by Thomas Wagner-Nagy (concentris research management GmbH)
Attention deficit hyperactivity disorder (ADHD) is a mental health condition that rarely occurs alone. More than 80 percent of adult ADHD patients suffer from a comorbid disorder, meaning there is at least one additional disease co-occuring with the primary disease.
In the case of ADHD, two common comorbid conditions are obesity and major depressive disorder. Therefore, the risk for comorbid obesity and major depressive disorder is increased in adolescents and adults with ADHD. Moreover, a disturbed circadian rhythm and altered sleep are key features of ADHD.
Bright light therapy, a so-called chronobiological modification, improves the day-night (circadian) rhythm and is an established therapy for major depression in adolescents and adults. Exercise prevents and reduces obesity in adolescents and adults along with improving depressive symptoms.
While these non-pharmacologic treatments are known to modulate dopaminergic transmission (DA) and circadian rhythm (CIRCA), two key mechanisms regulating mental wellbeing, no study has assessed their effect on ADHD and its comorbidities in an experimental setting yet. PROUD is therefore the first large scale, multicentre study to systematically evaluate the role of DA and CIRCA and scrutinize their potential relevance for developing disease biomarkers and thus obtaining measurable indicators for predicting and treating these ADHD comorbidities.
“The idea here is to employ non-pharmacological methods to improve patients’ lives. There is a well-established drug treatment for ADHD with stimulants – methylphenidate being the most famous one. However, that is only one step and we want to make use of the knowledge that sports on the one hand and bright light therapy on the other hand showed promising initial data to improve patients’ lives with ADHD”, says CoCA project coordinator Andreas Reif, Chair of the Department of Psychiatry, Psychosomatic Medicine and Psychotherapy at the University Hospital Frankfurt in Germany.
“So we put that into a clinical study where we compared treatment as usual with add-on sports therapy or add-on bright light therapy. Over this ten-week trial, we will see whether this affects not only ADHD symptoms but overall health symptoms like depressive symptoms or weight.”
Need a watchdog or motivator? There’s an app for that
Just how do you motivate obese patients to exercise regularly? “It’s very hard to get up and do sports on a daily basis”, says Reif. “We thought about how we can empower our patients to adhere to the study protocol. In order to do that, we have developed a mobile health application, the mHealth App.”
The mHealth App was specifically developed for the PROUD Study with the aim of keeping the patients motivated. “We achieve this by showing them videos of exercise, sending reminders as well as a daily feedback and summary on their achievements”, trial coordinator Jutta Mayer explains.
The study has started with its first participants at the University Hospital of Frankfurt in late March 2017. The CoCA team expects first results and insights by the end of 2017.
This post has also been submitted as a press-release to announce the start of the PROUD trial.
If we are to read what we believe on the Internet, dieting can cure many of the ills faced by humans. Much of what is written is true. Changes in dieting can be good for heart disease, diabetes, high blood pressure and kidney stones to name just a few examples. But what about ADHD? Food elimination diets have been extensively studied for their ability to treat ADHD. They are based on the very reasonable idea that allergies or toxic reactions to foods can have effects on the brain and could lead to ADHD symptoms.
Although the idea is reasonable, it is not such an easy task to figure out what foods might cause allergic reactions that could lead to ADHD symptoms. Some proponents of elimination diets have proposed eliminating a single food, others include multiple foods and some go as far to allow only a few foods to be eaten so as to avoid all potential allergies. Most readers will wonder if such restrictive diets, even if they did work, are feasible. That is certainly a concern for very restrictive diets.
Perhaps the most well-known ADHD diet is the Feingold diet (named after its creator). This diet eliminates artificial food colorings and preservatives that have become so common in the western diet. Some have claimed that the increasing use of colorings and preservatives explains why the prevalence of ADHD is greater in Western countries and has been increasing over time. But those people have it wrong. The prevalence of ADHD is similar around the world and has not been increasing over time. That has been well documented but details must wait for another blog.
