ADHD and Balance Impairment: Visual and Inner Ear Deficiencies

Balance dysfunctions and visual or vestibular deficiencies: Uncommon comorbids in the ADHD spectrum:

When we think of comorbid disorders to ADHD, we often envision disorders which can be diagnosed psychiatrically. Common examples such as depression, anxiety, Obsessive Compulsive Disorders (OCD), oppositional defiant disorders, and conduct disorders often come to mind. In addition, it is perhaps no surprise that learning disabilities are relatively common in children and adults with ADHD. If we do delve into physical comorbid disorders, things like Tourette's and tics may come to mind. For those skilled in the diagnosis and treatment of ADHD, even non-trivial comorbids such as bedwetting and sleep disorders may be apparent.

However, there is another impairment that often goes along with the ADHD population, especially in children. Sensory processing disorders are often seen in the ADHD population, especially in children. This includes more "physical" dysfunctions including the ability of the child to maintain balance and equilibrium. To the frustrated parent of coach of an ADHD child, this may introduce another complication with regards to sports or other activities which involve coordination and balance, such as basketball, baseball, tennis, soccer, gymnastics, musical instruments, dance, etc.

The aim of this post is to investigate and discuss impairments in balance function in children with the disorder, We will be citing and highlighting some key studies in the overlap between ADHD and balance dysfunctions (especially relating to functions derived from visual and tactile signals) and look for possible underlying causes and treatment methods:

Brain regions involved in Balance Dysfunction in the ADHD Child:

Most experts often cite specific "hot spot" regions of the brain for the ADHD patients. Among these, the prefrontal cortex part of the brain often receives the most attention. Less pronounced, however, are the studies associating the cerebellum, and their implications on ADHD. For a reference to the Prefrontal Cortex and Cerebellum brain regions, please consult the brain diagrams below:

Shown above is a human brain. The Cerebellum region, which plays a major role in governing balancing functions and may be compromised in a significant subsection of ADHD children, is shown in purple in the top picture. The area highlighted in orange in the bottom drawing roughly corresponds to the prefrontal cortex region of the brain, which plays a major role in impulse control. Deficiencies in blood flow and overall activity of this prefrontal cortex region of the brain are often seen in children (and adults) with ADHD, and may be responsible for some of the difficulties in filtering out comments and actions for appropriateness.

The inter-relationship between attention and balance/coordination: The strong association of the prefrontal cortex and cerebellum regions of the brain:

Many studies involving brain regions and ADHD often miss this connection. The relationship between these brain regions may go a long ways in explaining ADHD comorbid disorders as well, especially the more "physical" ones such as speech complications, developmental coordination disorders, etc. While perennial "hot spot" brain regions, such as the prefrontal cortex, are frequently mentioned in studies involving brain activity in ADHD, this particular brain region is actually intricately interconnected with the cerebellum (as well as another key brain region, the basal ganglia. The role of the basal ganglia in kids with ADHD has been discussed previously in other postings, but in general, the basal ganglia tell how fast a person "idles". 'Type A' personalities, such as workaholics, individuals with OCD and overly focused individuals typically have overactive basal ganglia, whereas many with ADHD often exhibit underactive basal ganglia.).

We have already mentioned that the balance-governing regions of the brain (the cerebellum) is interconnected with a key impulse-control region of the brain (the prefrontal cortex or PFC). We also mentioned that impulsivity is a characteristic of the Hyperactive-impulsive and Combined ADHD subtypes (as opposed to the more inattentive forms of the disorder). Interestingly, the prevalence of balance dysfunction cases seems to predominate in the combined subtype of ADHD (main paper as reference source). This correlation lends further credence to the hypothesis that the balance-governing and impulse-governing regions of the brain may be "co-affected" in the case of the balance-deficient, hyper-impulsive ADHD child.

Key points concerning balance related deficiencies and ADHD:

• ADHD is often associated with developmental delays. Indeed, studies highlighting a delay in cortical maturation in children with ADHD suggests that children and teens with the disorder may fall "behind the curve". By its own very nature, the vestibular system often does not fully develop until the age of 15, so immature development in this brain region may result in deficiencies in this system throughout almost the entire span of childhood in an individual with ADHD.


• Additionally, EEG and imaging studies have also demonstrated relative deficiencies in both size and activity (by measuring blood flow patterns) in various brain regions of ADHD children. These include the cerebellum and the caudate nucleus. Both are interconnected and associate with the "ADHD region" of the prefrontal cortex (PFC). This PFC region plays a major role in the impulse-control process and deficiencies in its function can result in a weak self-regulatory system of impulsive behaviors (which are hallmark characteristics of ADHD, especially in the hyperactive/impulsive and Combined subtypes).


• The cerebellum gathers input from visual, vestibular (inner ear), and somatosensory (mainly tactile senses, such as perceived through the skin and internal organs) systems. As we can imagine, a defect in one or more of these information-obtaining sensory systems, and the cerebellum (as well as the interconnected region of the PFC) may be compromised. Thus ADHD and sensory deficits may be intricately related.


• Taking this one step further, we may wish to explore the link between ADHD and sensory disorders, including processing disorders and sensory integration disorders. One thing is for sure, however: ADHD is not simply limited to deficits in the PFC!


• The vestibular system also plays a crucial role in what is known as "gaze stabilization" (i.e., stabilizing the focus on a particular fixed object when you yourself are moving). The very nature of "gazing" obviously has visual implications as well, so a deficiency in the vestibular component of gaze stabilization may also affect visual input success as well. Interestingly (an perhaps not surprisingly), visual input deficiencies are also seen at high rates in children with ADHD.
  
  This may actually serve as one of the key contributing factors as to why maintaining attention (to, say, a teacher), may be so difficult for ADHD kids, because they literally are having trouble focusing their visual attention (gaze) on their target of interest (i.e. a teacher standing up in class giving a lecture), especially if the child is already fidgeting around in their seat. In other words, there may be some inherent deficiency in this particular component of the attention span, and needs to be addressed further in the near future.

