In the past, we have investigated a large number of ADHD genes (that is, specific genes who have one or more forms or alleles which correlate to the disorder ADHD at higher-than-normal frequencies). We have also previously looked at some of the roles of gender effects on ADHD. However, we have not dedicated much time to exploring the possibility that these two factors may, in fact, be related.
A 2008 paper by Biederman and colleagues on sexually dimorphic effects of ADHD genes may shed some light on this potential association. They highlighted a total of four different genes which may be of influence with regards to the onset of ADHD. Two of these four genes appear to exhibit more of an influence on males, and the other two may exhibit more of an effect on females.
These four gender-related ADHD genes are listed below:
We will be exploring each of these four ADHD genes affected by gender in subsequent postings.
Saturday, March 7, 2009
Friday, March 6, 2009
Do ADHD Kids Use Their Brain Regions Diffferently?
There is a fair amount of debate as to whether ADHD is a developmental delay type of disorder. We are seeing a growing body of research which supports this assertion. One of these supporting pieces of evidence is a recent study done by McAlonan and coworkers on the topic of how relative volumes of specific brain regions correlates to ADHD behaviors such as inhibiting certain responses (a deficiency marked by impulsivity, a key attribute of ADHD), as well as the ability to shift attention to another area and refocus (a deficiency which is especially pronounced in ADHD individuals who exhibit symptoms or diagnoses of comorbid Obsessive Compulsive Disorders or OCD). Additionally, a relatively mild (but still notable) association was seen between age and improvement in reaction times for inhibiting responses and shifting focus, which suggests that the increasing of brain volumes (for specific brain regions) during the childhood developmental process can result in subsequent improvements with regards to efficiency in the impulsive behavior inhibition process as well as in attentional shifting capabilities.
Overview of the methods used in the study:
These next few paragraphs outline the method used in the McAlonan study to measure the two key reaction times which would later correspond to certain brain volume differences. Although a bit lengthy, I felt it necessary to include the details for the sake of understanding what these reaction times and their values are actually measuring.
The McAlonan study involved a computer-simulated measure in which the children watched a computer screen for an airplane to appear on either the left or right hand side. Once one appeared, they were to press a button corresponding to the correct side of the screen in which the airplane appeared. However, in one fourth of the cases, an auditory "stop" signal was presented and the children were instructed to push a third button instead as soon as possible. The timing of these responses were recorded throughout the test. There were actually two measurable components to this exercise, the stop signal reaction time portion of the response (the amount of advanced warning time the auditory "stop" signal needed to appear before the airplane for the child to avoid pressing one of the two airplane direction buttons), and the "change signal reaction time" portion of the response (the amount of time it took for the child to push the third button during the quarter of the trials involving stop behaviors).
To clarify, let's assume that it takes a particular child 0.500 seconds to press the correct button once an airplane flashes on the screen. This is the child's typical response time. If the auditory stop signal is given 0.499 seconds after the airplane appears, it is doubtful that the child could stop from pressing one of the "airplane buttons", since they only had 0.001 seconds to respond to the auditory warning. However, if the auditory signal is given at 0.200 seconds after the airplane appears, the child would have 0.300 seconds to stop from pressing the airplane button. The "stop" reaction time is essentially the amount of time needed for the auditory stop cue to precede the normal reaction time (which, in this child's case, is 0.500 seconds) for the child to successfully avoid pressing one of the airplane buttons.
The change response reaction time is measured by the amount additional time it takes for the child to press the correct third button beyond the stop time. In other words, it addresses how long it takes the child to re-engage in the behavior of choosing the correct button once he or she has successfully stopped the "wrong" behavior.
I realize that the test description above might not make intrinsic sense, but the two main things we should take home from these measurements from the article:
The top half of the chart entitled "Stop and Inhibitory Behaviors" refers to the brain regions whose relative volumes corresponds to stop signal reaction times (for both ADHD and non-ADHD children) and the bottom half, entitled "Response Changing Behaviors" deals with the brain regions whose relative volumes correspond to change response reaction times.
I have attached a handful of diagrams showing the approximate locations of several of the key brain regions listed above in the chart. These three diagrams (with brief descriptions) are shown below:
Above: The reddish region in the center part of the brain in the image above (the individual is facing to the left, and we're looking at a side view) is the basal ganglia (for original image source, click here). It is comprised of several parts, which are labeled above (don't worry about these sub-components for this article, it is possible we may explore them in further detail in later postings). Actually, a sub-region of the basal ganglia which has been cited by the McAlonan as the major player in response timing for ADHD individuals is called the lentiform nucleus. It is comprised of the Putamen region and globus pallidus, both of which are shown above. Again, don't worry about the exact locations or functions of these subregions, just realize that they show a connection to reaction response timing in ADHD individuals, in addition to their many other functions.
Above: The Cerebellum, Temporal Lobe and Frontal Lobe (which includes the Prefrontal Cortex, which is listed in the chart above in its outer layer) are all shown above (for orignal image source, please click here). We should note that individuals with ADHD generally exhibit lower activity in the prefrontal cortex (in most cases) and the temporal lobe (in several cases).
