Does Tyrosine for ADHD Actually Work as a Supplementation Strategy? (part 3)

Can we treat ADHD symptoms via Tyrosine supplementation?

This is the 3rd post in our series of discussions regarding ADHD and supplementation with the amino acid tyrosine. Some physicians (and ADHD patients) swear by it, but the results in the literature and clinical studies are often muddled. Why is this the case?

Over the past few postings, I have been going over the metabolic pathway of how the body converts the amino acid tyrosine to our desired brain chemicals of dopamine and norepinephrine. Imbalances of both dopamine and norepinephrine are typically seen in ADHD, and this imbalance is the target of most ADHD medications (especially the stimulants) during their modes of action.

Here is the metabolic pathway on Tyrosine to Dopamine and Norephinephrine again (you can click on the image to get a larger view, or see the original image source here):

In our first post on ADHD and tyrosine supplementation, we went through the overview of this pathway. In our last posting, we went through the first step of the process: the conversion of tyrosine (also referred to as L-tyrosine) to DOPA (also referred to as L-DOPA, Levodopa and a number of trade names such as Dopar, Laradopar or Sinemet), and the enzymes and nutrient co-factors involved in this conversion process. L-DOPA is a common treatment method for patients with Parkinson's Disease.

I was going to start with the next step of the process today: the conversion of L-DOPA to dopamine, and the major enzymes involved. However, one of our readers from the previous posting on the conversion of Tyrosine to L-DOPA, posed an excellent question on a topic I failed to address (which may be on the minds of several readers). As a result, I will dedicate the remainder of this post to this question and save the next step of the tyrosine to dopamine pathway for the next blog entry.

LynneC asked about the advantages of supplementing with tyrosine vs. supplementing directly with L-DOPA. As we saw in the previous posting on tyrosine supplementation for ADHD, the tyrosine to dopamine conversion requires one major enzyme (tyrosine hydroxylase) and several secondary enzymes (to produce some of the compounds needed to help the tyrosine hydroxylase enzyme to function properly), as well as nutrient co-factors such as iron, zinc, magnesium, and even antioxidants or reducing agents such as vitamin C.

Further complicating the issue, we saw that individual variation across the gene pool leads to different forms of this tyrosine hydroxylase enzyme, some of which are notably more effective or "potent" than others. In other words, some people are more disposed to having an efficient metabolic conversion of tyrosine to L-DOPA than others.

If this is the case, why should we mess with tyrosine at all? Shouldn't we just bypass this first step of the process entirely and start with L-DOPA? Here are a few things to consider:

1. Supplement Availability: L-Tyrosine is available over-the-counter. However (until relatively recently), L-DOPA required a prescription. This is not the case anymore, however, as L-DOPA supplements are available in countries like the United States (I believe that a prescription is still required in Canada, however, but I could be wrong).
   
   Blogger's note: Even though both of these agents are available without a prescription, this blogger believes is is EXTREMELY important for you to talk to your physician before giving either of these supplements a try.
   
   Both tyrosine and L-DOPA can undergo biochemical transformations via a number of different pathways (i.e. not just in the conversion to catecholamines in the brain such as dopamine and norepinephrine). Both can interact with other medications (especially certain classes of anti-depressants known as MAOI's or monoamine oxidase inhibitors), as well as with each other, and overdosing is possible. Additionally, individuals with certain forms of cancer (especially skin cancers) or eye disorders such as glaucoma are typically instructed to avoid both treatments entirely. PLEASE check with a physician before starting either of these as a therapy for ADHD or ANY other reason.
   
   ADVANTAGE with regards to ADHD treatment: Tyrosine
   
   


2. Cost: I did a quick search on the costs of both supplements (keep in mind that brand names, strengths and quantities can cause extreme variation), and from what I've seen, L-DOPA often costs somewhere from about $65 to $150 US dollars for 100 tablets. Please note that L-DOPA typically comes in a combination form of Levodopa and another compound called Carbidopa (Carbidopa greatly aids in the absorption of Levodopa and helps minimize unwanted side-reactions of the Levodopa drug, so almost all standard formulas now exist in this Levodopa/Carbidopa tandem). For tyrosine, the cost is much lower, as I've seen ads online for a bottle of 100 capsules (500 mg strength, note that many individuals who supplement with tyrosine take doses around this level 3 times a day) for only $2 to $3 dollars a bottle. Clearly, the cost of taking L-tyrosine is much lower.
   