Investigating the sources of balance impairment in children with ADHD:
In order to clarify where I am coming from on this, I will highlight an extremely recent publication in the Journal of Pediatrics by Shum and Pang. This study investigated the different systems of balance in children, including somatosensory (balance governed by tactile features), visual, and vestibular (inner ear and the sense of equilibrium). They tested approximately 50 children (ages 6-12) with ADHD for balance discrepancies by isolating each of the three systems listed above to test sensory organizations of balance. A highlight of the study can be seen below:

Instruments/Methods of the study:

1. A platform which can induce a feeling of motion on a child who stands upon it (this disrupts the somatosensory component of balance, forcing the child to use their visual or vestibular functions to compensate for the somatosensory impairment).
2. Surrounding scenery which can visually give the illusion of motion. This forces the child to use their vestibular and somatosensory methods of equilibrium, as the visual sense is disrupted. Another variation of this is to have the child perform with their eyes closed.
3. A combination of the two methods above will isolate the vestibular component of balance, as both the somatosensory and visual sources of balance are now both compromised.
4. A total of six different environmental conditions were performed to isolate one or more senses of balance. The researchers noted which of the three modes of balance were most likely to be compromised in the ADHD children. The findings are highlighted below:
   

While balance-related issues can stem from visual discrepancies, somatosensory issues (i.e. the sensations of touch and pressure from the skin and even internal organs), and vestibular (inner ear) imbalances, it appears that ADHD children are most likely to suffer from visual imbalances. This is closely followed, however, by deficits in vestibular function. Somatosensory difficulties appear to occur in ADHD children as well, but the role of this system is likely to be much smaller than for the other 2.

Possible academic implications of balance dysfunction and ADHD: Does the source of an ADHD child's balance deficiency affect his or her sensory learning style? The following points are simply the result of this blogger thinking out loud. Nevertheless, these might be some good topics of future study, as balance difficulties may be useful in evaluating academic strategies.

• These findings on balance may even extend to the classroom and affect the learning environment of an ADHD child. Given the above, abnormalities in these areas may even affect a child's mode of learning and learning style. While these assertions simply remain personal hypotheses of this blogger, a child with visual discrepancies leading to balancing difficulties may also be deficient in visual perception and therefore struggle in a visual-dominated learning environment. He or she may gravitate towards a more auditory or kinesthetic style of learning.
  

• Conversely, it is also possible that vestibular-regulated balance dysfunctions, which stem from the inner ear may actually extend to a child's auditory learning capabilities. Again, this remains a hypothesis, but given the fact that severe childhood ear infections can affect both balance and hearing (as well as ADHD symptoms, see previous post on childhood ear infections and ADHD), a child with vestibular-related balance deficiencies may also have more difficulty in a predominantly auditory-based learning environment. This may spell bad news if an ADHD child's teacher engages in more auditory discussions or as the child moves up to high school and college courses where an auditory lecture is the more common form of teaching and communication.
  

• A double-whammy?: Given the fact that children with ADHD may suffer from both vestibular and visual (and even somatosensory) information processing for balance, it leads us to wonder if the child may also have learning deficits in 2 of the 3 major forms of learning (visual, auditory or kinesthetic). If this is the case, trying to accommodate an ADHD child's education could be extremely difficult, if he or she must heavily rely on only one predominant mode of acquiring and processing information.
  
  For example, if a child were to undergo a study similar to the one listed above, and it turns out that he or she is weak in both the visual and vestibular forms of balance, and (this is a big "if" and is only hypothetical at the moment) the whole balance governing/learning style hypothesis holds true, he or she may have to rely on a predominantly kinesthetic form of learning. While this child may succeed in hands-on learning subjects (i.e. frog dissection or wood shop class), he or she may have an exceedingly difficult time in other subjects such as algebra or history where hands-on-learning opportunities are more difficult to implement.
  
  

• The role of balance and sensory stimulation may have even greater-reaching academic implications. Another study just came out recently investigating the role of posture stability (i.e. how well a person stabilizes their center of balance) on ADHD and dyslexia. The study found that comorbid ADHD symptoms greatly influenced the effects of posture stability in dyslexic individuals, which may even have implications to affecting the reading environment of the individuals with dyslexia. It's important to keep in mind that this study involved adults instead of children, but the fact that ADHD may play such an integrated role into sensory modulation of other disorders into adulthood may signify the deep level of inter-relationship between cognitive function and sensory motor stimulation.
  

Vestibular Stimulation as an alternative form of ADHD Treatment?: As an interesting aside, there has been some pronounced effect on treating ADHD symptoms with a non-pharmaceutical alternative method called vestibular stimulation. We will be addressing the validity of these findings and their potential for practical usage in a later discussion.

Childhood Ear Infections and ADHD: Why the link?

When we scan the literature for statistics on ADHD and search for early warning signs or tip-offs that a young child may be prone to the disorder, a few common trends seem to pop up again and again. One of these is the high rates of ADHD and attentional difficulties in kids suffering infection of the middle ear (Otitis Media) in early childhood.

During early childhood, the actual positioning of the ear canal is still adjusting, the pathway into the middle part of the ear is actually at a flatter angle than in a mature adult. This difference in positioning actually makes younger children much more prone to ear infections than older children or adults. Unfortunately, these infections may increase the risk of further complications down the road, including an increased onset of attentional difficulties, including ADHD. Here is what some of the literature has to say about the ADHD/ear infection connections:

Relationship between middle ear infections and inattention: The basis for inattentive ADHD?

The main culprit for attentional deficits is often believed to be the result of hearing loss (even mild), early in a child's life due to complications with the middle ear, including infections, allergy-related causes or build-up of fluids in the canal. As a result, the child begins to miss out on verbal cues, and does not develop the same level of response to an adult voice. Auditory deficiencies (including auditory processing disorders) may stem from this key development period, even if the hearing difficulties are only temporary.

