ADHD gene SLC6A4 favors males over females

In our last post, which asked the question "Are ADHD genes Gender Dependent?" we introduced four genes believed to be associated with the disorder of ADHD:

• SLC6A4 gene
• COMT gene
• SLC6A2 gene
• MAOA gene
  

In the next four posts, we will investigate each of the 4 ADHD genes listed above.

SLC6A4 gene, gender effects, and ADHD:

Out of the four genes listed above, the SLC6A4 gene has the least gender-based effects. The authors of the original paper on gender effects of four genes actually concluded that the gender specific influence of SLCA4 gene was not statistically significant. Nevertheless, the authors briefly noted that there was a greater influence on males than females for this particular gene (in the summarizing abstract portion of the paper).

The particular region of investigation on the SLC6A4 gene, which is located on the 17th human chromosome, was at a specific marker rs2066713 (If you are not familiar with this terminology, this is not important, it is just a way of citing a specific region of DNA and can be used to pinpoint a more exact location on a gene for studies on genetic variations, mutations, etc.). According to the study, at this specific marker on the SLC6A4 gene there was a higher likelihood that ADHD boys would receive the DNA base thymine ("T" for short) at this particular location than did ADHD females. This suggests that this "T" form (or "allele", which is a particular form or variation of a gene) at this particular spot on the 17th human chromosome which contains the SLC6A4 gene is more likely to be passed on to males with ADHD than females with ADHD. In other words, this "T" form of the SLC6A4 gene may be more associated with ADHD in males than in females. Of course, we must reiterate, that although a gender difference was observed, it was not sharp enough to be considered statistically significant, according to the original study.

Some other thoughts about the SLC6A4 gene and potential relevance to ADHD symptoms and behaviors:

• The SLC6A4 gene is often referred to by other more common names: the serotonin transporter gene (also abbreviated as 5-HTT, Serotonin Transporter, and SERT) is believed to be associated with a number of depression-related mechanisms. Interestingly, the link between the serotonin transporter gene and depression may also be susceptible to stress and other environmental factors. This gene is responsible for coding for and ultimately producing a serotonin transporter protein, which is frequently implicated in depression-related illnesses and is the target of antidepressant medications, such as Paroxetine (Paxil), Imipramine (Tofranil) and Fluoxetine (Prozac). In addition, the products of the SLC6A4 gene are also affected by amphetamines, which among some of the most common types of ADHD stimulant medications. In other words, the different forms of this SLC6A4 gene may actually play a role as to how an individual acts to a particular antidepressant or amphetamine medication. Again, keep in mind that there is often a fair amount of overlap of depression with ADHD (some experts argue that a "Depressive" form of ADHD should actually warrant its own ADHD subtype), so it is possible that gender based differences in this gene may be related to this hypothetical subtype in particular.

• However, other evidence suggests that the SLC6A4 gene may not be exclusively labeled as a "depressive gene". A study done on multiple genes believed to affect aggression and impulsivity (the latter being a common trademark of ADHD, while the former is occasionally seen extreme cases, although much more rarely, and typically only in the presence of additional comorbid disorders to ADHD), and found a nominal association between this SLC6A4 gene and cognitive impulsivity. Cognitive impulsivity, in essence, is associated with an individual making hasty decisions without carefully considering the consequences of one's actions, which frequently leads to negative or even dangerous outcomes. Not surprisingly, this is seen at much higher rates in ADHD individuals. Similar features are seen in ADHD individuals who have underactive functioning in the right frontal lobe region of the brain (a diagram of this region is given in an earlier blog post on differences in ADHD kids' brain regions), as well as those who have low tryptophan levels (which often correlates with depression and depression-like symptoms).

• There is also a possible connection of this particular SLC6A4 gene and autism, although numerous other studies have shown conflicting results. Nevertheless, given the fact that there appears to be a notable (but incomplete) overlap of ADHD and autistic symptoms, and the fact that autistic disorders are much more prevalent in boys, it is possible that there may be a tie-in between this "male-dominated" SLC6A4 gene form and a possible ADHD-autism connection.

• Finally, studies have linked variations in this serotonin transporter gene to bipolar disorders. This is also of interest because ADHD and bipolar disorders can occur together frequently and can sometimes be difficult to differentiate, especially at the pediatric level.

In the next few posts, we will be investigating three other ADHD genes believed to have gender-specific effects, which each have a potentially greater sex-related differences than this SLC6A4 gene.

Are ADHD Genes Gender Dependent?

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:

• COMT gene
• SLC6A2 gene
• MAOA gene
• SLC6A4 gene

We will be exploring each of these four ADHD genes affected by gender in subsequent postings.

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:

1. 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.
   
   
2. 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.
   

As a quick aside, errors (i.e. pushing the wrong button after an auditory stop signal was presented) were, not surprisingly, significantly higher in the ADHD group than the non-ADHD group.

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.

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.

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).

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:

1. 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.
   
   
2. * 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.
   
   
3. **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.

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:

1. 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.
   
   
2. 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).
   


3. 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.
   
   
4. 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.
   


5. 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.
   


6. 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.
   
   
7. 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.

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:

1. 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.
   
   
2. 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.