**There are a number of direct implications here. For those of us who parent or work with ADHD children, we often find ourselves directing the child to stop a certain negative behavior and restart an appropriate one such as: "Billy, stop spinning in circles and pick up your truck!". We may often find ourselves frustrated by the length of time it takes for the child to follow both portions of the directions, but we should keep in mind that at least part Billy's slow response may be due to innate delays in stop and change reaction times highlighted in the McAlonan article. Thus, there may be practical implications to the findings of this study beyond the general overview of brain regions at work here.
One last thing to note (which was not brought up by the study):
In the computerized airplane task mentioned above to test for "stop" and "change" signal reaction times, the authors used an audible stop signal to get the child to stop. However, we have recently investigated the co-occurrence of ADHD and auditory processing disorders. Given the relatively high prevalence of this association, it is entirely possible that part of the delay in reaction times for the ADHD group may, in fact be attributed to an underlying comorbid auditory processing disorder (which often goes undetected as a side disorder in a number of cases involving ADHD children).
In fact, the temporal lobes of the brain (see diagrams above) play a critical role in auditory processing. From the chart of brain regions listed above, we see that both the left temporal lobe (whose volume is associated with stop signal reaction times in ADHD children) and the right temporal lobe (whose volume correlates to change response reaction times in non-ADHD children) are both key components with regards to reaction timing, at least based on the McAlonan paper. It would be interesting to see if there was much of a difference in reaction times had the "stop" signal been a visual instead of auditory cue instead, and whether the correlation between temporal lobe size and reaction times would still exist in either the ADHD or non-ADHD cases.
Summary:
To summarize, we have seen that multiple brain regions have been implicated in both the reaction times related to impulse control/stop behaviors as well as change response time/shifting behaviors. We should also note that the two processes often utilize completely different brain regions, whose rates of development can differ significantly. Furthermore, the correlation of specific brain region volumes to these two types of reaction times was significantly different in ADHD vs. non-ADHD children. This may indicate either a developmental delay in some of these brain regions for ADHD children, or an entirely different set of functioning of specific brain regions in ADHD vs. non-ADHD children.
Overview of the methods used in the study:
These next few paragraphs outline the method used in the McAlonan study to measure the two key reaction times which would later correspond to certain brain volume differences. Although a bit lengthy, I felt it necessary to include the details for the sake of understanding what these reaction times and their values are actually measuring.
The McAlonan study involved a computer-simulated measure in which the children watched a computer screen for an airplane to appear on either the left or right hand side. Once one appeared, they were to press a button corresponding to the correct side of the screen in which the airplane appeared. However, in one fourth of the cases, an auditory "stop" signal was presented and the children were instructed to push a third button instead as soon as possible. The timing of these responses were recorded throughout the test. There were actually two measurable components to this exercise, the stop signal reaction time portion of the response (the amount of advanced warning time the auditory "stop" signal needed to appear before the airplane for the child to avoid pressing one of the two airplane direction buttons), and the "change signal reaction time" portion of the response (the amount of time it took for the child to push the third button during the quarter of the trials involving stop behaviors).
To clarify, let's assume that it takes a particular child 0.500 seconds to press the correct button once an airplane flashes on the screen. This is the child's typical response time. If the auditory stop signal is given 0.499 seconds after the airplane appears, it is doubtful that the child could stop from pressing one of the "airplane buttons", since they only had 0.001 seconds to respond to the auditory warning. However, if the auditory signal is given at 0.200 seconds after the airplane appears, the child would have 0.300 seconds to stop from pressing the airplane button. The "stop" reaction time is essentially the amount of time needed for the auditory stop cue to precede the normal reaction time (which, in this child's case, is 0.500 seconds) for the child to successfully avoid pressing one of the airplane buttons.
The change response reaction time is measured by the amount additional time it takes for the child to press the correct third button beyond the stop time. In other words, it addresses how long it takes the child to re-engage in the behavior of choosing the correct button once he or she has successfully stopped the "wrong" behavior.
I realize that the test description above might not make intrinsic sense, but the two main things we should take home from these measurements from the article:
- Stop signal reaction time (SSRT): The time it takes for a child to inhibit a particular behavior (i.e. the amount of warning time a child needs to avoid pressing an airplane button after receiving a stop signal in the process described above). For a frame of reference, the average stop signal reaction time was around 0.45 seconds for the ADHD children and 0.36 seconds for the non-ADHD children. Interestingly, in addition to their slower stop signal reaction times, there was a much higher degree of variability within the ADHD group. We have seen this trend of higher variability with response times in ADHD individuals before, in an earlier post on nicotine withdrawal effects in ADHD smokers. Additionally, there was a much greater improvement in stop signal reaction times with the ADHD group compared to the non-ADHD group, and that, around the age of 12, the ADHD kids often "caught up" to their peers with regards to reaction times. This may support the idea that ADHD children may suffer from functional delays in development early on, but can catch up over time.
- Change response reaction time (CRRT): This is the amount of time it takes to shift gears and execute an appropriate response (pushing the correct third button in the airplane task described above). The average change response reaction times were around 0.188 seconds for the non-ADHD kids and 0.263 seconds for the ADHD kids. Once again, there was a much greater variability in reaction times for this category for the ADHD children than the non-ADHD children, and the differences between the ADHD and non-ADHD groups diminished with age.
