Our unclear understanding of ADHD

Attention-deficit hyperactivity disorder, or ADHD, has engendered a great deal of debate over the past several decades. ADHD is a psychiatric disorder that involves symptoms of inattention (e.g. being easily distracted, having difficulty focusing) or symptoms of hyperactivity (e.g. being fidgety or restless), or a combination of both types of symptoms. The controversy surrounding ADHD became a bit louder in the 1990s, when the number of children being prescribed stimulant drugs like methylphenidate (Ritalin) and amphetamine (e.g. Adderall) to treat the disorder increased dramatically.

Part of the debate has focused on the long-term safety of prescribing these stimulant medications to children. There has also been a significant amount of discussion, however, about the nature of the disorder itself. For example, some have argued that ADHD is not a true pathology, but instead indicative of normal behavior that is considered less appropriate in certain cultures. According to this "social construct" hypothesis, only in those cultures where things like orderly behavior are emphasized is ADHD regarded as a disorder. Others have suggested that ADHD is overdiagnosed, and that diagnosis accuracy is inherently inconsistent because the physician often is forced to rely on second-hand reports of a child's behavior to make a diagnosis. On the other side of the debate are those who assert that ADHD is a distinct condition characterized by a specific neuropathology.

The controversy surrounding ADHD has only grown more vociferous over time because the number of children and adolescents in the United States diagnosed with ADHD has consistently been rising since the 1970s. By 2011, about 1 in every 10 children ages 4 to 17 in the United States had been diagnosed with ADHD. Of course, as the number of diagnoses increases, so does the number of children and adolescents who take stimulant medication (which is now at about 1 in every 20 to 25).

While these disagreements about medication safety and how to classify ADHD continue, however, another debate has been going on, if perhaps more quietly, among neuroscientists--most of whom subscribe to the perspective that ADHD has a neurobiological etiology. That discussion has centered on the neural bases of ADHD, and on the question of how accurate the hypotheses we've been relying on to understand the disorder really are.

ADHD and the brain

The two most widely-used pharmaceutical treatments for ADHD are methylphenidate and amphetamine. Although their mechanism of action is slightly different, both drugs cause levels of dopamine and norepinephrine to increase in the synapse, allowing increased interaction between those neurotransmitters and the receptors they act upon. Based on the purported effectiveness of amphetamine and amphetamine-like drugs, and because of the high levels of dopamine activity in areas of the brain thought to be important for attention, early hypotheses about the cause of ADHD focused on the potential role of deficits in dopamine functioning. In other words, it was recognized that drugs that increased dopamine levels improved the symptoms of ADHD, and then (with the support of experimental evidence) it was deduced that low levels of dopamine function might be part of what was causing the problem to begin with.

For example, one popular hypotheses, referred to as the low arousal hypothesis, suggests that low baseline levels of dopamine lead to deficiencies in attention and other executive functions. This may cause an individual to have trouble paying attention and be less interested in stimuli that aren't overly exciting (like schoolwork). The person may compensate for this lack of interest (i.e. low arousal) by frequently looking for stimulation from other things in the environment, which may lead to hyperactivity.

However, research has not consistently supported the idea of a deficiency in dopamine signaling in ADHD patients. Early studies did indicate increased levels of the dopamine transporter in the ADHD brain, which would suggest dopamine was being removed from the brain more quickly in ADHD patients. This would theoretically cause dopamine hypoactivity, supporting dopamine deficiency as part of the etiology for ADHD. Later studies, however, didn't find increased dopamine transporter levels in ADHD patients, and some even found levels of the dopamine transporter to be decreased.

Another approach has been to look at levels of dopamine receptors in areas of the brain thought to play a role in attention, like the striatum and prefrontal cortex. Lower levels of receptors in these areas might suggest a reduced level of dopamine signaling there. Again the results of these studies have been mixed, with outcomes varying depending on the imaging method used, the brain region examined, the age of the participants, and even whether the participants had previously taken ADHD medication or not.