The Feingold and other elimination diets have been studied by meta-analysis. This means that someone analyzed several well controlled trials published by other people. Passing the test of meta-analysis is the strongest test of any treatment effect. When this test is applied to the best studies available, there is evidence that exclusion of fool colorings helps reduce ADHD symptoms. But more restrictive diets are not effective. So removing artificial food colors seems like a good idea that will help reduce ADHD symptoms. But although such diets ‘work’, they don’t work very well. On a scale of one to 10 where 10 is the best effect, drug therapy scores 9 to 10 but eliminating food colorings scores only 3 or 4. Some patients or parents of patients might want to this diet change first in the hopes that it will work well for them. That is a possibility, but if that is your choice, you should not delay the more effective drug treatments for too long in the likely event that eliminating food colorings is not sufficient. You can learn more about elimination diets from: Nigg, J. T. and K. Holton (2014). “Restriction and elimination diets in ADHD treatment.” Child Adolesc Psychiatr Clin N Am 23(4): 937-953.
Keep in mind that the treatment guidelines from professional organization point to ADHD drugs as the first line treatment for ADHD. The only exception is for preschool children where medication is only the first line treatment for severe ADHD; the guidelines recommend that other preschoolers with ADHD be treated with non-pharmacologic treatments, when available. You can learn more about non-pharmacologic treatments for ADHD from a book I recently edited: Faraone, S. V. & Antshel, K. M. (2014). ADHD: Non-Pharmacologic Interventions. Child Adolesc Psychiatr Clin N Am 23, xiii-xiv.
A short while ago, three of our professors were in the media, featuring an article and a TV-documentary about ADHD. Professor Andreas Reif wrote an elegant piece for the Frankfurter Algemeine – a German national newspaper – explaining the biology of ADHD and the need for treatment [see also this recent post on Andreas Reif’s recent appearances in German Media]. Around the same time, professors Barbara Franke and Phillip Asherson appeared in a documentary in which Britisch comedian Rory Bremner went on a personal mission to discover the science of ADHD. As not everyone can read German, and the BBC show is unfortunately only viewable inside the UK, I’ll tell you about the highlights of both pieces.
Do you know the stories by Heinrich Hoffman (1845)? The psychiatrist who wrote a children’s book about naughty children. One of the stories is about Fidgety Philip – or Zappelphilip in German – a boy who can’t sit still and as a result pulls down the tablecloth including everything that’s on top of it, smashing all the table’s contents on the floor. Both Andreas Reif and Rory Bremner mention Fidgety Philip, as the characteristics of this boy resemble several symptoms of ADHD: fidgetiness, restlessness and impulsivity. This example illustrates that ADHD is not a new or modern day phenomenon.
Interestingly, it’s not just the behaviour of people with ADHD that is restless. As Rory Bremner describes it “the music in my brain is [..] pounding and rapid and switching”. This ‘busy brain’ is often described by people with ADHD. And this makes it logical to expect that you should be able to see this with an MRI-scanner – a machine that allows researchers to measure brain activity. Unfortunately, reality is not so simple. Despite a lot of research on people with ADHD and their brain activity, we still can’t diagnose ADHD by using a brain scan. As professor Katya Rubia explains to Rory Bremner, differences in the brains of people with ADHD, compared to those without ADHD, can be seen when you average over large groups (see figure below). For instance, children with ADHD have smaller brain structures in the frontal parts and in deeper areas of the brain (the basal ganglia). These regions are also known to be less activated in children with ADHD, when they need to inhibit a response. As an example, in the documentary Rory Bremner finds it very difficult to inhibit his comments about Katya Rubia’s accent and beauty. This could be due to under activation of his frontal brain and basal ganglia. However, the MRI findings are only based on averages, and can be very different for individual people. Just like that you can’t tell if someone is a man or a women just by measuring their length – even though men on average are taller than women – you can’t tell if someone has ADHD by just looking at their brains.