   ADVANTAGE for treating ADHD: Tyrosine
   
   


3. Step in the conversion pathway: In the previous post, we saw how certain enzymes (tyrosine hydroxylase) and nutrient "co-factors" (co-factors essentially function as "helpers" to the enzyme, making it function more effectively. If these co-factors are missing or deficient, the enzyme is often compromised, and the metabolic conversion process is reduced. In this blogger's opinion, co-factor shortages are one of the most overlooked reasons why natural, dietary or supplementation strategies for ADHD treatment often fail), such as iron, zinc, magnesium, and vitamin C are needed, either directly or indirectly to aid the process.
   
   ADVANTAGE for ADHD treatment: L-DOPA*
   * Starting directly with L-DOPA bypasses these factors or complications (but poses its own set of challenges, as we'll see later in this post, more about this in a minute).



4. Transportability across the blood-brain barrier: We talked at length about the blood-brain barrier in the past two posts, but to recap: The blood-brain barrier is a biochemical barrier designed to keep potentially hazardous or toxic compounds (that accidentally get into the blood) from getting into the brain (where these substances are often much more devastating). It also acts like a sort of "filtering" system, controlling or regulating the transport of "good" compounds in the brain, reducing the risk of imbalances from these chemicals.
   
   Unfortunately (especially for drug manufacturers), this barrier also blocks out many potential therapeutic agents, so drugs targeting specific brain regions must be chemically designed to pass through this blood-brain barrier to be effective. It is worth noting that both tyrosine and L-DOPA can cross through this barrier, so both are acceptable methods of delivery to increase or balance out dopamine and norepinephrine levels in the brain.
   
   On a side note (and mentioned in our previous discussions on the matter), dopamine and norepinephrine typically are NOT able to pass through the blood brain barrier, meaning that these compounds need to be manufactured inside of the brain. This is why we cannot supplement with either of these agents directly.
   
   ADVANTAGE for ADHD: A draw. Both Tyrosine and Levodopa can cross the blood-brain barrier**
   
   **We will see in the next few points, how this "tie" between the two may not be entirely true.
   
   
5. "Target" specificity: Here is where the real difference lies. In the past few posts, we have been vague with regards to the specific brain regions in which chemical imbalances of dopamine and norepinephrine are found in the ADHD brain. It is important to note, that these deficiencies/imbalances are not uniform throughout the body (or even the brain) in the ADHD individual.
   
   Certain brain regions are frequently identified as target sites of chemical imbalances (which typically exist as deficits, not excesses) of the neurotransmitters dopamine and norepinephrine. By no means is this list extensive, but two brain regions which are commonly associated with shortages of these signaling chemicals are the striatum and the prefrontal cortex (as an interesting aside, these 2 brain regions have been found to be proportionally smaller in ADHD individuals according to some studies and bloodflow patterns to the prefrontal cortex have been found to be different in the ADHD brain vs. the brains of patients with other disorders such as Obsessive Compulsive disorders).
   Shown above is a picture of an individual's brain. We are looking from the top down on a patient facing forward (the front is towards the top of the page). Several key "ADHD brain regions" are highlighted. The rough location of the prefrontal cortex, shown in brown, is a major region of importance where ADHD treatment is of concern. The green, red and blue regions represent approximate locations of sub-components of a brain region collectively called the corpus striatum. Both the prefrontal cortex and the corpus striatum regions of the brain are thought to be common sites of imbalance of the brain chemicals dopamine and and norepinephrine.
   
   Getting back to our main point here, however, is the fact that supplementation with tyrosine typically reaches its targets with much more specificity than does L-DOPA. In other words, if target region specificity is what we're after, then supplementation with tyrosine shows a slightly better track record, at least according to the literature reviewed by this blogger. Keep in mind, however, that this assertion hinges on only a few older studies, and the findings are far from definite.
   
   SLIGHT ADVANTAGE for treating ADHD: Tyrosine
   
   


6. Fewer negative side effects: This ties in with the previous point, to a certain extent. L-DOPA, is, and continues to be, a treatment for Parkinson's, and not designed specifically for ADHD. However, in addition to being a chemical precursor to dopamine and norepinephrine, L-DOPA can also be converted to the agent melanin (which is responsible for skin pigmentation, among other things). The problem with this, however, is the fact that this conversion process can sometimes go overboard, and result in rapid generation and buildup of this (and related) compounds, increasing the risk of melanoma and related skin cancers.
   