Recent findings

A study published in 2013 may help to shed some light on what is really going on in the ADHD brain. In the study, del Campo and colleagues used neuroimaging to assess structural differences in the brains of ADHD patients and healthy controls, and then looked at functional differences in the brains of these two groups before and after taking methylphenidate.

They found that the ADHD patients had less grey matter in several brain areas--including those thought to be involved in attention like the prefrontal cortex. Such structural abnormalities in ADHD patients have been seen before, and may be associated with deficits in attentional processes subserved by those structures.

When it came to dopamine function, however, the ADHD patients and healthy controls were about the same. The groups had similar levels of dopamine receptor availability and both displayed equivalent increases in dopamine levels after taking methylphenidate. The individuals with ADHD did display overall deficits in attention compared to the control group, but the lack of differences in dopamine activity would suggest dopamine functioning was not the primary explanation for these differences. Interestingly, methylphenidate improved performance in a sustained-attention task in a baseline-dependent manner in both groups, regardless of ADHD diagnosis.

When the researchers looked only at the individuals in both groups who performed most poorly on tasks of attention, however, they saw something interesting. Poor performers in both groups had lower levels of dopamine activity in the caudate, an area of the brain that has previously been implicated in attention. Methylphenidate raised caudate dopamine levels in the poor performers from both groups back to normal levels. Thus, methylphenidate acted to change dopamine levels in areas associated with attention, and this improved performance--but it wasn't an effect that was limited to patients with ADHD. Instead, methylphenidate improved performance in everyone, and it seemed to rectify dopamine imbalances that were seen in poor attention performers, whether they had ADHD or not.

What this means for dopamine and ADHD

The study conducted by del Campo and colleagues supports the hypothesis that dopaminergic mechanisms are involved in processes of attention. However, because potential dysregulation of dopaminergic attentional processes was seen in poor performers in both groups, it suggests that dopamine dysregulation may not be the primary cause of ADHD.

It should be noted that del Campo et al. did not examine differences in dopamine activity in all areas of the brain, including some areas important for attention like the frontal cortices. However, the lack of abnormalities in dopamine function in ADHD patients in other areas of the brain involved in attention makes a dopamine-centered hypothesis of ADHD seem a bit tenuous. And that, of course, leaves us with more questions than answers.

If a dopamine deficiency isn't the underlying cause of ADHD, then what is? Perhaps other neurotransmitter systems, like the noradrenergic system, are also heavily involved. But another possibility is that ADHD is a heterogeneous disorder, characterized by a number of different underlying mechanisms. Which mechanisms are most important may depend on the individual case.

With this in mind, maybe a spectrum approach is a better way to look at ADHD. According to this perspective, attention deficits can be found on a continuum that ranges from minor to more severe symptoms, and the presentation and causes may vary from case to case. As we discover that many mental disorders are much more complex than we initially assumed, it seems the appreciation of heterogeneity offered by a spectrum approach is often more in line with what we see in real practice.

Either way, ADHD research seems like it might be providing us with another lesson in avoiding the allure of simplicity. Although dopamine may still very well play an important role in ADHD, the condition probably should not be explained as a disorder of dopamine deficiency, and this seems to be the direction we were headed in. If we've learned anything from our experiences with supposed serotonin deficiency and depression, it's that these one neurotransmitter explanations of mental disorders seldom turn out to be true.

del Campo, N., Fryer, T., Hong, Y., Smith, R., Brichard, L., Acosta-Cabronero, J., Chamberlain, S., Tait, R., Izquierdo, D., Regenthal, R., Dowson, J., Suckling, J., Baron, J., Aigbirhio, F., Robbins, T., Sahakian, B., & Muller, U. (2013). A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment Brain, 136 (11), 3252-3270 DOI: 10.1093/brain/awt263





Dear CNRS: That mouse study did not "confirm" the neurobiological origin of ADHD in humans

Late last week the French National Centre for Scientific Research (CNRS - the acronym is based on the French translation) put out a press release describing a study conducted through a collaboration between several of its researchers and scientists from The University of Strasbourg. CNRS is a large (30,000+ employees), government-run research institution in France. It is the largest research organization in Europe, and is responsible for about 1/2 of the French scientific papers published annually.