Not surprisingly, there is a wealth of data associated with hearing loss due to middle ear complications can lead to language processing difficulties. We have seen how auditory processing disorders can often occur as a comorbid factor in ADHD, and may be linked to seemingly unrelated behaviors including comorbid anxiety and conduct-related disorders.

It is important to note, however, that other early childhood studies have not seen a link between infection and attentional difficulties (observed by parents, teachers, or clinicians).

Interestingly, environment may play a huge role in explaining this discrepancy between study results. One study found that children who had middle ear complications early on along with poor home environments were significantly more likely to develop attentional difficulties (along the lines of what would be classified as ADHD). Therefore, the effects of early ear infections on compromised attentional difficulties may be significantly reduced if a supportive home environment is maintained for a child. This is good news for parents of children with ear infections. But what about the hyperactive component of ADHD?

The link between hyperactive behaviors and middle ear complications: The basis for hyperactive/impulsive or combined subtype ADHD?

While it seems more intuitive that ear infections could lead to auditory problems and subsequent attentional difficulties (especially to auditory cues), the relationship between ear infections and hyperactivity is less inherently obvious. This association would be more relevant to the hyperactive/impulsive and combined subtypes of ADHD.

For over 30 years, researchers have linked high rates of ear infections and hyperactivity (this study used the term "minimal brain dysfunction", a phrase which this blogger has personal objections, nevertheless, it is a relatively common term in the literature). Later studies confirmed these findings, including one which reported the majority of children medicated for hyperactivity had a past history of 10 or more childhood ear infections. These numbers were in sharp contrast to the prevalence of ADHD in non-hyperactive children.

One thought may be that ADHD which includes a significant hyperactive component (as opposed to the more inattention-dominated form of the disorder) is more likely to be associated with comorbid disorders that correspond to ear infections. We have seen previously that comorbid disorders to ADHD are often related to particular subtypes.

For example, anxiety and depressive-like symptoms are often more likely to co-exist with primarily inattentive ADHD, while conduct disorders are more likely to co-exist if there is a high hyperactive/impulsive behavior (especially in the combined subtype). In general, the prevalence of more severe learning disabilities is often more associated with the inattention-dominant form of ADHD, while motor tics are more likely to be a hyperactive/impulsive trait. Carrying these associations in mind, are the studies linking early ear infections to hyperactivity simply due to associations with hyperactive subtype-dominated comorbid disorders?

One particular study found that children with hyperactivity vs. children with learning disabilities (and not hyperactivity, remember, learning disabilities are often seen at higher rates in the inattentive forms of the disorder) had similar numbers of total childhood ear infections. However, the timing of the infections did seem to matter. Children with hyperactivity experienced more recent ear infections (within the previous year) compared to the learning disability kids.

In other words, the question surrounding hyperactivity and ear infections may be more of a "when" question than a "how many" question. This may also suggest the possibility that hyperactivity due to middle ear troubles may be more of a temporary condition (this is supported by trends as an individual with ADHD ages, typically, the hyperactive symptoms of the disorder begin to subside as a child gets older and reaches adulthood, while the inattentive symptoms are more likely to plateau) as opposed to inattentive problems stemming from ear infections. Severity of the infections may also be a triggering cause or associated warning sign of an increased risk of developing hyperactive behaviors. The same study found that earaches and upper respiratory tract infections were higher in the hyperactive group than in the less-hyper learning disability group.

So what's going on with the connection between ear infections and ADHD-like hyperactivity?:
Although none of the above studies mentioned this possibility, as a blogger I have a few ideas on the subject. One of the most probable reasons for the ear infection/hyperactivity correlation may be due to the treatment process of ear infections. Let me explain:

Ear infections are typically treated with antibiotics. While these drugs work wonders for most infections, they also can disrupt the healthy bacterial counts in the digestive tract (that is, they kill off many of the "good" bacteria in our digestive systems in addition to the "bad" bacteria which may be causing our infections).

If the "good" digestive bacterial counts fall too low, the digestive process is compromised. The absorption and digestion process may suffer, as key nutrients may now be compromised (even if no major dietary changes occur). We have spoken extensively about nutrient deficiencies and ADHD as well as ADHD-related nutrition strategies in earlier posts.

Additionally, if good bacterial counts fall low, incomplete digestion results, which can lead to byproducts such as higher concentrations of organic acids, as well as incomplete breakdowns of potential allergens (which can increase sensitivity to food allergens, among others). These allergens and acids can actually begin to penetrate the blood brain barrier and show up in higher concentrations in the brain. Neurological disorders, including abnormal hyperactivity may actually be triggered by digestive imbalances (to a degree beyond what most of us realize). We are just beginning to recognize the huge degree of inter-relationship between the nervous and digestive systems, including brain-gut interactions.

There has been a longstanding "hot" discussion surrounding food allergies and ADHD (as well as possible connections between food allergies and disorders like fibromyalgia and chronic fatigue syndrome), and the disrupted bacterial balance in the digestive system due to frequent antibiotic usage for recurrent ear infections may be a governing factor. This seems to make sense, especially considering the fact that hyperactivity was more linked to recent ear infections (and resultant antibiotic treatment), while the more inattentive behaviors and learning disorders seem to be a more long-standing symptom. Since bacterial counts begin to re-stabilize following antibiotic treatment (if a proper diet is maintained), the food-related hyperactivity may begin to subside, but for recent infections and treatments, the digestive bacteria may still be imbalanced, triggering an onset of ADHD-like hyperactive behaviors.

Of course this is just the blogger's personal hypothesis, but it at least seems plausible that the actual treatment for ear infections may play an equally strong role on the high rate of occurrence between ADHD and ear infections.

Daytrana Absorption and Metabolism Patterns Compared to Ritalin and Concerta

In the previous post, we introduced the relatively new ADHD medication Daytrana. Composed of the same chemical compound as Ritalin and Concerta (methylphenidate), Daytrana offers the distinct advantage of existing in the patch form, which is typically worn on the hip. At the present moment, this medication is used exclusively for children with ADHD and related disorders, although it can also be used off-label for adults with the disorder.

