Showing posts with label genes. Show all posts
Showing posts with label genes. Show all posts
Saturday, March 4, 2017
Genes and ADHD Brainwave Patterns
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to hold a higher frequency, often through some type of interactive computer game which stops when beta frequencies are no longer maintained.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 Ive 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 Ive 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 ADHDers, 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).
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Sunday, February 19, 2017
Saturday, February 4, 2017
Genes and Low Birth Weight Combine to Increase Risk of Conduct Problems Alongside ADHD
Genes and Low Birth Weight Combine to Increase Risk of Conduct Problems Alongside ADHD
In the past, we have investigated the role of the COMT gene and its effects on the onset and severity of ADHD cases. Now it appears that this gene may play a role not only in the ADHD itself, but conduct or behavior disorders which often occur alongside (or are comorbid to) of ADHD.
Recall from earlier posts that COMT (which is short for Catechol O-Methyltransferase) refers to both a gene and an enzyme protein encoded by the gene, which is responsible for maintaining a balance of neurotransmitters such as dopamine in key regions of the brain. In essence, the COMT enzyme is responsible for breaking down levels of free dopamine in the prefrontal cortex region of the brain (the area highlighted in orange). Keep in mind that in another key brain region, called the striatum, another series of enzymes called the dopamine transporter (DAT) proteins play a greater regulatory role in maintaining dopamine levels. However, in the prefrontal cortex region of the brain (see area below), the COMT gene and COMT enzymes play a much greater role in regulating the balance of key neurotransmitters necessary for communication between brain cells.
The prefrontal cortex region of the brain is approximated by the area in orange in the figure above. Note that we are looking from the left side of the brain of an individual facing to his or her left. The numbering system refers to a subseries of brain regions from which this original figure was taken.
As a reference, the striatum region of the brain can be seen in the green areas of the figure below (original file source here):
Returning to our discussion on the COMT gene and the prefrontal cortex region of the brain, it is important to note that there are two main "flavors" of this gene and subsequent enzyme, the "Val" and the "Met" (Ive mentioned previously in other posts what "Val" and "Met" stand for, but as a quick summary: "Val" is short for valine, and "Met" is short for methionine, both of which are common amino acids found in almost every protein in our bodies. However, these two amino acids exhibit slightly different biochemical properties, and a simple substitution of one for the other can actually result in significant changes as to how a protein functions. For the COMT enzyme, which is a special type of protein, the simple change from a "Val" to a "Met" or vice versa can actually dictate how efficient the whole enzyme becomes). COMT enzymes comprised of the "Val" form are actually 3-4 times more efficient at breaking down dopamine in key brain regions such as the prefrontal cortex, which results in overall lower levels of neurotransmitters such as dopamine.
Since individuals with ADHD are often deficient in free levels of dopamine in the prefontal cortex region of the brain, having the "Val" form of the COMT gene often poses a greater risk of exhibiting ADHD behavior. We have seen the effects of this Met/Val difference with regards to cognitive tasks and even the effects of these different gene forms on the onset of alcoholism-related ADHD symptoms. For example, on a post on gene variations and attentional control, we saw that individuals with the "Met" form of the gene (and enzyme) had improved attention-related control than those with the "Val" form.
With regards to conduct disorders comorbid to ADHD, it also appears that the lower dopamine levels associated with the "Val" forms of these enzymes is also a major determining factor in the childhood onset of anti-social behavior and conduct disorders. Furthermore, it appears that environmental factors and this "Val" form genetic factor can actually interact and combine, to increase the risk of an individual with ADHD in developing some sort of conduct problem to go alongside his or her ADHD symptoms.
Low birth weight, which has a number of implications for other disorders, was found to be a good indicator of childhood conduct problems appearing alongside of ADHD in its own right. It is believed that low birth weight is a good indicator of a poor prenatal environment, which is why so many disorders and developmental issues are often associated with low birth weights. Statistically, it was noted that children with low birth weights (less than 2.5 kilograms or 5.5 pounds) were at an increased risk of developing co-existing behavioral problems (conduct disorders) alongside of an ADHD diagnosis. As mentioned before, individuals who were unfortunate enough to have one or more copies of the "Val" version of the COMT gene plus a low birth weight, were statistically more likely to exhibit problems associated with conduct-related disorders.
As a quick reference to the severity of the effects of low birth weight and the "Val" version of the COMT gene, please consult the table below. This data was taken from an article by Thapar and coworkers on the effects of COMT genes and low birth weight on the onset of antisocial behavior in children with ADHD.