   The actual magnitude of this L-DOPA/skin cancer association, however, is often questionable. While higher rates of skin cancer are seen in Parkinson's patients treated with L-DOPA, this finding is often negated by the fact that the cancer was present before the start of the L-DOPA treatment. Furthermore, general medical recommendations are often to refrain from L-DOPA or tyrosine supplementation in Parkinson's patients who are in various stages of these cancers. In other words, tyrosine may not be much better in this regard.
   
   Both tyrosine and L-DOPA have limitations, and potentially negative interactions. This includes kidney and liver dysfunctions, cases of depression where specific anti-depressants called MAOI's (short for monoamine oxidase inhibitors) are taken (both tyrosine and L-DOPA can negatively interact with MAOI function).
   
   Possible buildup of the compound homocysteine (a pro-inflammatory agent which has been implicated in everything from heart disease and cardiovascular disorders to depressive symptoms to cancer) can also be linked to tyrosine and L-DOPA intake, because both can serve as chemical precursors to this potentially dangerous compound. We will see how homocysteine ties in to all of this within the next few posts (as we work our way down the tyrosine to dopamine and norepinephrine pathway), and how its buildup can be reduced by taking in adequate levels of certain B vitamins and other nutrients. More on this later.
   
   In the meantime, please realize that there are hundreds of different ways tyrosine and L-DOPA levels can affect the body, so trying to classify one as "safer" is not necessarily so cut-and-dry. However, in this blogger's opinion, tyrosine, since it is a naturally occurring dietary food-source, has the advantage of over L-DOPA in that it is one step closer to "nature". Tyrosine is typically less potent than L-DOPA, so a higher dosage of tyrosine is typically required to get the same effects (in other words, we shouldn't be comparing, say a 500 mg dose of tyrosine with a 500 mg dose of L-DOPA, the effects of L-DOPA at this dose would be much more pronounced).
   
   Furthermore, as we have seen in the last post on tyrosine and ADHD, the enzyme-mediated conversion of tyrosine to L-DOPA is actually limited or shut off by the generation of the catecholamine "end-products" dopamine and norepinephrine. When high levels of these compounds are generated under normal conditions, these catecholamine compounds actually bind to and inhibit the enzyme tyrosine hydroxylase (which converts tyrosine to L-DOPA), thereby limiting further tyrosine to dopamine conversion.
   
   In other words, it appears that tyrosine has slightly better designed "control-switches" to keep its end products in check than does L-DOPA. We may be splitting hairs here (since both tyrosine and L-DOPA are natural metabolites of the body, both can be quite safe if the correct levels are taken and none of the pre-existing conditions exist or competing medications are being used), but according to all of the information this blogger currently has, tyrosine supplementation for ADHD treatment seems to be the safer bet here.
   
   ADVANTAGE: Tyrosine (just make sure to consult with a physician before trying this supplement, even though it is readily available over-the-counter).
   
   


7. Overall effectiveness and potency: While both L-Dopa and tyrosine have often been prescribed for ADHD as more natural or "gentler" alternatives to pharmaceuticals, and "success" stories abound on individual cases, the overall literature tends to be less praise-worthy. From the studies this blogger has seen most of them show a temporary boost in effectiveness, but the positive results are often short-lived. Tolerance generally seems to be an issue, as in the case of a small study on direct tyrosine treatment for ADHD. In this study, the effectiveness of tyrosine wore off after 2 weeks. A similar study was done with L-DOPA (levodopa) on ADHD boys, and the results were similar. Initially, there was a positive response, but these results were also short lived.
   
   Curiously, most of these studies involving direct tyrosine or L-Dopa dependent treatment of ADHD are relatively old ones, most of which took place in the early 1980's (many were done by the same research group). There currently does not seem to be a whole lot of new material on this topic (at least to the best of this blogger's current knowledge).
   
   Furthermore, neither of these studies co-supplemented with the aforementioned nutrient "cofactors" to help with the metabolism and conversion to dopamine or norepinephrine. There is no telling what the status of magnesium, zinc, iron, or antioxidant levels (all of which can have an effect on tyrosine metabolism, as we've seen in the previous post on tyrosine supplementation for ADHD).
   
   Additionally, another nutrient called pyridoxal phosphate also plays a role in the next step of the chemical conversion process of L-DOPA to dopamine (pyridoxal phosphate is a derivative of vitamin B6 which is used to help the enzyme dopa decarboxylase to function properly. We will be investigating this nutrient/enzyme pairing in the next post, when we look at the next step of the dopamine conversion process). Levels of this key ingredient (at least in this blogger's opinion) need to be factored in when we evaluate the true merits of tyrosine or L-DOPA treatment for ADHD and related disorders.
   