Given the entirely different delivery system of the patch form of Daytrana vs. the conventional pill form of Ritalin and Concerta, the question arises on how the rates and patterns of drug delivery compare between the two forms of the medication. A copy of a table from the previous post, titled Daytrana Dosing Equivalents to Ritalin and Concerta is given below:

Patch size refers to the size of the Daytrana patch worn by the individual. The total content of drug per Daytrana patch (in milligrams methylphenidate) and rate of delivery (per hour) of the different patch sizes are also listed above. The standard wear-time for the patch is 9 hours, so a comparison in total drug dosage for a 9-hour period is also listed. Finally, equivalents to Ritalin (Immediate release, abbreviated "MPH-IR", the dosage listed is given 3 times per day, in milligrams), as well as Concerta (given once per day, also in milligrams) are also listed.

As far as total methylphenidate content delivered, the three methods of comparison are all similar. However there are some differences in rates of delivery, drug absorption patterns, and drug metabolism between the three different methods. A comparison, based on a report from Pierce and coworkers on the pharmacokinetics of the methylphenidate transdermal system (a technical term for Daytrana) is highlighted below. Please note that some of the data are supplemented from other similar studies on children with ADHD, so don't take these numbers as absolute. There is still a large amount of variation between the different studies. Nevertheless, these values are, to the best of this blogger's knowledge and current research, a good representation of values typically found in the literature (sometimes numerical ranges are given in lieu of exact numbers to reflect this). In other words, look at the numbers for comparative purposes instead of absolute values. The important thing to note below are some of the trends and comparative differences between the different forms of methylphenidate.

About the table above:

The columns going across include Immediate Release methylphenidate ("MPH-IR", similar to short-acting Ritalin and the like), Osmotically released methylphenidate (MPH-OROS, which is the drug form used by Concerta) and the four different patch sizes of Daytrana currently available ("DT" 10, 15, 20 and 30, which reflect the amount of methylphenidate delivered in milligrams to the body over the standard 9 hour patch-wear time of the 4 different patch sizes, listed in our first table).

For the first column, Max Concentration reflects the highest concentrations of the drug methylphenidate which are typically seen (again, don't scrutinize the exact numbers too closely, just look for trends across the chart). The next entry, Time to Reach Cmax, reflects the approximate amount of time after first taking the methylphenidate capsule or putting on the Daytrana patch for this maximal concentration to occur (in hours, again, an approximation).

Effectiveness is a more relative term, but it is based on how long the desired effects typically last (in hours) of each drug formulation. Again, experts and studies disagree, so just use these as relative guidelines. Finally, the term half-life is used as a measuring tool for how fast the drug is eliminated or cleared from the body. For example, a drug with a half life of 3 hours means that every three hours, the amount of drug remaining in the system is cut in half (used in a similar matter to how radioactive decay is measured).

4 important trends to note from the table:

For convenience, the same table is listed again below.

1. Higher drug concentrations from the patch form: Note that much higher plasma concentrations are typically seen with the Daytrana patch form of the drug than the other delivery system. This is likely due to the route of administration which bypasses several enzymes and other metabolic factors in the digestive system reserved for oral delivery routes. As a result, higher plasma concentrations can more easily occur. This is especially apparent in the two largest Daytrana patch sizes, where maximum plasma concentrations are close to double the levels attained via the traditional oral delivery methylphenidate medications for ADHD.
   


2. Greater time to reach high concentrations: The time to reach these high concentrations is greater as well. This is often an advantage, given the fact that stimulant medications which exhibit the greatest abuse potential typically enter the bloodstream (and, subsequently the brain), extremely quickly (often in 15 minutes or less), and then leave the brain and body quickly. As a result, while this more drawn out process (relatively similar to that of Concerta, but slightly longer), is good news for lower abuse potentials. However, the relatively long time to reach maximum concentration can be difficult for seeing the desired effects shortly after medication. However, given the higher apparent "ceiling" for these patch-style delivery systems, adequate drug concentrations are typically seen within 2 hours (data not shown). In other words, medication effects can be felt long before these high maximal concentrations occur.
   


3. Longer duration of effectiveness: The pharmacokinetics study of the methylphenidate patch for ADHD noted that detectable levels of the drug, when given in the patch form, were still seen in the blood the next day, up to 15 hours after the patch was removed (although only around 5% of the maximum concentration). Nevertheless, this 9-hour patch delivery method may prove useful in maintaining a constant presence of the medication throughout the day, and may extend the drug's effectiveness beyond even some of the longest-lasting oral methylphenidate forms. This may prove useful for individuals who still need to control for lack of focus and hyperactivity, such as a child with a big homework project. Of course, the flipside to this could be a greater potential for long term side effects, due to the constant persistence of the drug (keep in mind that this Daytrana system is only 2-3 years old, so long-term evaluations are still not available to any sufficient extent).
   


4. Similar rates of clearance: Perhaps the most consistent parameter across the board, it appears that the clearance rates of the patch and oral systems of methylphenidate all seem to hover around the three hour mark. This suggests that once the drug is actually delivered (albeit by a different delivery system), the rest of the metabolic processes are pretty much the same for the different forms of methylphenidate.
   
   
   

The enantiomer effect of Daytrana:
Before going, I just wanted to mention another peculiarity of the transdermal (patch-based) form of the methylphenidate delivery system:

Most methylphenidate medications are actually a mixture of two compounds of the same formula that exist as mirror images of each other. These mirror images are called enantiomers. While they have the same chemical formula and structure, the two different mirror image forms of the drug can behave entirely differently. In some extreme cases, getting the wrong enantiomer or mirror image of a drug can even produce disastrous side effects. For example, for the drug thalidominde, which was prescribed for morning sickness in pregnant mothers was actually found to have one safe enantiomer, but the other enantiomer, or mirror image resulted in severe birth defects. As we can see, this one minor change in drug shape can have huge repercussions if we're not careful.