Relevance and applications of the study:
For comparison purposes, the association between volumes of specific brain regions and reaction times for inhibition and attention shifting tasks was carried out in both ADHD and non-ADHD children. Interestingly, there was a fair amount of difference between the specific brain regions involved for the ADHD children vs. the specific brain regions involved in the non-ADHD children for inhibition of response and attention-shifting behaviors. This may at least suggest that ADHD children may be using different parts of their brains to elicit certain responses than their non-ADHD counterparts.
For comparison purposes, the association between volumes of specific brain regions and reaction times for inhibition and attention shifting tasks was carried out in both ADHD and non-ADHD children. Interestingly, there was a fair amount of difference between the specific brain regions involved for the ADHD children vs. the specific brain regions involved in the non-ADHD children for inhibition of response and attention-shifting behaviors. This may at least suggest that ADHD children may be using different parts of their brains to elicit certain responses than their non-ADHD counterparts.
Given the fact that specific brain regions develop at different rates (some are mostly developed by early childhood, while others continue on into late adolescence and even into one's 20's), it is entirely possible that ADHD individuals may use slower-developing brain regions for certain tasks than their non-ADHD counterparts to control certain behaviors. This combined with the fact that an overall delay in brain maturation is often evident in ADHD individuals, may provide clues as to why ADHD children (and even adults) are less likely to elicit age-appropriate control of certain behaviors.
Reaction Timing vs. Brain Region Volumes:
To elucidate this possible connection, I have constructed a chart which highlights the brain regions whose volumes were connected to faster response times for inhibiting for inhibiting responses and shifting attention in both ADHD and non-ADHD children according to the McAlonan study. These assertions were based on the premise that larger volumes in the following specific brain regions are connected to improvements in stop signal reaction times (related to impulsivity, a key factor in ADHD) and change response reaction times (related in the ability to shift topics, which is often a difficulty in obsessive compulsive disorders, which can also co-occur alongside ADHD) described above.
To elucidate this possible connection, I have constructed a chart which highlights the brain regions whose volumes were connected to faster response times for inhibiting for inhibiting responses and shifting attention in both ADHD and non-ADHD children according to the McAlonan study. These assertions were based on the premise that larger volumes in the following specific brain regions are connected to improvements in stop signal reaction times (related to impulsivity, a key factor in ADHD) and change response reaction times (related in the ability to shift topics, which is often a difficulty in obsessive compulsive disorders, which can also co-occur alongside ADHD) described above.
The top half of the chart entitled "Stop and Inhibitory Behaviors" refers to the brain regions whose relative volumes corresponds to stop signal reaction times (for both ADHD and non-ADHD children) and the bottom half, entitled "Response Changing Behaviors" deals with the brain regions whose relative volumes correspond to change response reaction times.I have attached a handful of diagrams showing the approximate locations of several of the key brain regions listed above in the chart. These three diagrams (with brief descriptions) are shown below:
Above: The reddish region in the center part of the brain in the image above (the individual is facing to the left, and we're looking at a side view) is the basal ganglia (for original image source, click here). It is comprised of several parts, which are labeled above (don't worry about these sub-components for this article, it is possible we may explore them in further detail in later postings). Actually, a sub-region of the basal ganglia which has been cited by the McAlonan as the major player in response timing for ADHD individuals is called the lentiform nucleus. It is comprised of the Putamen region and globus pallidus, both of which are shown above. Again, don't worry about the exact locations or functions of these subregions, just realize that they show a connection to reaction response timing in ADHD individuals, in addition to their many other functions.
Above: The Anterior Cingulate region of the brain is approximated by the numbers "24" , "32" and "33" in the brain region chart listed above (for original file source, click here). Note that we are looking from the side at a brain diagram of a person facing to the left. The cingulate acts as a "gear shifter" in the brain. Obsessive behaviors and constant worrying are indicative of an overactive cingulate (think of a car whose gear shift gets "stuck" in a particular gear), while an underactive cingulate region often results in a constant shifting of thoughts and behaviors. Not surprisingly, individuals with ADHD show underactivity in the cingulate (note the similarities between over and underactivity of the cingulate and basal ganglia in OCD and ADHD individuals, respectively).
From the brain region chart listed above, we should note a few of the overall trends:
- In general (as mentioned earlier in this post), the correlation between age and volume of specific brain regions was more pronounced in the ADHD children than the non-ADHD children. This refers to the "Age dependent" column in the chart listed above, and may suggest that these brain regions mentioned above may experienced delayed growth patterns in ADHD children but are more likely to be "full-grown" in non-ADHD children. This would explain the age-related effects of brain volume, and possibly (again, assuming that volume of these specific brain regions is connected to faster response times) the resulting differences in response times between ADHD and non-ADHD children.
- * The stop response reaction time and change response reaction time utilized different brain regions, with the exception of the right basal ganglia (which was present in both reaction times, but only in the cases of ADHD children). It is interesting to note that the basal ganglia region of the brain essentially governs how fast "idle" is for a specific individual. Individuals with ADHD typically have underactive basal ganglia, while individuals with Obsessive Compulsive Tendencies and workaholics typically have overactive basal ganglia. In addition, symptoms such as poor concentration, poor handwriting and poor fine motor skills, all of which commonly exist in ADHD individuals, are often indicative of underactive basal ganglia.