   ADVANTAGE as an ADHD treatment method: Too close to call. In addition to their individual usage, tyrosine/L-DOPA/carbidopa (we will discuss why this carbidopa compound is often used alongside L-DOPA in the next section) can be used together to boost each others' effectiveness. Anecdotal reports laud the effectiveness of tyrosine/L-DOPA/carbidopa in combination as an effective ADHD treatment, but again, detailed clinical trials specifically designating ADHD are relatively scarce. In other words, although the literature findings on the subject seem to be scarce and somewhat discouraging, additional factors (such as the extra nutrients and enzyme co-factors which we are currently laying out) could possibly lead to more effective studies with more promising results on the topic of ADHD treatment via tyrosine and/or L-DOPA supplementation.
   

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.

Long Wave Infrared Imaging: A new detection method for ADHD?

Detecting ADHD using the long-wave infrared spectrum:

I always enjoy covering new breakthroughs in the diagnosis and treatment methods in the medical field. A new study just came out which may have a number of potential applications to aid in the diagnostic process of ADHD, which I believe is worth sharing. Called Long-Wave Infrared Imaging, this method utilizes the infrared spectrum to detect biological activity (namely bloodflow patterns) via the differences in radiation emitted by these activities. The study, titled Sensitivity and Specificity of Longwave Infrared Imaging for Attention-Deficit/Hyperactivity Disorder, found that this method may be a surprisingly powerful way of separating ADHD from other related disorders, aiding in the always-difficult process of differential diagnosis.

The basics of Long-Wave Infrared Imaging:

The term "long-wave" is a relative term, of course, referring to wavelengths of approximately 10 nanometers (or only one one-hundred millionth of a meter). Differential bloodflow patterns can result in temperature differences by a full degree (Celsius), making this technology useful in tracking bloodflow disorders. A recent publication in the Journal of Medical Physics by Bagathaviappan and coworkers suggests describes how this long-wave infrared imaging can detect areas in the circulatory system where bloodflow activity is sluggish or reduced. Typically, these areas appear "cooler" on the spectrum, due to the lack of a new, replenishing blood supply.

Applications for ADHD:

A number of studies have confirmed the hypothesis that individuals with ADHD have reduced bloodflow levels marking a recuction of activity to multiple key brain regions. Additionally, while several disorders have a number of overlapping symptoms (which can make the diagnostic process more complicated, especially if multiple comorbid disorders are present), differential blood flow patterns to the brain may be able to help make these distinctions. For example, blood flow patters to the brains of ADHD and OCD (Obsessive Compulsive Disorders) can show pronounced differences, which can aid the diagnostic process between these two disorders (while ADHD and OCD are often considered to be on "opposite" ends of the spectrum with regards to neuro-chemical signaling levels, these two disorders can often exhibit similar symptoms, such as a severe impairment in the response to verbal directions. This is especially true in younger children).

This technology may even be extended to measuring or predicting which medications may work for an individual diagnosed with ADHD, based on blood flow in specific localized brain regions. Cerebral blood flow patterns may help predict the response to common ADHD drugs such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana). For example, a study by Cho and coworkers found increased blood flow in at least three different brain regions for individuals who showed poor response to methylphenidate treatment compared to their peers who did show improvements under the drug.

While the medication response study was done utilizing a different type of brain imaging device known as SPECT, which utilizes gamma rays and radioactive tracers to detect brain activity in 3-dimensional patterns. While SPECT has proven to be an extremely powerful and effectively safe method of detection (the radioactive isotope used in this method is relatively non-invasive and breaks down quickly, and the gamma rays are carefully controlled), concerned parents may still have an inherent fear of the terms "radioactivity" and "gamma rays" tend to shy away from this powerful detection method on their kids.

While this blogger personally has a very high opinion about the use of SPECT as a diagnostic tool for ADHD and related disorders, it is at least worth mentioning the possibility that long-wave infrared imaging methods may be a viable alternative method in at least some of these imaging cases (SPECT technology has been around for over 30 years, but the recent advances in computational power resurrected this technology in the very recent past, similar possibilities may abound by this infrared technology, which has been around even longer).

Keep in mind that the studies utilizing this range of infrared imaging technologies for detecting and differentiation disorders such as ADHD are still relatively scarce. Nevertheless, long-wave infrared imaging appears (at least in this blogger's personal opinion) to be a powerful diagnostic tool for ADHD and related disorders in the near future.

