

• For the Primarily Inattentive (PI) subtype of ADHD, the inattention difficulties improved most dramatically with the first 18 mg of medication. Beyond this dosage, only slight effects were seen. This is in agreement with another earlier study which analyzed different doses of another form of methylphenidate for treating ADHD. For the accompanying hyperactivity and impulsive behavioral symptoms (which are often present in the inattentive subtype, just not at the same elevated level of the Combined subtype) were most effectively reduced with the first 18 mg of the medication. While the effectiveness of higher doses leveled off, slight but noticeable improvements were also seen as medication dosage was increased from 18 to 36 mg. At 54 mg, however, improvements stopped or even regressed. This suggests that the "sweet spot" for the Inattentive Subtype of ADHD is somewhere around 18 mg (or slightly higher). Note that Concerta is also available in the 27 mg level, a dosage which was not tested in the study.

• In contrast to the Inattentive Subtype, where the greatest gains were seen from 0 to 18 mg of Concerta, for the Combined Subtype of ADHD, the greatest overall boost in effectivness was seen between 36 to 54 mg. Based on the trends of the graphs in the paper, as well as data from other studies, it appears that doses beyond 54 mg may still be of benefit for several individuals with the combined subtype. In other words, treatment of individuals with the Combined ADHD Subtype typically requires at least 18 mg more medication than those of the Inattentive Subtype (see note at end of the post for an important caveat and exception to this).

• Negative side effects of the medication were minimal at low (18 mg) to middle (36 mg) doses. However, beyond 36 mg, these negative side effects became more pronounced.

• Sleep problems (such as insomnia) began at the 36 mg dosage for Concerta, with the most pronounced effects seen in younger and smaller children.

• Noticeable appetite suppression was seen even at low doses (from 0 to 18 mg), especially for younger and smaller children. However, the overall severity of this was limited. However, the percentage of children who experienced "severe" appetite suppression dramatically increased between 36 to 54 mg treatments of Concerta.

• At 36 mg, the presence of or increase in tics (see related post on ADHD and tics) was seen, and a further increase was seen for some children at the 54 mg dosage.

• None of the dosage levels corresponded to blood pressure increases, and only minimal increases in pulse rates were seen. Compare this to another post on the cardiovascular risks of ADHD stimulant medications.

• A much earlier study on the ADHD medication methylphenidate (an earlier non-Concerta form) suggested that while hyperactive behavior continued to improve at higher doses, the ability to perform cognitive tasks decreased at higher levels of medication. While these effects were difficult to duplicate in future studies, it does suggest an upper limit for certain medications in which going above may lead to a reduction in improvement. We have seen similar effects in previous posts (see the "upside down U curve" in point #6 for tyrosine and clozapine treatment for ADHD here as an example).

A caveat and final blogger's note: Based on the conclusions of the study, it appears that going above the 54 mg limit may be beneficial for certain individuals of the Combined Subtype. While the data of the study may support this, it is important to note that the study only lasted 3 weeks. As a result, long-term effects of high doses of medication were unable to be observed. Additionally, we saw in one of the points above that negative side effects began to creep in at the 36-54 mg level. Based on other blog posts with regards to risk factors of certain ADHD medications as well as potential medication side effects, I urge you to err on the side of caution, especially on issues concerning young and small children (who are at much greater risk for developing severe side effects). In the above study, the highest dosage (54 mg of Concerta) was omitted for the smallest study participant as a precautionary measure.

A quick overall summary of this post: It is imperative that we take ADHD subtype seriously. The take-home message of this blog post should be that lower doses of methylphenidate are often optimal individuals with the Inattentive subtype for ADHD, while those of the Hyperactive-Impulsive (not studied in the above journal article) and Combined subtypes of ADHD typically require significantly higher levels of medication.

ADHD gene #6. Serotonin receptor 1B gene (HTR1B)

ADHD Genes

ADHD Gene #6: Serotonin Receptor 1B (HTR1B), human chromosome #6 (section q13)

This is our sixth gene of topic in our discussion of ADHD genes. The Serotonin Receptor 1B gene (HTR1B). Like the 5 ADHD genes previously discussed, the gene HTR1B is thought to have at least some influence on the development of ADHD. (If you would like some more background information on what genes, chromosomes, DNA and alleles are, and how they relate to ADHD, please check out this link to another section of the blog here. I have outlined some of the specifics in this area). As its name suggests, this gene is responsible for creating a specific binding site (or think of a "docking site"), for the important neurochemical serotonin. Essentially, there are multiple forms of this gene, which is located on the 6th chromosome in humans (the "q13" refers to a more specific location of the gene on the chromosome, if you would like further explanation on how this looks, please click here).

As mentioned in another post, sometimes the smallest changes in DNA can produce noticeable results in the resulting biology, and ultimately, behaviors, of an individual. This gene appears to be no exception. At one specific point of this serotonin receptor gene (HTR1B), some individuals have a DNA base of "G" (short for "Guanine"), while others have the DNA base of "C" (short for "Cytosine", for more info on what this means, please click here). It appears that the simple change of one small piece of DNA from a "C" to a "G" on this particular "ADHD gene" can have a significant effect with regards to ADHD. Individuals with the "G" form of this particular gene are statistically more likely to have ADHD than those with the "C" form.

Furthermore, the connection with ADHD seems to be strongest to a particular subtype of ADHD. Individuals with the "G" form, or allele, tend to exhibit behavior that is more concentrated on what is referred to as the inattentive subtype of ADHD. The inattentive subtype, as its name suggests, is a form of ADHD in which the inability to maintain attention for a necessary period of time is the dominant negative attribute of the disorder (in contrast to other subtypes of ADHD, which have a more concentrated impulsive component, and/or hyperactive components, which are highlighted by highly impulsive or hyperactive behavior, respectively). While other genes may be tied to these other types of ADHD, the "G" form of the HTR1B serotonin receptor gene appears to be significantly correlated primarily with the inattentive ADHD subtype.

Please remember that the "G" form of this gene is not some weird mutation or genetic malfunction. It is a perfectly common form of the gene that is found in a number of regular individuals. Furthermore, there have been several studies done on this form or allele of the HTR1B gene, including one done on fraternal twins that did not show a significant correlation between the "G" form of the gene and the frequency of ADHD. Nevertheless, the data from several other studies, when pooled together, have strongly suggested a significant statistical correlation between the "G" form and the likelihood of exhibiting inattentive ADHD behavior. In other words, we should be cautiously optimistic about this association. Keep in mind, however, that the presence of this form of the gene, or any of the previously discussed "ADHD genes" does not, single-handedly, "doom" an individual to ADHD, it simply means that individuals with this form of the gene are statistically more likely to develop ADHD. We will be wrapping up this section of posts on ADHD genes with the seventh and final ADHD gene, the SNAP 25 gene, in tomorrow's blog.

ADHD genes