- **There was a tremendous amount of difference with regards to the brain regions associated with reaction times between the ADHD and non-ADHD groups. Of all the brain regions listed above, only the left cerebellum had a correlation between its relative volume and improved reaction time (change response reaction time to be more specific) for both ADHD and non-ADHD cases.
**There are a number of direct implications here. For those of us who parent or work with ADHD children, we often find ourselves directing the child to stop a certain negative behavior and restart an appropriate one such as: "Billy, stop spinning in circles and pick up your truck!". We may often find ourselves frustrated by the length of time it takes for the child to follow both portions of the directions, but we should keep in mind that at least part Billy's slow response may be due to innate delays in stop and change reaction times highlighted in the McAlonan article. Thus, there may be practical implications to the findings of this study beyond the general overview of brain regions at work here.
One last thing to note (which was not brought up by the study):
In the computerized airplane task mentioned above to test for "stop" and "change" signal reaction times, the authors used an audible stop signal to get the child to stop. However, we have recently investigated the co-occurrence of ADHD and auditory processing disorders. Given the relatively high prevalence of this association, it is entirely possible that part of the delay in reaction times for the ADHD group may, in fact be attributed to an underlying comorbid auditory processing disorder (which often goes undetected as a side disorder in a number of cases involving ADHD children).
In fact, the temporal lobes of the brain (see diagrams above) play a critical role in auditory processing. From the chart of brain regions listed above, we see that both the left temporal lobe (whose volume is associated with stop signal reaction times in ADHD children) and the right temporal lobe (whose volume correlates to change response reaction times in non-ADHD children) are both key components with regards to reaction timing, at least based on the McAlonan paper. It would be interesting to see if there was much of a difference in reaction times had the "stop" signal been a visual instead of auditory cue instead, and whether the correlation between temporal lobe size and reaction times would still exist in either the ADHD or non-ADHD cases.
Summary:
To summarize, we have seen that multiple brain regions have been implicated in both the reaction times related to impulse control/stop behaviors as well as change response time/shifting behaviors. We should also note that the two processes often utilize completely different brain regions, whose rates of development can differ significantly. Furthermore, the correlation of specific brain region volumes to these two types of reaction times was significantly different in ADHD vs. non-ADHD children. This may indicate either a developmental delay in some of these brain regions for ADHD children, or an entirely different set of functioning of specific brain regions in ADHD vs. non-ADHD children.
Thursday, March 5, 2009
Iron Levels, Sleep Disorders and ADHD
The aim of this post is to investigate the potential connection between ADHD and sleep disturbances, and how a deficiency in iron levels may in fact be a possible triggering factor for both disorders. We will be drawing heavily from a very recent article by Cortese and coworkers on Sleep Disturbances and Serum Ferritin Levels in children with ADHD. Iron typically does not exist in the body in its free form, but rather in the form of larger complex molecules such as hemoglobin or ferritin (think of iron being "encaged" in these larger complexes).
We have previously dabbled in the field of ADHD and sleep issues in earlier posts, such as a recent one entitled CREM gene, Melatonin and ADHD. I also plan on doing further posts on the connection between ADHD and Restless Legs Syndrome, which is also believed to be connected to low iron levels. It is interesting to note that there may also be an underlying genetic component to this association as well.
Some of the major findings of the Cortese article are listed below:
We have previously dabbled in the field of ADHD and sleep issues in earlier posts, such as a recent one entitled CREM gene, Melatonin and ADHD. I also plan on doing further posts on the connection between ADHD and Restless Legs Syndrome, which is also believed to be connected to low iron levels. It is interesting to note that there may also be an underlying genetic component to this association as well.
Some of the major findings of the Cortese article are listed below:
- Children with iron-containing ferritin below a concentration of 45 micrograms per liter (don't worry about these numbers yet, we will be discussing them further down) had higher levels of ADHD symptoms as well as sleep disorders than those above this concentration. We must consider the fact that sleep disorders appear at higher levels in individuals with ADHD than in the general population. With regards to ADHD, these results are in agreement with another prominent study by Konofal on Iron Deficiency in Children with ADHD. According to the study, among the different sub-categories of sleep disorders, the only disorders associated with a deficiency of the iron-rich protein ferritin were Sleep Wake Transition Disorders (SWTD). These SWTD's are characterized by "abnormal movements in sleep", according to the Cortese article.
Carrying this a bit further, we find that iron-related sleep disorders are also seen in children with autism, a disorder which shares a fair degree of overlap with ADHD on a genetic basis as well as structure and function of specific brain regions and an overlap of motor problems and other symptoms. It is also important to note that iron is a critical factor for the synthesis of the brain chemical dopamine (which is often at lower levels in the areas between nerve cells in specific brain regions of individuals with ADHD), and that dopamine related functions are connected to motor control behaviors. - While it may be tempting to assume that these problems may be fixed by iron supplements, we need to be careful, especially based on the content of the study. The Cortese article indicated that none of the children had anemia. Keep in mind that anemia comes in multiple forms, with the most common being iron deficiency anemia, which can be caused either by a lack of dietary iron (a possibility) or inflammatory conditions such as parasitic infections (which was not seen in any of the patients). It is interesting to note that serum ferritin is also a bio-marker of inflammatory processes, so the fact that no inflammatory conditions were present was a crucial control for the Cortese study.