ADHD, Methylphenidate and Blood Sugar Levels

ADHD medications may interfere with blood sugar levels and glucose metabolism:

When we think of common side effects of ADHD medications (especially of the stimulant variety), we often consider things such as cardiovascular risks (increased heart rates and blood pressure), appetite suppression (which may subsequently result in temporary growth impairment), interference with sleep, dampening of creativity and emotions (i.e. taking on a zombie-like state), irritability, moodiness, and the like.

However, it appears that another equally important, but often less-considered side effect of many ADHD medications is a change in blood sugar and glucose metabolism. The first part of this post will investigate some of the research out there on the effects of common ADHD medications on brain glucose metabolism. The second half will zero in on some of the general metabolic differences between the ADHD brain and the non-ADHD brain, and will also investigate possible effects of age, gender and co-existing disorders:

1. A drop in blood sugar following methylphenidate treatment: A case study involving a diabetic woman who underwent a surgical operation for a brain tumor. While we cannot make any logical conclusions about the population based on one individual of unique needs, the fact that a pronounced drop in blood glucose (over 25%) following methylphenidate treatment is at least worth noting. It is unclear as to whether the effects were due merely to the methylphenidate (common forms of this drug include Ritalin, Metadate and Concerta), or rather to a drug-drug interaction.
   
   
2. Methylphenidate reduces required brain glucose amounts to perform cognitive tasks: A study done at the National Institute of Drug abuse found that the administration of methylphenidate reduces the amount of glucose (the brain's desired energy source) needed to perform a thinking task. It is believed that this lower energy requirement is mainly due to less "wasted" energy from a constantly wandering and side-tracked mind, such as one seen in individuals with ADHD.
   
   Interestingly, this same study also found that during non-cognitive tasks, the differences in brain energy requirements did not change with or without the drug. This may at least call into question the merits of ADHD stimulant medication usage if higher order cognitive tasks are not required. Furthermore, if the brain is already focused, the utilization of methylphenidate may even be overkill. The authors concluded that this may be a primary reason why adverse effects in concentration and focus can be seen when methylphenidate is administered to "normal" functioning brains.
   
   
3. Methylphenidate's influence on brain metabolism may be regio-specific: Another study done by the same author as in study #2 found that the effects of methylphenidate on brain glucose metabolism may depend on individual subregions of the brain. For example, this study found that for the basal ganglia region of the brain (this brain region essentially governs how fast a particular individual's brain "idles"), the relative activity of this brain region was typically reduced following methylphenidate treatment, compared to activities in other brain areas. This may be a bit counter-intuitive, since basal ganglia activity is typically lower in individuals with ADHD and higher in individuals with obsessive compulsive or anxiety-ridden behaviors.
   
   However, other brain regions such as the frontal and temporal regions of the brain (which are responsible for filtering out unimportant external stimuli and inhibiting impulsive behaviors, and, perhaps not surprisingly, often show lower levels of activity in the ADHD brain), experienced a boost in metabolic activity following methylphenidate treatment. It is believed that these responses are modulated through categories of receptors for the brain chemical dopamine (called Dopamine D2 receptors, which help control levels of this important neuro-signaling agent, which is often deficient in key regions of the ADHD brain).
   
   In this blogger's opinion, this dual action of inhibiting impulsivity (which can potentially dampen creativity) and shutting down some of the basal ganglia activity may actually be a reason why "zombie-like" behaviors are sometimes seen in children medicated or overmedicated with stimulants for ADHD.
   
   
4. The "Energy Deficient" Hypothesis of ADHD: While still in the hypothetical stage, there is a fair amount of evidence suggesting that ADHD may be due, in a large part, to a lack of energy to specific neurons in key brain regions such as the prefrontal cortex (part of the "frontal" regions of the brain discussed in the past point). This ADHD as an energy-deficiency hypothesis carries that astrocytes (star-shaped cells that provide energy and nutrition for growth and repair of neuronal cells) may be starved of some of their important nutritional needs for glucose and related nutrients. As a result, they are unable to effectively "feed" the neurons in these key brain regions associated with governing attentional and impulsive behaviors in the brain. Should this hypothesis hold true, it would stand to reason that regulating and improving glucose levels either via either medication-manipulated, or alternative dietary methods may help offset some of the energy deficient imbalance in ADHD. Some natural supplemental options to boost glucose levels in the ADHD brain may include ginseng and carnitine.
   
   
5. Reduced brain metabolism in teenagers with ADHD: The results of this study on metabolic differences in teenage ADHD brains agree with many of the findings discussed in point #3 above. This study investigated the effects of an auditory-based attentional task on rates of brain glucose metabolism in adolescents with ADHD. It found that there was minimal differences between glucose metabolic patterns in the brains as a whole when comparing the ADHD and non-ADHD individuals.
   