In the case of methylphenidate, however, the effects of the differnt mirror images of the drug are much less pronounced. However, one of the two enantiomers (called the "d form") of the drug is much more potent or active than the other form. As a result, new formulations containing only the more "active" form of the drug began to develop. The drug Focalin (dexmethylphenidate) is an example of this. It has been demonstrated that Focalin can produce similar effects to regular methylphenidate at half of the methylphenidate dosage. We will save further discussion on this topic for later posts.

The reason I mention this enantiomer effect is that the two mirror images of the methylphenidate are metabolized and cleared at different rates. What is interesting is that the actual form of delivery for the drug (i.e. the patch for Daytrana, or the oral form for Ritalin or Concerta) actually affects the ratio or balance of the two mirror images of the drug after short periods of time.

To illustrate, consider the following:

• For Methylphenidate Immediate Release (Ritalin-IR), the "L" form (the less active form) is almost non-existent shortly after dosage is administered. That is, the "D" form (the more active form, or the mirror image which exists exclusively for Focalin), is the overwhelmingly predominant form of the drug remaining within a period of 1-2 hours.

• For Concerta (a slower releasing form of the drug compared to the immediate release Ritalin form of methylphenidate), the ratio is still skewed shortly after administration of the drug, with the "D" form: "L" form exhibiting a ratio of around 40:1 (after a few hours). Once again, the more potent form of the drug predominates shortly after the drug is given, and the less active form is more quickly cleared.

• However, with Daytrana, the "D" to "L" mirror image ratio of the drug is still in favor, but not by nearly the amount of the two oral delivery forms (Ritalin and Concerta). In the case of Daytrana, the "L" form stays around longer, sitting at about 55-60% of the more active "D" form of the drug. It is still unclear at the moment as to why this is, but some possibilities include the difference in enzymes and enzyme systems used to break down the drug between the skin and the digestive forms of delivery. Nevertheless, this blogger would not be surprised to see another patch form of delivery comprised exclusively of the more potent "D" form of the drug (as in a patch form of Focalin) on the horizon as an even more effective treatment for ADHD.

To summarize, Daytrana appears to be an effective alternative form of delivering methylphenidate for children with ADHD. Given the fact that the individual can now control two variables (patch size and wear time), it appears that this form of the medication may be easier to tailor to the individual than the oral form of methylphenidate.


We will continue our discussion about some of the other pluses and minuses of the Daytrana form of methylphenidate and how they relate to strategies of ADHD treatment in the next few posts.

2 Key Brain Regions Which Are Smaller in ADHD Individuals

We have previously held several different discussions about brain regions and ADHD. Some have hinted at reduced activity, often measured by lower bloodflow patterns either during resting states or mental challenge, while others have examined different patterns in brain waves and food allergy-induced changes in brain electrical activity. Still others have pointed towards gene-based lowering of chemical signals in key brain regions of ADHD individuals. Additionally, we have looked at articles dealing with alcoholism and the relative size of specific brain regions with regards to ADHD.

Adding to this growing body of evidence on the differences between brains of ADHD'ers and non-ADHD individuals is recent article by Ellison-Wright and coworkers on structural brain differences in ADHD individuals. We will be extracting some of the key findings of this meta-analysis (a review which combines and analyzes bodies of data amassed from a number of previous findings and publications and compiling it into a larger set of data to look for underlying trends and relationships). Here are 10 key points to take home from Ellison-Wright's findings (as well as from some of the other articles he cites in the analysis study):

1. An overall reduction in gray matter in the right putamen (shown in red) and globus pallidus (shown in blue) regions of the brain has observed in ADHD patients compared to controls. This is an underlying theme among multiple previous studies. The image below is of the human brain with the approximate regions of the putamen and right portion of the globus pallidus regions (the view is from the top down on a subject with the front part of the brain at the top and the back part of the brain at the bottom of the image).
   
   




2. Brain volume changes in two other regions, the frontal lobe and the caudate nucleus have been associated with genes related to processes of the key neurotransmitter dopamine. Please note that the frontal lobe has often been tied to ADHD, both through a decrease in size (in the prefrontal cortex region part of the frontal lobe, see below for details). Additionally, the caudate nucleus, actually combines with the putamen and globus pallidus to form a larger brain region called the corpus striatum (see diagram below). The approximate locations of the prefrontal cortex (brown), globus pallidus (blue), caudate nucleus (green) and right putamen (red) are shown in the image below. As in the image above, we are looking from the top down on an individual who is facing forward towards the top of this page.
   
   



3. Adding to this discussion, the article refers to a process in which the globus pallidus acts like a type of highway (the article uses the term "circuitry", but a highway or series of highways may be easier to visualize) between other brain regions, including the caudate and putamen regions. Therefore, the size and shape of this globus pallidus may play an even more crucial role with regards to ADHD and other related disorders, as multiple other brain regions can be critically dependent on it.
   
   
4. Many previous publications frequently study brain regions which are easier to study (i.e., ones that are less complex and easier to map and analyze than the smaller and more elaborately dense brain regions), often out of necessity. However, this selection process for sake of convenience can leave out several critical brain regions and sub regions which may actually play a critical role in the brain volume/ attentional disorders connection. At this point, it appears that we are just scratching the surface with regards to studies involving these key brain regions and ADHD.
   
   
5. ADHD seems to be more correlated brain volume imbalances due to decreases of specific brain regions, namely the putamen and globus pallidus (see diagram above), rather than relative increases in other brain regions. In other words, ADHD appears to be more of a "brain volume decrease-based" type of disorder, at least at the moment.
   
   
6. Further adding to the idea that the striatum region of the brain as a whole is another study done by Bush and coworkers, which have pinpointed this brain region as one bearing a significant role on the disorder of ADHD. The striatum is comprised of the putamen and caudate nucleus (on both left and right halves of the brain), and is shown in green in the diagram below:
   
   




7. Studies involving brain damage (such as those caused by impact or injuries to the brain) found a strong association between ADHD symptoms and lesions for both the right and back parts of the putamen region of the brain. It appears that reductions in these sub regions either due to lack of size or damage can elicit similar results which include an increase in ADHD or ADHD-like behaviors.
   