Notes on the table above: Relative Conduct Symptom Score refers to the severity of conduct problems which are given a numerical value (higher being more problems). I have assigned the first group a value of 1 as a reference. This refers to individuals who have at least one copy of the "Met" (which, in the cases of ADHD appears to be the "good") form of the COMT gene and enzyme, as well as a normal birth weight. As we can see from the table, having either a low birth weight or both copies of the "Val" (the "bad" form of the COMT gene with regards to ADHD) form resulted in a roughly 50% increase in symptoms of conduct or behavioral problems. However, for individuals who possessed both "Val" forms of the COMT gene and enzyme and had a low birth weight, we can see that conduct symptoms associated with ADHD shot up to over three times the original level. This at least suggests that while both genes and developmental environments can play a significant role in the onset of behavioral problems associated with ADHD, it is when these two factors are combined, that remarkable differences in symptoms begin to appear. In other words, strong gene-environment interactions are associated with antisocial behaviors in individuals with ADHD.
Keep in mind that these findings are somewhat inconclusive. Another research group performed a similar experiment, but was unable to replicate these findings which associated low birth weight and the "Val" form of the COMT genes to an increase in antisocial behavior in children with ADHD. Nevertheless, an additional study tied the presence of "Val" forms of the COMT gene to increased aggressiveness, conduct problems, and criminal behavior in individuals with ADHD. Although the information and conclusions from different studies on these topics remains controversial, the fact that the "Val" form of the COMT gene has been implicated in so many other deficits associated with ADHD, I believe that we should take notice of some of these recent findings.
The term conduct disorder itself has a relatively widespread range of meanings. With regards to ADHD and the content of this post, I consider conduct disorders to include behaviors such as oppositional behaviors towards parents, teachers and other authorities, negative peer interactions, pervasive negative attitudes and interactions towards peers and authorities, and, in more extreme cases, illegal substance abuse, cruelty to animals and other individuals, destruction of property, stealing, and other criminal behaviors (please not that the Thapar article highlighted more of the latter and more severe behaviors on the list when addressing the topic of conduct disorders). Of course, there is a fair degree of ambiguity and a wide range of severity in the behaviors from this list, but I think we can all begin to picture the difference between a child who is merely hyperactive, implulsive and inattentive versus one who has a pervasively antagonistic attitude and behavioral patterns to go along with the classic ADHD symptoms.
The unique thing about antisocial behaviors with regards to ADHD is that they appear to be more genetically heritable than generalized antisocial behaviors, and that ADHD-like hyperactivity can potentiate and worsen the severity of accompanying conduct problems. Furthermore, it appears that children may be much more susceptible to antisocial behaviors arising from damage to the prefrontal cortex than are adults. This article suggests that when two or more factors which each have notable effects on ADHD-related conduct problems or comorbid disorders, the combined effects of two or more of these factors can operate in a synergistic fashion. It is my opinion that many of these genetic and early developmental factors will take on an increasingly powerful role with regards to both the diagnosis and treatment of ADHD and accompanying comorbid disorders such as behavioral and conduct problems.
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Tuesday, January 24, 2017
Genes Omega 3s Alcohol and ADHD
Genes Omega 3s Alcohol and ADHD
In our last discussion, we were exploring the theory behind omega-3 fatty acid supplementation for ADHD, and alluded to the fact that there may be some genes at work involving this process. Additionally, there is some evidence that alcohol use can inhibit the effectiveness of some of the enzymes that are coded for by these genes, and possibly be a factor in the onset of ADHD. We will be exploring these associations in this blog post.
Omega-3 fatty acids are crucial for our overall well being for a number of reasons, with many of them being tied to maintaining the structure of all different types of cells in our bodies. Among these omega-3s are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA converts to EPA (and eventually DHA) through a series of steps, several of which use the enzymes governed by the genes listed above. A summary of this process is highlighted below (original file source here):
The diagram above may look quite complicated, but were just focusing on a few of the objects listed above.As a quick side note: a lot of the other objects on this diagram above are showing the role these omega-3s and omega-6s play in the inflammatory process of immune reactions. This discussion is beyond the range of this post, but I have included it to illustrate that omega-3 and omega-6 fatty acids play a critical role in regulating a number of different functions and systems. Omega-3 imbalances can lead to immune dysfunction, which is thought to be one of the reasons why individuals with ADHD, who often have lower blood levels of omega-3s than their peers, are also more likely to have immune system disorders such as allergies. This ADHD/allergy connection will be explored in the future. Also, notice that omega-3s and omega-6s use the same enzymes. This is important, and was discussed at length in the previous post.
The section on the left of the above diagram describes how one omega-3 fatty acid is converted to another, for example, the a-linolenic acid (top left) eventually makes its way to forming EPA (fourth one down on the left), which eventually is converted to DHA (last one in the left column). Bringing our attention to the center, we see a series of enzymes with names like ?6 desaturase, elongase, etc. These enzymes play a major role in the actual chemical conversion process of one type of omega-3 fatty acid to another.
Keep your attention on the enzymes that have the key term desaturase in their title. These are the ones we need to be concerned about when dealing with the aforementioned genes and alcohol. Without these enzymes functioning at their highest level, the incorporation of dietary omega-3s into the actual structure of the cell membrane is significantly. Genetic differences and the presence of external factors (such as alcohol or other types of fats) can significantly impair the function of these enzymes and slow the conversion process (and ultimately uptake and incorporation into cell membranes) of these critical omega-3s.