Fruit flies and ginger bread men
So why does someone have ADHD? Are you born with ADHD? Is it the fault of your parents? Or should we blame society? Extensive research has shown that there is a strong genetic component to ADHD. This means that you inherit the risk for developing ADHD from your parents – even when they don’t raise you, as for instance in the case of adoption. Professor Andreas Reif describes that there are hundreds or even thousands of genes that can contribute to ADHD. Each single gene by itself will not cause ADHD, but together they contribute to the risk for ADHD. The situation with the genes is therefore similar as to that of the brain scans: no gene test can prove that you have ADHD as there is too much variation between individuals. So why should we put time and money in investigating the genetics of ADHD?
For one thing, if we understand which combination of genes contributes to a high risk for developing ADHD, screening could help in early detection of those at risk. For instance, ADHD is known to often co-occur with other disorders, such as depression, substance abuse or obesity. If we know who is at risk of developing such a secondary disorder, the person can be informed about the importance of behavioural adaptations that reduce this risk, such as regular exercise in the case of obesity. Another reason is that better understanding of causal mechanisms can aid in developing new treatments for ADHD.
In order to study these causal mechanisms, professor Barbara Franke uses fruit flies (drosophila melanogaster). With these flies she can investigate which gene is associated with which specific aspect of ADHD, such as hyperactivity or inattention. In the documentary Barbara Franke shows Rory Bremner how she releases fruit flies in a specially designed maze. At the end of the maze, the fruit flies can find food. The more often they go through the maze, the better they learn the route. But while the flies go through the maze, they are being distracted by a light which they should ignore. For this experiment, some fruit flies have undergone modifications of genes that we suspect to pose risk for ADHD. And it turns out that the ADHD-like flies are more distracted by the lights than the ‘normal’ flies. In this way, we can find out which genes cause increased distractibility.
But it’s not just genes that contribute to ADHD. Although genes explain about 80% of ADHD, environmental influences, such as preterm birth or toxins during pregnancy also contribute to the risk for ADHD [i.e. see this recent post by Stephen Faraone)]. In the documentary, Peter Hill shows Rory Bremner how genetic and environmental factors can contribute to slightly different appearances – also called phenotypes – by baking gingerbread men. Peter and Rory bake several of these cookies, but with slight differences in the ingredients and procedure. One gingerbread man for instance is baked less long, which translates to environmental. The other gingerbread men lack eggs, contain less flour, or have no ginger. These are exemplary of the genetic influences of ADHD. All in all, the gingerbread men still look like gingerbread men – and probably are just as tasty – but knowledge about what happened in the preparation and baking process can help understand why they are different.
Medication & treatment
As mentioned earlier, ultimately we hope that a better understanding of ADHD enables better treatment. At the moment, psychostimulant medication, such as Ritalin and Concerta, is the most widely used form of treatment. As Andreas Reif explains, methylphenidate (which is the active substance in Ritalin) increases the availability of dopamine and noradrenaline in the brain. These two substances are necessary for a wide range of cognitive tasks, including learning, paying attention and inhibiting responses. In people with ADHD there seems to be too little dopamine available, which is why they benefit from this medication. Rory Bremner tries it for the first time in the documentary, just before he gives a comedy show. He describes the effect as “It’s a bit like someone switched my brain from techno radio 1 to classic fm”. However, as professor Phillip Asherson tell us, although this medication can help you to focus, some people will feel more nervous or restless. In that case, the medication doesn’t work for them.
Alternative forms of treatment are also being tested, such as neurofeedback. Friederike Blume from Tübingen shows Rory Bremner how she uses EEG (measuring electric signals in the brain by using a device that looks like a swim cap) combined with virtual reality in order to train people to improve their neural signals. Similar to going to the gym, regular neurofeedback training may help to improve brain functioning and hence reduce symptoms.