   However, it is also worth mentioning that in other related studies on brain metabolism in teens with ADHD, it was found that metabolic deficits were seen at significantly lower levels throughout the brain as a whole. Interestingly, according to the second study mentioned, these differences in brain metabolism were only seen in the girls with ADHD and not the boys, which suggests possible gender-specific differences in the etiology of the disorder.
   
   However, upon investigating for the more hyperactive forms of the disorder in the first study (remember that ADHD behaves as a spectrum, in which some individuals have the predominantly inattentive symptoms, while others exhibit the hyperactive and impulsive symptoms more readily, these different predominant features are typically grouped together as unique subtypes of ADHD), it was found that the hyperactive component of ADHD corresponded to a significantly reduced level of glucose metabolism in the whole brain. This brings up the question as to whether these metabolic differences exhibit any sort of subtype-dependent effects with regards to ADHD.
   
   Also, as in point number 3 above, metabolic deficits were apparent in more specific brain regions such as the left frontal lobe regions of the brain. Even more remarkably, there appeared to be somewhat of a sliding scale with regards to the relationship between reduced glucose metabolism and increased symptom severity in this particular "hot spot" (the left frontal lobe) region of the ADHD brain.
   
   The following sidenote is a personal comment by the blogger regarding some of the methods of the previous study. As mentioned above, the test for this adolescent ADHD study involved an auditory based attention task. However, as discussed in earlier posts on this blog, we have seen that auditory processing disorders sometimes accompany ADHD.
   
   Furthermore, due to a high degree of symptom overlap, a comorbid auditory processing disorder can often be missed in an ADHD child or adolescent. Because of this, we should not rule out the possibility that comorbid auditory processing issues may interfere with the results of studies such as this one.
   
   We can see that auditory processing takes place in multiple regions throughout the brain, many of which do not have significant overlap with the "ADHD brain regions". One would expect the brain of an individual with an auditory processing disorder to work harder to achieve the same results as that of a non-auditory disordered individual. Thus, a confounding processing disorder could, in theory result in an increased demand for energy utilization to the portions of the brain responsible for stimulatory processing, which could leave less available energy for the frontal lobe regions of the brain responsible for modulating hyperactive and impulsive ADHD behavior. These assertions remain hypothetical at the moment, but this blogger feels that the presence of undetected comorbid disorders can easily skew the results of these metabolic studies on the ADHD brain.
   
   
6. Age-Dependent Decline in Brain Glucose Metabolism in Adults with ADHD: Apparently, metabolic differences in ADHD brains are not limited just to children, adolescents, and young adults with the disorder. Some of the findings of this following study may seem inherently counterintuitive at first. While ADHD symptoms often decline as an individual with the disorder ages, we would expect that an accompanying level of improvement in glucose metabolism in ADHD-specific brain regions would hold true. However, according to this study on brain glucose metabolism in older ADHD adults, it appears that the opposite is actually the case.
   
   The authors hold that the decrease in glucose metabolism may actually be markers of a more efficient process of brain metabolism (i.e. these older ADHD brains may somehow conform to an efficient energy-conservation state allowing them to function more optimally, thereby decreasing the prevalence of ADHD symptoms), although this finding is somewhat suspect in this blogger's personal opinion.
   
   As an interesting side note, the decrease in brain glucose metabolism in adults is apparently gender-specific, according to the study. This parallels the findings from some of the adolescent ADHD brain metabolic studies. The notable metabolic decreases were observed in women with the disorder to a much larger degree in men. The authors of the study suggested this may be due to hormonal influences, such as changes in post-menopausal women.
   
   Given the anecdotal evidence supporting the association between ADHD and higher onsets of neurodegenerative diseases later in life, this blogger finds the results of this study to be of particular interest. There may even be some claims that genetics may be partly to blame for the overlap between ADHD and neuro-degenerative diseases. For example, a gene referred to as DAT1 (short for dopamine transporter gene 1, located on the 5th human chromosome) may be connected to both ADHD and parkinsonism (a secondary or alternate form of Parkinson's disease). DAT1 also helps regulate dopamine function, (although via a different method than the dopamine receptors mentioned in point #3), by coding for an enzyme that helps transport or shuttle dopamine into and out of neuronal cells. We have discussed these dopamine transporter genes in earlier posts.