While none of the children in the study exhibited outward signs of nutritional deficiencies, diet-related anemia is the result of prolonged deficiency in iron and other supporting nutrients, so it is entirely possible that the children in the Cortese study were simply not far enough along in their iron deficiency situation for anemia detection. However, we must be careful before administering iron supplementation as a potential treatment option. While studies have shown that iron supplementation can effectively reduce the occurrence of periodic limb movements, we must watch out for the toxic effects of rampant iron supplementation (for a general upper limit for iron supplementation, please click here). - Nevertheless, the effects of an iron deficiency can be drawn out, and symptoms can be delayed. Ferritin, which, mentioned above, is a type of storage protein for holding iron in the body, typically exists at a concentration roughly between 30-45 millionths of a gram (micrograms) of ferritin protein per liter of serum (serum is the watery part of the blood which does not include blood cells) in children, but can be significantly higher in adults. While this number may not mean much on its own to most of us, we should be more cautious about the next number: 12 millionths of a gram per liter of serum. If the concentration of iron-containing ferritin protein falls below this critical level, then hemoglobin synthesis begins to be impaired.
While the difference between the 45 micrograms/liter and 12 micrograms/liter indicates that there is some room to play with between low iron levels and a hemoglobin deficiency, the same study that found the 12 micrograms/liter cutoff point also found that much higher levels than 12 micrograms/liter must be reached before iron stores (and subsequent hemoglobin synthesis) resume to full levels. Therefore, the complex restoration of iron balance is not something that can be typically achieved overnight or even within a week.
Furthermore, the Cortese paper suggested that the transfer of iron stores in the nervous system may also take sufficient time to build back up and may depend on significant iron storage levels. In other words, the effects of iron supplementation and treatment and restoration of iron-containing complexes may not be felt immediately, especially in the brain region and the central nervous system, which is bad news for those suffering from ADHD and related disorders. While no exact quantity was specified, the 30-45 micrograms/liter concentration range seems to be a good starting place for children. - While many comorbid disorders are predominantly connected to one of the three major subtypes of ADHD (inattentive ADHD, hyperactive/impulsive ADHD or combined subtype ADHD), the sleep disorders in the Cortese article showed no particular subtype affiliation.
- Another recent article may shed some light on the subject as far as to why serum ferritin levels and sleep disturbances may occur. We have previously reported the possible connection between ADHD and Celiac Disease and that Celiac Disease can Cause ADHD Symptoms. Picchietti and coworkers reported that treating patients who had restless legs syndrome and low serum ferritin levels but not overtly low iron levels responded well to a gluten-free diet (the most common treatment for celiac disease). Similar associations were seen in other studies involving iron deficiency and celiac disease (as well as generalized intestinal absorption difficulties).
In other words, celiac disease and other digestive issues may be the underlying factor in individuals who exhibit low serum ferritin levels, but not abnormally low overall iron levels, and may contribute to negative symptoms such as restless legs syndrome. Unfortunately, the while generalized gluten-free diets can single-handedly restore the body to pre-anemic conditions, the process can take time, up to 6-12 months.
It would be interesting to see how many of the patients in the Cortese study who exhibited low serum ferritin levels without other forms of iron deficiency have undetected cases of celiac disease or other digestive problems as potential underlying causes to their ADHD and sleep disturbances. This could be a great follow-up study for the population in the Cortese study. - It is also important to note that a large number of the children with ADHD in the study also had at least one type of comorbid (co-occurring) disorder. Among the most common ones were Oppositional Defiant Disorder (ODD, seen in around half of the patients in the study) and Anxiety Disorders. At the moment, it is unclear as to what the confounding effects of these comorbid disorders may be with regards to iron-related sleep problems. We will be discussing the nature and effects of these comorbid disorders in a later post, but for now, we must keep in mind that these co-occurring disorders have pronounced direct and indirect effects on the symptoms and treatment strategies for ADHD.
- Finally, the Cortese paper cited another study in which Methylphenidate (Ritalin, Concerta, Daytrana), and Dextroamphetamine (Dexedrine), both of which are ADHD stimulant medications, decreased the amount of nocturnal motor activity in patients. Cortese suggested that iron supplementation, which can boost free dopamine levels in a manner similar to most ADHD stimulant medications, may possibly accentuate these postive effects. While this is certainly a possibility (which remains to be seen), I also recommend extending this drug/mineral supplementation strategy to zinc, which has been shown to boost Ritalin's effectiveness as an ADHD treatment.
This article ties together well with our recent posts on the numerous ADHD comorbid disorders. We will be having several further discussions on ADHD and sleep disorders, including potential underlying causes, in the near future.