   
8. The basal ganglia (the odd "snail-shaped" region in the diagram below, which includes the aforementioned putamen, globus pallidus and caudate nucleus, as well as a few other sub regions we haven't yet discussed) is another key brain region which is believed to be involved in ADHD and other related disorders. The basal ganglia region of the brain essentially determine how fast a person's brain "idles". This region has often been found to be underactive in ADHD and similar disorders and overactive in obsessive compulsive or anxiety-related disorders. Thus the basal ganglia function can have some far-reaching implications. Not surprisingly, then, is the fact that mis-development in the "wiring process" of the basal ganglia (such as seen in the formative years), may play a crucial role on the onset of ADHD both directly, and indirectly (via interaction with other key "ADHD" brain regions).
   
   
   


9. Returning to the two main brain regions of investigation (the globus pallidus and the right putamen) for a moment, we see that these brain regions may also play a key role in governing the response to and effectiveness of potential ADHD medications.
   
   For example, a positive response to the ADHD stimulant methylphenidate (Ritalin, Concerta, Daytrana) may be influenced, at least in part, to the function of the right putamen region of the brain. According to this study, a higher level of bloodflow to the right putamen region (among a few others listed in the study), was significantly correlated to a positive response to the methylphenidate medication. In other words, a functionally active right putamen brain region may increase the odds of a child being able to tolerate their Concerta, while children with reductions or abnormally slow developments of the right putamen might be prone to less success with this type of medication. As of now, it is unclear if this brain region exhibits the same effects on other ADHD stimulants as well.
   
   
10. It is also likely that metabolic differences in the globus pallidus play a role in ADHD. A metabolic study involving the ratio of two types of "fuel" (creatine and N-acetylaspartate or NAA), which is often a good indicator of neuronal health in several key brain regions, found that individuals with ADHD had an abnormally low ratio of NAA to creatine. Taking this one step further is the topic of supplementation. Creatine supplements, often used by exercise enthusiasts, have been shown to boost levels of this nutrient to the brain as well, which can decrease the NAA to Creatine ratio (i.e., more creatine and less NAA). This brings up the hypothetical question as to whether creatine supplementation can actually exacerbate some of negative effects of ADHD by tampering with this desired ratio. We will actually be exploring the topic of creatine supplementation and its effects on the brain in another blog post in the near future.

Gender, Age and Subtype Effects on ADHD Comorbid Disorders

We have spoken extensively on some of the related or comorbid disorders associated with ADHD ("Comorbid" here refers to an accompanying disorder that frequently occurs alongside ADHD. These may include disorders such as depression, Tourette's Syndrome, allergies, substance abuse problems and the like). The topic of this post is to investigate whether there is a pronounced gender effect on these comorbid disorders; in other words, whether boys and girls are more prone to a particular disorder comorbid to ADHD based on their gender. As we will see later, age and ADHD subtype effects are also important factors with regards to comorbid disorders.

Much of this info was taken from an article titled Gender Differences in ADHD Subtype Comorbidity by Levy and coworkers. Here is a summary of some of the main points in the study:

• Approximately half to over three quarters of ADHD children carry some type of comorbid behavior disorder. These include oppositional defiant and conduct disorders, learning disabilities and communication disorders (including speech and reading difficulties). Additionally, many exhibit anxiety disorders such as generalized anxiety disorders or separation anxiety disorders.

• Additionally, ADHD has traditionally been separated into three different forms or subtypes: inattentive, hyperactive/impulsive, or combined (a combination of the other two subtypes). All three subtypes are heavily skewed towards the boys, which outnumber girls from anywhere around 2:1 to 5:1 (some studies skew this gender difference even higher, up around 10:1). Based on the study by Levy and coworkers, here is an approximate distribution (numbers indicate overall percentages among the study population, which includes non-ADHD individuals) among the prevalence of the three subtypes for both genders:
  

As we can see, all three subtypes are skewed heavily in favor of the boys.

• Of the three subtypes listed above, it appears that the subtype (again, perhaps not surprisingly) most associated with comorbid disorders (listed in the first point) is the combined subtype.
  

• There appears to be a discrepancy between the genders as far as internal/external symptoms of ADHD and related disorders. Some studies have suggested a general trend in which many of the symptoms or problems of girls with ADHD and related disorders are more internalized (i.e., they do not outwardly manifest themselves as readily as boys), which may contribute to the skewed gender differences mentioned above. On the contrary, the same study suggests that external or outward symptoms are more apparent in boys, which may compound this effect.

• Reading disabilities are, perhaps not surprisingly, more common in children with ADHD. It appears that reading disabilities correlate more to "internal" symptoms in girls and "external" symptoms in boys with ADHD, however, reading disorders appear to have very little overlap with conduct or oppositional behaviors such as aggression or delinquent behavior. Furthermore, reading difficulties appear to be more related to the inattentive side of the disorder of ADHD than the hyperactive/impulsive side of the disorder. In other words, the inattentive and combined ADHD subtypes are significantly more likely to have problems with reading than the exclusive hyperactive/impulsive subtype for both genders. It appears that reading difficulties and inattentive behavior may have an even stronger correlation in girls.

• Furthermore, with regards to reading and speech disabilities, there is a strong gender difference for non-ADHD individuals. However, once the disorder of ADHD is introduced, the gender difference becomes less of a factor (this holds for all three ADHD subtypes). This may at least suggest, that ADHD symptoms may override or overpower what appears to be more subtle gender differences with regards to speech and reading disorders.

• There is a significant association between generalized anxiety disorders and ADHD for both genders. Gender differences for the combined ADHD subtype were especially pronounced, with rates among females with the combined ADHD subtype being significantly higher than the combined subtype males. In addition, the combined subtype was more associated with generalized anxiety for both genders (when compared to the inattentive subtype), which suggests that hyperactivity/impulsivity may play some sort of role in generalized anxiety for both genders.
  