We have covered a number of works on the metabolic differences of glucose in the ADHD brain, and how they differ from the brains of non-ADHD individuals. There is the distinct possibility that stimulant medications used to treat ADHD, such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana) can significantly alter brain glucose requirements. It appears that significant differences in brain glucose utilization patterns and efficiency may affect the entire brain, but certain ADHD "hot spot" regions of the brain may be particularly hard-hit. It is unclear whether this is due to preferential metabolic differences of the ADHD brain (compared to the "normal" brain), or whether it is due to an all-out brain energy shortage.

It is also worth noting that significant gender-specific factors may also affect this process, with ADHD girls in particular showing the greatest metabolic deficits. It also appears that these effects are also being observed across the lifespan of the ADHD individual. Finally, there is at least a hypothetical possibility that sensory processing difficulties or other comorbid disorders commonly seen alongside ADHD may also play a role in these metabolic differences of ADHD brains.

Ritalin and Cocaine: Similarities and Differences

We have previously investigated some of the similarities between the chemistry and modes of action of Ritalin and cocaine. In this past post, however, we looked more at the rates of uptake and metabolism of the two drugs and investigated a side-by-side structural comparison.

I was originally planning on continuing with posts on Daytrana, which is very similar to the more common ADHD medications Ritalin and Concerta (it is actually comprised of the same chemical agent, methylphenidate. However, I recently saw an interesting article on the topic of methylphenidate, cocaine and nicotine, and the mechanism of interaction between these different stimulants. As a result, in lieu of the Daytrana postings, I would like to discuss these findings in the next couple of posts.

Here are seven key points to be aware of regarding the similarities and differences between methylphenidate and cocaine:

1. SIMILARITY: Uptake patterns into the brain: Both methylphenidate and cocaine enter the brain at similar rates and target similar specific regions of the brain. When injected, around 7.5% of the injected compound makes it into the brain tissue for each compound at similar rates (peak uptake only takes around 2 to 8 minutes for cocaine and 4 to 10 minutes for methylphenidate in the injected form, oral administration, which will be discussed later, is significantly longer, especially for methylphenidate). The most favored target region of the brain is the striatum for both cocaine and methylphenidate (see brain diagram below). In fact, several studies have indicated that the two drugs share a number of target binding sites within the brain, to the point where the ADHD medication methylphenidate has actually been used as a treatment option for cocaine abuse.
   
   
2. Brain Regions Targeted by each drug: In addition to similar uptake patterns in the brain between the two drugs, there is a relatively large degree of overlap for particular brain regions targeted. However, there is at least one notable exception, which bears relevance to our discussion. On an interesting note, the method of delivery not only affects the speed of uptake of a drug (injected is almost always faster than snorted, which is almost always faster than ingested), but also the actual brain regions targeted by the drug. For example, another brain region, called the Nucleus Accumbens (see image below for approximate location) is targeted by cocaine and injected methylphenidate. However, when methylphenidate, such as Ritalin, Concerta or Metadate is taken orally, this nucleus accumbens region is not targeted (at least not anywhere near the level of injection).
   
   The nucleus accumbens is believed to play an important role in the addiction potential of a number of drugs, including many stimulant medications. Thus, proper use of the methylphenidate medication actually bypasses a key brain region believed to be critically involved in the "high" or addiction process of a stimulant drug. This highlights a major difference in the pharmacology between Ritalin and cocaine.
   
3. Key Difference between methylphenidate and cocaine: Rate of clearance from the striatum region of the brain: As mentioned in an earlier post, the addiction potential of a drug is typically correlated to the rate of exit or clearance from the brain. In other words, drugs that linger in the brain's receptors for extended periods of time are often much less addicting than ones which exhibit a short and rapid spike in their brain levels and then a quick drop-off in their concentration in the brain. In the striatum, the rate of clearance takes about 90 minutes for methylphenidate, and only 20 minutes for cocaine. If we go by peak concentration duration (i.e. the amount of time the highest concentration typically lasts in the brain before going back down), we see that methylphenidate's peak lasts around 15 to 20 minutes, while cocaine's is a fleeting 2 to 4 minutes. In both cases, the higher dissipation of the drug from high levels in the brain is much more pronounced in cocaine, giving this drug a much more addiction-worthy effect over methylphenidate (even when methylphenidate is abuses and either snorted or injected, it still cannot match the rates of clearance of cocaine).
   