The study in question, conducted by Mathis et al., investigated the role of a brain region called the superior colliculus in disorders of attention. The superior colliculus, also known as the tectum, is part of the brainstem. It is strongly connected to the visual system and is thought to play an important role in redirecting attention to important stimuli in the environment. For example, imagine you are sitting in your favorite coffee shop quietly reading a book, when someone in a gorilla suit barges in and runs through the middle of the room. You would likely be surprised and you would, somewhat reflexively, direct your attention towards the spectacle. This rapid shift in attention would be associated with activity in your superior colliculus.

It has been proposed that individuals who suffer from disorders like attention-deficit hyperactivity disorder (ADHD) may experience increased activity in the superior colliculus, which causes rapid, uncontrolled shifts of attention. Mathis et al. investigated the role of the tectum in attention using mice with a genetic abnormality that makes the superior colliculus hypersensitive.

The researchers exposed mice with this defect to a series of behavioral tests. They found that the mice performed normally on tests of visual acuity, movement, and sensory processing. However, the mice seemed to be less wary than control mice of entering areas of bright light (usually something mice avoid as open spaces make them vulnerable to attacks from natural predators). Additionally, the mice performed worse on a task that required them to inhibit impulses. These abnormalities in behavior were associated with increased levels of the neurotransmitter norepinephrine in the superior colliculus.

The authors of the study mention that their work supports the hypothesis that superior colliculus overstimulation is a contributing factor in ADHD. I have no qualms with the verbiage used in the paper, but CNRS's press release about the study is titled "Confirmation of the neurobiological origin of attention-deficit disorder" and they state in the article: "A study, carried out on mice, has just confirmed the neurobiologial origin of attention-deficit disorder (ADD)..."

When it comes to psychiatric disorders without a clearly defined molecular mechanism (which is almost all of them), it is improbable that a finding in mice can confirm anything in humans. Our understanding ADHD in humans is limited. We have no objective diagnostic criteria; instead we base diagnosis on observable and self-reported symptoms.

If our understanding of a disorder in humans is based primarily on symptomatology (as opposed to the underlying pathophysiology), then it makes the results of experiments that use animals to model the disorder more difficult to interpret. For, if we don't know what molecular changes we can expect to see as a correlate of the disease (e.g. senile plaques in Alzheimer's), then we are resigned to trying to match symptoms of mice with symptoms of men. In this type of situation where we don't know the true pathophysiology, we can never be sure that the symptoms we are seeing in mice and those we are seeing in men have an analogous biological origin.

Thus, when it comes to psychiatric disorders, translating directly from animals to humans is difficult. In the case of ADHD, because the biological origins of the disorder are still mostly unknown, animal models can be used as a means to explore the neurobiology of a similar manifestation of symptoms in the animal. They can't, however, be used to "confirm" anything about the human disorder. In this case, CNRS drastically overstated the importance of the study. Of course, the wording used by CNRS in their initial press release was also found on dozens of other media outlets after they picked up the story.

Do I doubt that ADHD has a neurobiological origin? No. But the study by Mathis et al. did not confirm that it does. CNRS, as an institution of science, should be more careful about the claims they make in their communications with the public.

 

Mathis, C., Savier, E., Bott, J., Clesse, D., Bevins, N., Sage-Ciocca, D., Geiger, K., Gillet, A., Laux-Biehlmann, A., Goumon, Y., Lacaud, A., Lelièvre, V., Kelche, C., Cassel, J., Pfrieger, F., & Reber, M. (2014). Defective response inhibition and collicular noradrenaline enrichment in mice with duplicated retinotopic map in the superior colliculus Brain Structure and Function DOI: 10.1007/s00429-014-0745-5