• With regards to separation anxiety disorders (such as from parents or loved ones), it also appears that there is a higher correlation to girls with ADHD, especially with regards to the inattentive ADHD subtype. For boys, the separation anxiety disorders were highest for the combined ADHD subtype. The study suggested that separation anxiety disorders may be a sign of immaturity for both genders, and may be indicative of later "internalizing" problems in girls. Furthermore, this assertion is in agreement with several studies which associate ADHD with a delay in maturity.
  

• Based on the two findings above, in which girls with the inattentive ADHD subtype had higher rates of separation anxiety disorders and girls with the combined subtype having increased rates of generalized anxiety disorders (both of which are considered more "internal" symptoms) than their male peers, it may be suggest that screening for ADHD in girls who exhibit anxiety disorders may be beneficial, in that it may reveal underlying comorbid ADHD and offset some of the skew among gender differences and ADHD.

• Finally, age has been shown to be an important factor with regards to symptoms and severity of ADHD comorbid disorders. In this study, comparisons were done between the younger (ages and and under) and older (ages 11 and older) children in the study population. For males, the prevalence of most of the comorbid disorders (speech and reading difficulties, oppositional defiance, generalized and separation anxieties) decreased with age, with the notable exception being conduct disorders, which increased with age. For females, age was less of a factor for all of the comorbid disorders listed above with the exception of Separation Anxiety Disorders, which decreased with age (supporting the earlier assertion that this disorder is tied to maturity levels and would naturally decrease as a child gets older). In addition, inattentive symptoms associated with ADHD actually increased with age for the female population of the study. This was the exception to the overall trend of decreasing ADHD symptoms with age, which was seen in the other two subtypes for females and all three subtypes for males.
  

I would like to conclude with a final note of personal opinion. I firmly believe that when screening, diagnosing and attempting to treat ADHD and comorbid disorders, we employ far too little emphasis on the gender differences surrounding these disorders. This can lead to several potential problems such as stereotyping or pigeon-holing certain behaviors (i.e. attributing hyperactivity/impulsivity as being a "male" characteristic and either intentionally or unintentionally overlooking these symptoms or behaviors in girls).

In addition, it appears that girls may have a higher prevalence of the more "internal" comorbid disorders such as anxiety, which are often more difficult to detect than the more outward comorbid disorders of oppositional defiance and conduct disorders. This may play a major part in the gender discrepancy of ADHD diagnosis, which may leave a number of girls with ADHD undiagnosed and untreated.

Additionally, the more "internalized" nature of female cases may also lead to a lack of diagnosis and treatment for comorbid disorders associated with ADHD as well. The Levy study pointed this out, citing the discrepancy between referrals for ADHD-related reading disabilities. Reading disorders for boys were more likely to be associated with some of these outward characteristics, while girls with reading disorders exhibited more of the aforementioned "inward" traits. As a result, the rates of referral for boys with reading disabilities (based on their overall representation in the population) was almost twice that of girls.

Furthermore, this study by Levy, as well as several others, indicate that there are several (sometimes unusual or counter intuitive) associations between gender, and ADHD subtype and the expression of symptoms of specific comorbid disorders. For example, attributing an increase in Separation Anxiety disorders to younger females with the Inattentive ADHD subtype or Conduct Disorders to the Combined ADHD subtype in males may give us some possible insight as to which subpopulations of ADHD children are most "at risk" for developing some of the aforementioned comorbid disorders.

Since several of these comorbid disorders carry their own lines of medication and other treatments, the subclassification of ADHD children based on age, gender and subtype may be especially beneficial with regards to developing successful individualized treatment plans. I firmly believe that by separating out and subcategorizing ADHD and its comorbid disorders based on factors such as age, gender and subtype whenever possible could lead to a new a wealth of information for diagnosing and treating ADHD and its associated comorbid disorders.

Do ADHD Stimulant Drugs Stunt Growth?

Here are seven questions or factors we need to address to assess the validity of studies on ADHD stimulant medications and their effects on growth:

1. Is there a history of prior stimulant medication use? Surprisingly, a number of studies on the inhibitory effects of ADHD stimulant medications either neglect or downplay the fact that children in their studies had a previous history of stimulant medication usage for their conditions. This can seriously confound effects, for if a child was taking a stimulant medication previously, he or she may still be on track for a lower baseline growth rate. Furthermore, if a child was taken off stimulant medications recently, there remains the possibility that his or her system is beginning to play "catch-up" by displaying a greater-than-normal increase in growth following a medication "holiday". In either case, baseline readings are skewed, and these effects muddy the accuracy of current stimulant medication studies on growth effects. Poulton and Nanan make this observation in their article on prior treatments with stimulant medication and growth in children with ADHD. They go on to say that growth is an accurate indicator of prior treatment with stimulant medication.
   
   
2. Beware of the pretreatment bias with regards to effectiveness of stimulant medications: Poulton and Nanan also warned about the natural bias of individuals with a previous treatment history of stimulants in that they have already proven to have a greater tolerance to potential side effects (otherwise they would have likely discontinued earlier stimulant treatments) and an overall higher levels of compliance and positive response to stimulant medications. This too, can give a potential "false positive" with regards to evaluating the effectiveness of current stimulant medication treatments for ADHD.
   
   
3. Do untreated children and adolescents with ADHD have different growth patterns than non-affected children? This is also a much-neglected consideration. Spencer and coworkers performed a study in which they saw a slower growth rate in the earlier years for children with ADHD, which was followed by a significantly later "catch" up period. In other words, compared to non-ADHD children, individuals with ADHD may be more predisposed to being "late bloomers", even when they are unmedicated. This potential difference in growth patterns between ADHD'ers and non-ADHD'ers, while still highly debatable, should at least raise the question as to whether delays in growth patterns for medicated individuals with ADHD can actually be attributed to the medications or to the nature of the disorder itself (or a combination of both).
   