Sunday, March 1, 2009
ADHD and Auditory Processing Disorders
ADHD and Auditory Processing Disorders can share a number of overlapping symptoms and behaviors in children. However, when these two disorders exist alongside each other as comorbid disorders, then the two can feed off of each other and increase the likelihood of onset of a third (or fourth) psychological or developmental disorder. A recent publication done by Ghanizadeh on ADHD and auditory processing problems found that two other disorders commonly associated with or comorbid to ADHD were more likely to appear if an auditory processing problem exists in an ADHD child. I am not going to cover the contents of the whole article, but some of the main points are listed below:
- Auditory processing disorders are independent from the mechanical process of hearing (in other words, the peripheral hearing, or ability to pick up background sounds is not affected), but rather have difficulties in the screening, filtering and differentiating "important" sounds from background noise. Difficulties in this result in an impaired ability to utilize important auditory information properly. On an interesting side note, it appears that methylphenidate (Ritalin, Concerta, Daytrana), which is a common stimulant medication for ADHD, may actually help improve auditory processing in children. Perhaps, on an equally interesting note, the dietary mineral zinc has also been associated with information processing disorders in boys with ADHD. In an earlier blog post, we covered the topic of how supplementation with zinc could boost Ritalin's effectiveness. Therefore, it is possible that a similar underlying cause and mechanism may be at work behind ADHD and auditory processing disorders and their effective treatments, at least in this blogger's opinion.
- Auditory processing problems were divided into two subcategories in the article, hyposensitivity (under-reacting or under-processing a sound/auditory stimulus) and hypersensitivity (over-reacting or over-processing a sound/auditory stimulus) to sound (an actual distinction whose existence was questioned by the author towards the end of the article). Both types can lead to similar behaviors or deficits, including difficulties screening important sounds from background noise, picking out verbal cues and selectively listening to an important voice (i.e. a parent's or teacher's voice amongst the chatter of other children), and (not surprisingly) an increased tendency towards distraction. Perhaps not surprisingly, deficits in language comprehension, utilization and verbal skills, as well as learning problems often do not fall far behind when an auditory processing disorder is present.
- Although hypo- and hyper-sensitivity may be two sides of the same coin, it is interesting to note that they each appear to be correlated to different comorbid disorders common to ADHD. For example, ADHD children with comorbid auditory hypersensitivity are (at least based on data from the study) more likely to exhibit characteristics of a separation anxiety disorder (which is characterized by apparent stress or emotional outbursts when separated from a parent or particular loved one). What is interesting about this is the fact that separation anxiety behaviors typically decrease with age, but, according to the Ghanizadeh article, hypersensitivity shows little age-related correlation.
- On the other hand, auditory hyposensitivity which occurs alongside ADHD is more likely to be associated with Oppositional Defiant Disorder (ODD), which is characterized by long-term verbal hostility, arguing, intentional disobedience, and disrespectful behaviors towards authorities. ODD can be an early symptom of later conduct disorders, which include violent and criminal behaviors. In addition, an accompanying oppositional defiant disorder can increase ADHD symptoms.
- Additionally, these findings are interesting because they buck some of the trends and associations previously seen in comorbid disorders. For example, hypersensitivity in other sensory areas such as touch is frequently seen in Separation Anxiety and related disorders. This "touch" hypersensitivity is more frequently seen in girls. However, with regards to the ADHD/auditory processing/separation anxiety disorder component of the study, gender differences were not observed. This may suggest either that the gender effects on sensory hypersensitivity and its connection to separation anxiety disorders may reside more in the tactile form of sense, while auditory hypersensitivity has a much smaller gender component with regards to anxiety disorders. As a quick aside, we have looked at another form of sensory hypersensitivity recently in a post titled Does ADHD Improve your Sense of Smell?
- In the past, we have seen that comorbid disorders may favor one particular subtype of ADHD (either inattentive ADHD, hyperactive/impulsive ADHD or combined ADHD subtypes). It appears that, at least for the most part, auditory processing disorders are independent of ADHD subtype.
In conclusion, we should take home two important messages from this article:
- Children diagnosed with ADHD may often be missed for a comorbid diagnosis of auditory processing difficulties, a fact which is seen by the high degree of overlap between ADHD and auditory processing disorders and their shared symptoms.
- Additional comorbid disorders such as anxiety disorders or defiant behaviors may actually provide clues that an underlying sensory processing disorder (such as an auditory processing difficulty) is present. Of course there are numerous potential causes to any of these accompanying disorders, but if a prescribing physician is borderline on diagnosing an ADHD child with an additional auditory processing disorder, the presence or absence of a comorbid separation anxiety disorder or persistence of oppositional behavior may prove to be a potentially useful tool for pointing the physician in the right direction if the Ghanizadeh study findings are verified and replicated by additional works.
Friday, February 27, 2009
CREM Gene, Melatonin and ADHD
In the past, we have investigated several different ADHD genes, or genes that are believed to play some type of role in the disorder of ADHD. A recent article, titled CREM mutations and ADHD symptoms suggests that another specific gene, called CREM (short for Cyclic Adenosine Monophosphate Responsive Element Modulator), may actually play an integral role in the onset of ADHD and its symptoms as well.
Before we go any further, we must bear in mind that the journal in which this article is located is titled Medical Hypotheses. As the name suggests, we should be careful not to confuse hypothesis with thoroughly-investigated scientific data. However, the arguments are typically well laid out, and many of these hypotheses are in fact well-grounded based on a number of well-researched facts which point in their directions. In other words, a number of scientific studies or findings are often preceded by publications of these hypotheses, so we could very well be at the cusp of a new scientific discovery.