A number of these desaturase enzymes are all coded from a specific genetic region located on the 11th chromosome in humans, located at the 11q25 region (chromosomes have 2 "arms", a "p" and a "q", the numbering refers to relative location on that arm, so "11q25" refers to the 25th region on the "q" arm on the 11th chromosome). Interestingly, this region is located near the 11q22 region, which has been linked to ADHD. The closer two genetic regions are, the higher the chances they will be co-transmitted (passed on together from parent to child). In other words, gene forms which are located near each other on a chromosome are more likely to be passed on together, suggesting the possibility that the 11q22 ADHD region may in fact be influenced by some of the genes from nearby 11q25 region.
Brookes and coworkers did a study on the association between these desaturase genes and ADHD (on a personal note, I would like to acknowledge the authors of this particular study. Much of the information in these past two posts is gleaned from their work, and this paper provided a great starting point for much of my research for this post). They found that the 11q25 region contained three genes which code for desaturase enzymes located next to each other: Fatty Acid Desaturase 1, Fatty Acid Desaturase 2, and Fatty Acid Desaturase 3 (abbreviated as FADS1, FADS2 and FADS3, respectively). These genes each exist in different forms, called alleles, which have slightly different DNA configurations (which can differ by as little as one letter in the DNA "code").
Key findings from the Brookes study: This group saw a significant difference in the prevalence of ADHD stemming from two different alleles in the FADS2 gene. It appears that a single point difference was all it took to boost the likelihood of association with ADHD. Individuals with ADHD were significantly more likely to have the "C" form of the FADS2 gene than the "T" form of the gene at marker 498793 (this number just gives the detailed location on which spot of the DNA this form can be found).
Additionally, it appears that the onset of ADHD stemming from prenatal alcohol exposure may be somewhat genetic as well. For individuals who were exposed to alcohol via maternal consumption during pregnancy, there is some nominal evidence linking "G" allele instead of the "C" allele at two different locations on the FADS1 gene was correlated with a higher likelihood of being diagnosed with ADHD. However, the authors concluded that this connection was only "speculative".
This possible ADHD/genetics/fatty acid consumption/alcohol exposure connection is somewhat intriguing. The study established a strong ADHD connection to a specific allele of the FADS2 gene on the 11th chromosome, and also cited a number of other studies on the effects of omega-3 consumption on ADHD symptoms, but the connections with alcohol are more strained. Nevertheless, the findings from other studies offer support for this possible alcohol association with these other factors:
- We have seen before that omega-3 fatty acid deficiencies are more prevalent in individuals with ADHD. The previous post describes the process of how omega-3s affect cell membrane integrity, which, in turn, can effect the passage of key chemical signaling agents such as dopamine (which has repeatedly been found to deficient in specific brain regions of ADHD individuals). The desaturase enzymes, which are products of the genes listed above are partly responsible for the process of omega-3 metabolism and incorporation into the cell membranes.
- Different alleles (alternate forms of a gene) can result in slightly different forms of these enzymes, some of which are more efficient than others. In other words, enzymes coded for by one form of a gene are somewhat better at metabolizing omega-3s and incorporating them into cells than the "alternate" enzymes coded for from the "alternate" forms of the gene. As a result, small changes in the gene code in these aforementioned regions can indirectly affect the efficiency of omega-3-to-membrane incorporation.
- Several studies have pointed to the the connection between alcohol and fatty acid metabolism in animal models of ADHD.
- It also appears that an individual may be able to "recover" from some of the negative effects on cognition due to alcohol exposure by an increase in dietary omega-3s. This includes increasing maternal dietary levels of omega-3s during pregnancy (based on animal model studies).
To summarize the whole post (as well as the previous one), it appears that omega-3 fatty acid metabolism plays a major role in ADHD. This is thought to be at least in part to the effects of omega-3s on maintaining cell membrane structure and integrity and their effects on regulating levels of the brain signaling agent dopamine (which is a crucial neurotransmitter and is often deficient in ADHD cases). However, properly functioning enzymes are required for these steps. Desaturase enzymes are coded for by a genetically "hot" region for ADHD on the 11th chromosome in humans. Different versions of these genes can result in a reduction in enzyme function and potentially affect the way these omega-3s are metabolized. In mammals, alcohol exposure can also lead to reduced desaturase enzyme activity. Additionally, there is at least some evidence that alcohol can increase the likelihood of specific forms of FADS1 gene giving rise to ADHD. This may be due to the two factors combining to reduce desaturase enzyme activity to a point where omega-3 metabolism falls past a hypothetical "break-point" resulting in a sharp increase in the onset of ADHD and other related disorders.
We have been focusing heavily on the ADHD and alcoholism connection for the past couple of weeks. We will be investigating a few more studies on this connection in the upcoming posts.
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