   
4. Do "drug holidays" work? This is actually comprised of several questions and considerations. It is not uncommon for parents or prescribing physicians to allow for "drug holidays" for unmedicated ADHD children. These holidays can vary from a few days to longer periods such as an entire summer vacation. If the period of these drug holidays is long enough, such as in a summer-long study by Gittleman-Klein and coworkers on methylphenidate and growth, significant changes may be seen. This study saw a relative increase in weight but not in height following a summer off of medication of the stimulant methylphenidate (Ritalin). Of potential interest was the observation that following a second holiday from medication the following summer, a relative increase in height but not in weight was observed. It is entirely possible that the duration and frequency of drug holidays may effect the two parameters (height and weight) in slightly different fashions. Another article by Poulton suggests the possibility that height gains may take longer to remedy because gains in weight may drive subsequent growth in height.
   
   
5. Does the type of stimulant medication make a difference? In a preliminary sense, it appears that the answer would be "yes". For example, it appears that the stimulant drug dexamphetamine (d-amphetamine, also called by common name Dexedrine) has a greater inhibitory effect on growth during the first year of treatment than does methylphenidate (Ritalin, Concerta, Daytrana).
   
   
6. What is the typical extent of growth impairments due to stimulant medications? We need to be careful on this one, especially with regards to some of the earlier factors and considerations mentioned above. Nevertheless, a review of the literature seems to indicate a relative deficit in growth of around 1 cm per year for up to about 3 years which can be attributed to stimulant medication treatment. Furthermore, it appears that weight may be even more affected than height due to stimulant medication treatment, although it also appears that weight differences are easier to remediate than height differences and therefore pose less of a concern.
   
   
7. Are the growth changes due to stimulant medication temporary or permanent? Although hotly debatable, it appears that growth impairments due to prescribed stimulant medication usage is more of a short-term effect. A follow-up study of medicated ADHD children into adulthood indicated that even at moderately-high doses of the stimulant medication methylphenidate (45 mg/day average), medicated children with ADHD eventually reached normal final heights when compared to controls. It is worth mentioning, however, that these children eventually discontinued their medications. It is unclear as to what the effects may have been had they continued on with the methylphenidate usage into adulthood (especially since there has been a sharp trend towards continuing stimulant medication treatment into adulthood for adult ADHD).

Treating ADHD with Magnesium and Vitamin B6

In the last post, we examined how magnesium levels are tied to ADHD and how supplementation with magnesium can potentially help for the disorder. We will be adding one more step to this process by including the role of vitamin B6 into the mix of magnesium treatment for ADHD. Vitamin B6 has been shown to improve the absorption of magnesium as well as other minerals into cells, allowing higher levels of this key mineral to be attained. Essentially, this allows smaller doses of magnesium to be taken by making the intake process more efficient. Additionally, B vitamins have their own set of properties and numerous studies have linked the B vitamin family to improved mental function.

A study was done on the effectiveness of the Magnesium/Vitamin B6 combination treatment for ADHD. While the subjects of this study were young children, many of these results can carry over to adult cases of ADHD. A quick synopsis of the original publication can be found here. I will summarize some of the key points here:

• Individuals with ADHD have lower than normal levels of magnesium inside their blood cells than do individuals without the disorder. However, magnesium levels in the serum (liquid part of the blood which does not include the blood cells) were not tied to ADHD. Since Vitamin B6 helps get the magnesium into the blood cells, it is a key ingredient in treating ADHD with Magnesium.

• Low magnesium levels can also lead to irritability (which is also a potential side effect of Vitamin B6 supplementation by itself. This is another reason why taking Magnesium and B6 together can be useful). Hyperactivity, inattention, aggressive behavior and sleep problems are also associated with low magnesium levels. It also has been tied to reduced blood flow to the brain, which is a common phenomena frequently seen in brain scans of ADHD individuals.

• Treatment with magnesium and vitamin B6 reduced negative symptoms of inattention, aggressiveness and hyperactivity in a study of young children (average age around 6-7 years old). The amounts used were 6 mg/kg/day for magnesium and 0.6mg/kg/day for vitamin B6. This is roughly 100-200 mg of magnesium, which is in line with the recommended amounts (see here for these numbers) and around 10-20 mg for Vitamin B6.

• Although most ADHD symptoms were improved with Magnesium/Vitamin B6 treatment, the most improvement was seen in hyperactivity. Thus this Magnesium/Vitamin B6 treatment combination would likely have the most success in the Hyperactive Impulsive or Combined ADHD subtypes.

• Symptom improvements were seen the most in individuals who had higher (closer to normal) magnesium levels to begin with. This suggests that there may be some type of minimum threshold in cells or tissues that must be attained to achieve the desired results. This supports the idea that Magnesium/Vitamin B6 should be more of a long-term treatment strategy for ADHD, as opposed to a "quick fix".

• It also suggests that it may take awhile (2 months or more, based on some of the study's parameters) for the full effectiveness to kick in. This was further supported by the fact that when treatment was discontinued, the undesired ADHD symptoms returned within a few weeks. The good news behind this is that missing a day will not have the pronounced immediate effects of missing a day of a stimulant medication for ADHD.

• Speaking of stimulant medications, the article referenced other studies which noted that stimulant medications such as dextroamphetamine and methylphenidate boost magnesium levels in the blood. This is important to note, especially for individuals who already take ADHD stimulant medications. It is possible that combining these meds with magnesium/vitamin B6 supplementation can lead to magnesium levels above the upper limit. Please consult your physician before taking Magnesium/Vitamin B6, especially if you are already taking stimulant medications for ADHD. For more information on magnesium overdose and its symptoms, please click here.

This study presents compelling evidence that deficits in just one mineral can be a major factor in the onset of ADHD. It also suggests that a relatively simple treatment via slight dietary changes or supplementation can produce significant results in treating ADHD. Although the study had some flaws (relatively short duration, few test subjects and minimal placebo controls), the results are difficult to overlook.

In our next post, we will investigate the role of magnesium in some of the other disorders that frequently occur alongside ADHD, also known as ADHD comorbid disorders.