   
4. Potency of the two drugs: The following may seem surprising at first. With regards to specific brain targets, methylphenidate is almost twice as potent as cocaine. We have discussed at length the role of the dopamine transporter protein (DAT), and its role in ADHD and related disorders. Essentially, this DAT protein is responsible for retaining a proper balance of the important brain chemical dopamine in and out of nerve cells. For individuals with ADHD, this balance is often skewed, typically with too much dopamine being taken up into the neuron cells and not enough in the gaps between the cells. Many stimulant medications remedy this problem by essentially binding to and plugging up the dopamine transporter proteins in the nervous system, which inhibits their abilities to shuttle dopamine into the cells. As a result of this medication-effected correction, dopamine balance can be somewhat restored. As a frame of reference, based on some of the current literature, it takes often takes at least a 60% saturation of these dopamine transporters with a drug to elicit the "high" (of course, there is a significant degree of variation between individuals).
   
   With regards to potency, we see that both cocaine and methylphenidate love to bind to these dopamine transporter proteins. To shut down the function of these dopamine transporter proteins to 50% of their original function (a common way of measuring the potency of a drug in pharmaceutical and laboratory testing), a 640 nanomolar concentration was needed for cocaine, while only a 390 nanomolar concentration was needed for methylphenidate to do the trick. If you're not familiar with these units of concentration, don't worry. These numbers work out to very small amounts (around the neighborhood of only 0.001 grams of drug per liter of fluid). I just put the numbers out there to show that only about half the amount of methylphenidate was needed to share the same effects with cocaine (i.e. the methylphenidate is approximately twice as potent for this particular process).
   
   
5. Difference between Ritalin and Cocaine: DAT saturation levels and perceived high: The relative saturation of these dopamine transporters are also believed to play a role in the "high" of stimulant drugs such as methylphenidate and cocaine. However, research by Volkow and coworkers found that while the level of saturation of the dopamine transporters with cocaine correlated with the "high" associated with this drug, the methylphenidate drug tells a different story. As mentioned previously, the reinforcing effects of a drug including the "high" typically correlate with the rate of clearance from the brain.
   
   We have also seen that methylphenidate clears much more slowly than cocaine. However, in the case of methylphenidate, the diminished effects of the the high occurred long before the drug had fully cleared from the dopamine transporter. In other words, there appears to be a relatively strong connection between the binding of cocaine to the dopamine transporter proteins and the perceived "high" but the effects are much less pronounced with methylphenidate. This highlights a major difference between methylphenidate and cocaine and at least suggests the possibility of a difference in mechanisms between the two stimulants.
   
   
6. Divergence in metabolic patterns between methylphenidate and cocaine: Furthering this issue a bit more, there is some evidence that the pathway of the two drugs is almost identical for the first part of the journey into the system, but their modes of action split off at some point when it comes to dopamine transporter occupancy and the corresponding reinforcement effects (see sketch below).
   
   
   
7. Difference between methylphenidate and cocaine: Drug lingering and tolerance: The persistence of methylphenidate on the dopamine transporter proteins may result in more than its reduction of abuse potential. It also appears that this "lingering" of the drug on these dopamine transporter proteins may also play a significant role in the phenomena of tolerance to methylphenidate.
   
   Acute tolerance to methylphenidate is nothing new. Newer formulations of the drug (Concerta, Metadate) were designed in part to address the problem of the reappearance of ADHD symptoms by ramping up and releasing increased levels of the drug throughout the day. This is important, because, the effects of methylphenidate appear to be best felt when its levels are climbing or building up, and not stabilizing (i.e. you do not want a constant level of methylphenidate throughout the day, but rather a constantly increasing one to maintain the same effects). Essentially, this is "micro-tolerance" to methylphenidate and is seen on a daily level. The ideal dosing strategy for methylphenidate typically entails a morning dosage which is approximately 50% of an evening dosage, i.e. a "ramping" effect of the drug throughout the day is often needed to maintain the desired results.
   
   It is suggested that this tolerance to methylphenidate may be due, at least in part to its continued presence and relatively slow clearance in specific areas, such as on the dopamine transporter proteins. Other faster-clearing drugs, such as cocaine, do not exhibit this property. However, given the fact that cocaine tolerance is also common, it is unlikely that the whole "dopamine transporter saturation" theory can fully address the issue of tolerance for stimulant drugs. Volkow and coworkers explored this role of blocking dopamine transporters with methylphenidate and the perceived high in greater detail. Nevertheless, at least in this blogger's personal opinion, the lingering effect of methylphenidate still plays some degree of significance to the process of tolerance to the drug, and the need for ramping its dosage to treat disorders such as ADHD.

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.

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.