A second point worth mentioning is that the CREM mutation article is actually based on the mouse model. This in itself is not unusual, as numerous other studies on ADHD have used analogous murine models, such as the spontaneously hypertensive rat (SHR) model. Numerous comparison studies have supported the validity of SHR as a relevant and accurate model of ADHD in humans (although a few studies have disagreed, these disagreement studies are relatively small in number, however). Furthermore, based on the high degree of similarity between the DNA sequences in the human and mouse CREM genes, there is also a potentially high degree of functional overlap between the two. As a result, it is highly possible that CREM gene findings in the mouse may carry over well into CREM gene studies in humans. Additionally, mice with mutations in the CREM gene have been shown to exhibit ADHD-like behaviors.
Location of the CREM gene:
If you are not familiar with human genetics, the human genome typically has 23 different chromosomes (which come in pairs, so 46 chromosomes total), which are numbered 1 through 23. Scattered out through these 23 different chromosomes are some 30,000 to 50, 000 total different genes (the number is constantly in debate, but this is typically a good estimate), which means that the average chromosome will typically carry between 1,000 to 2,000 different genes on it. Further numbering and lettering schemes denote more specific locations of these genes on the chromosomes. In humans the CREM gene is located on the 10th chromosome. For a more detailed look at the specific location of the CREM gene, please click here.
The association between CREM function and ADHD:
The CREM gene is believed to play a significant role in regulating the secretion of the hormone melatonin throughout the day. Melatonin, which is chemically similar to another key hormonal and neuro-signaling agent serotonin (serotonin actually converts to melatonin in the body), plays a number of roles, such as the regulation of sleep patterns. Melatonin is typically secreted by a specific gland called the pineal gland. For most individuals, lower levels of melatonin are produced during daylight, while higher levels are produced during darkness, which leads to the feeling of sleepiness. Furthermore, emotional states such as chronic stress can also effect melatonin production and secretion.
The CREM gene is believed to exhibit a controlling mechanism on the melatonin secretion patterns throughout the daily process. However, mutations or deletions (i.e. removal) of the CREM gene can result in a number of changes, such as different melatonin secretion patterns and excessive movement (locomotion) and activity at night. In other words, day/night differentiation is typically reduced if mutant or lower-functioning forms of the CREM gene are present.
The connection to ADHD:
Numerous findings suggest that individuals with ADHD are prone to differences in genes which regulate key chemicals in the neurosignaling process (as well as their receptors, or biological targets to which they bind). These include serotonin, dopamine and norepinephrine. Melatonin levels are also typically different in individuals with ADHD, and these ADHD individuals are more prone to daytime sleepiness due to oversecretion of melatonin. Furthermore, several studies indicate that individuals with ADHD are more prone to sleep disorders and abnormal sleep patterns in general, although a number of other studies have indicated conflicting results to this assertion. As a result, the melatonin regulating activities of CREM may be at work as underlying factors to these melatonin-related sleep disorders.
The role of ADHD medications on regulating melatonin levels:
Abnormal melatonin levels (caused by CREM mutations or other factors) may be able to be offset by common ADHD medications. For example, methylphenidate (Ritalin, Concerta, Daytrana), has been implicated as a potential agent in correcting sleep disorders in children with ADHD. This is somewhat interesting, because it contradicts numerous other findings in which stimulant medications have been shown to interfere with sleep.
**Blogger's note: While there are a number of studies regarding impaired sleep quality due to ADHD stimulant medication, we must remember that strategic timing and lower dosing of stimulant medications can significantly reduce the number of sleep-impairments. Most of the sleep problems, at least in my opinion based on personal experiences, are due to the administration of medication doses which are too high and given too late in the day. Although outnumbered with regards to the current number of publications for or against it, I personally side with the assessment that methylphenidate, when administered at the proper dose and the proper time for real ADHD cases, is actually beneficial for promoting and regulating sleep patterns. Again, I want to reiterate that this is simply my opinion based on personal observations and research.
The CREM mutations and ADHD symptoms authors referred to a small study they did on the effects of methylphenidate on lowering melatonin levels. Based on these (extremely limited) findings, it is possible that melatonin regulation via methylphenidate treatment may be a contributing factor to the drug's effect on sleep performance. However, we should be careful not to put too much stock into this finding, since melatonin levels are highly variable among individuals (i.e. comparison of absolute melatonin concentrations between individuals is often ineffective, and intra-individual fluctuation of melatonin levels occur throughout the day anyway).
While the hypothesis that the CREM gene (which, as mentioned, is located on the 10th chromosome in humans) may play a significant factor in regulating melatonin levels and affecting ADHD behavior is predominantly theoretical at this point, I personally believe that this possible connection is at least worth mentioning. Additionally, potential gene/medication interaction studies may emerge, such as studies involving different methylphenidate dosage requirements based on the different CREM gene mutations. We have discussed analogous gene/medication interaction studies in previous posts such as the one entitled ADHD Genes Influence Medication Dosage . We should remain on the lookout for future studies on the possible connections among these different areas.
Before we go any further, we must bear in mind that the journal in which this article is located is titled Medical Hypotheses. As the name suggests, we should be careful not to confuse hypothesis with thoroughly-investigated scientific data. However, the arguments are typically well laid out, and many of these hypotheses are in fact well-grounded based on a number of well-researched facts which point in their directions. In other words, a number of scientific studies or findings are often preceded by publications of these hypotheses, so we could very well be at the cusp of a new scientific discovery.
A second point worth mentioning is that the CREM mutation article is actually based on the mouse model. This in itself is not unusual, as numerous other studies on ADHD have used analogous murine models, such as the spontaneously hypertensive rat (SHR) model. Numerous comparison studies have supported the validity of SHR as a relevant and accurate model of ADHD in humans (although a few studies have disagreed, these disagreement studies are relatively small in number, however). Furthermore, based on the high degree of similarity between the DNA sequences in the human and mouse CREM genes, there is also a potentially high degree of functional overlap between the two. As a result, it is highly possible that CREM gene findings in the mouse may carry over well into CREM gene studies in humans. Additionally, mice with mutations in the CREM gene have been shown to exhibit ADHD-like behaviors.
Location of the CREM gene:
If you are not familiar with human genetics, the human genome typically has 23 different chromosomes (which come in pairs, so 46 chromosomes total), which are numbered 1 through 23. Scattered out through these 23 different chromosomes are some 30,000 to 50, 000 total different genes (the number is constantly in debate, but this is typically a good estimate), which means that the average chromosome will typically carry between 1,000 to 2,000 different genes on it. Further numbering and lettering schemes denote more specific locations of these genes on the chromosomes. In humans the CREM gene is located on the 10th chromosome. For a more detailed look at the specific location of the CREM gene, please click here.
The association between CREM function and ADHD:
The CREM gene is believed to play a significant role in regulating the secretion of the hormone melatonin throughout the day. Melatonin, which is chemically similar to another key hormonal and neuro-signaling agent serotonin (serotonin actually converts to melatonin in the body), plays a number of roles, such as the regulation of sleep patterns. Melatonin is typically secreted by a specific gland called the pineal gland. For most individuals, lower levels of melatonin are produced during daylight, while higher levels are produced during darkness, which leads to the feeling of sleepiness. Furthermore, emotional states such as chronic stress can also effect melatonin production and secretion.
The CREM gene is believed to exhibit a controlling mechanism on the melatonin secretion patterns throughout the daily process. However, mutations or deletions (i.e. removal) of the CREM gene can result in a number of changes, such as different melatonin secretion patterns and excessive movement (locomotion) and activity at night. In other words, day/night differentiation is typically reduced if mutant or lower-functioning forms of the CREM gene are present.
The connection to ADHD:
Numerous findings suggest that individuals with ADHD are prone to differences in genes which regulate key chemicals in the neurosignaling process (as well as their receptors, or biological targets to which they bind). These include serotonin, dopamine and norepinephrine. Melatonin levels are also typically different in individuals with ADHD, and these ADHD individuals are more prone to daytime sleepiness due to oversecretion of melatonin. Furthermore, several studies indicate that individuals with ADHD are more prone to sleep disorders and abnormal sleep patterns in general, although a number of other studies have indicated conflicting results to this assertion. As a result, the melatonin regulating activities of CREM may be at work as underlying factors to these melatonin-related sleep disorders.
The role of ADHD medications on regulating melatonin levels:
Abnormal melatonin levels (caused by CREM mutations or other factors) may be able to be offset by common ADHD medications. For example, methylphenidate (Ritalin, Concerta, Daytrana), has been implicated as a potential agent in correcting sleep disorders in children with ADHD. This is somewhat interesting, because it contradicts numerous other findings in which stimulant medications have been shown to interfere with sleep.
**Blogger's note: While there are a number of studies regarding impaired sleep quality due to ADHD stimulant medication, we must remember that strategic timing and lower dosing of stimulant medications can significantly reduce the number of sleep-impairments. Most of the sleep problems, at least in my opinion based on personal experiences, are due to the administration of medication doses which are too high and given too late in the day. Although outnumbered with regards to the current number of publications for or against it, I personally side with the assessment that methylphenidate, when administered at the proper dose and the proper time for real ADHD cases, is actually beneficial for promoting and regulating sleep patterns. Again, I want to reiterate that this is simply my opinion based on personal observations and research.
The CREM mutations and ADHD symptoms authors referred to a small study they did on the effects of methylphenidate on lowering melatonin levels. Based on these (extremely limited) findings, it is possible that melatonin regulation via methylphenidate treatment may be a contributing factor to the drug's effect on sleep performance. However, we should be careful not to put too much stock into this finding, since melatonin levels are highly variable among individuals (i.e. comparison of absolute melatonin concentrations between individuals is often ineffective, and intra-individual fluctuation of melatonin levels occur throughout the day anyway).
While the hypothesis that the CREM gene (which, as mentioned, is located on the 10th chromosome in humans) may play a significant factor in regulating melatonin levels and affecting ADHD behavior is predominantly theoretical at this point, I personally believe that this possible connection is at least worth mentioning. Additionally, potential gene/medication interaction studies may emerge, such as studies involving different methylphenidate dosage requirements based on the different CREM gene mutations. We have discussed analogous gene/medication interaction studies in previous posts such as the one entitled ADHD Genes Influence Medication Dosage . We should remain on the lookout for future studies on the possible connections among these different areas.
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