And what happens when ADHD is left untreated? In some cases, not so much. Rory Bremner was never diagnosed with ADHD, even though in the documentary he finds out that he does have all the symptoms of ADHD. For a comedian as himself, an impulsive and associative mind is very beneficial. However, for others, untreated ADHD can cause big problems. About 30% of the offenders in prison has ADHD, and most of them have not received treatment. As most of these offences concern impulsive offences, such as spraying graffiti, medication can help to prevent such behaviour.
So, what have we learned?
All in all, both the documentary and the newspaper article give us an idea of what the research on ADHD is all about: from fruit flies to brain scans, researchers are trying to discover the biology of ADHD. As Andreas Reif puts it, better knowledge and diagnostics of ADHD, in all stages of life, can greatly improve detecting and treating ADHD. And this can greatly improve quality of life of those with ADHD. That’s what inspires us to do the research.
Given the high heritability, significant impairment, morbidity and increased rates of mortality of psychiatric disorders, several hypotheses have been proposed to explain why natural selection does not remove the causal alleles of these phenotypes from the population.
This question is universal for any frequent phenotype that reduces the fitness of the carriers of the risk variants, and literature is full of examples of phenotypes were natural selection seems to paradoxically behave in an opposite way than expected. Nevertheless, once one looks deeper into the biology of the analyzed system, realizes that selective forces are still acting according to the laws of Darwinian selection. For example, thalassemias are a type of anemia that are caused by mutations in the genes coding for the hemoglobin chains; despite of the impairing conditions associated to the disease, thalassemias are present at a relatively high frequency in particular geographic regions. A simplistic interpretation of the principles of Darwinian selection would suggest that this situation is impossible. However, from a genomic point of view, it has been shown that most causal alleles show genomic signatures of selective sweeps. Why mutations that produce anemia are naturally maintained in the population? This paradox can be solved by realizing that thalassemias occur in regions that show (or have traditionally shown) a high prevalence of malaria, a disease produced by a protozoa that needs to infect blood cells during its reproductive cycle. Digging a bit more into the epidemiology of thalassemia and malaria, it can be seen that individuals that do not carry thalassemia mutations are more prone to suffer from malaria, whereas individuals that carry two thalassemia mutations tend to have anemia. However, carriers of only one thalassemia-causing allele (heterozygotes) are more resistant to malaria and do not suffer from anemia.Thus, from a selective point of view, heterozygotes have a fitness advantage over both types of homozygotes and more chances of producing descendants.
This classical example of population genetics provides some main lines that any study that attempts to explain the prevalence of a disorder in a population must take into account:
The hypothesis of selection must be validated in the causal alleles of the phenotype. This can be cumbersome if the causal variant of the phenotype is unknown.
Identification of the factor triggering the selective pressure requires deep knowledge of the etiology of the phenotype, which is usually something not really available.
The factor triggering the selective pressure must be set in a historical context.
In the case of complex phenotypes, such as psychiatric disorders, all these lines are compromised, making everything more difficult. First of all, complex phenotypes involve many causal loci (i.e. they are polygenic) with a very small effect on the phenotype; moreover, alleles associated to a particular complex phenotype are usually identified by means of genome-wide association studies (GWAS), but the causal loci are not known. Second, statistical tests for detecting polygenic adaptation are still in their infancy and classical tests for detecting selective sweeps are usually underpowered for detecting selection at complex phenotypes. Finally, each locus can affect more than one phenotype (pleiotropy), each under different selective pressures.
Nevertheless, this does not imply that detecting signatures of polygenic adaptation in psychiatric disorders is not affordable. Recently, Polimanti and Gelernter published a study in Plos Genetics (http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006618) where they conducted analyses to detect polygenic adaptation in five psychiatric disorders: attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BP), major depressive disorder (MDD), and schizophrenia (SCZ). The authors take advantage that there are GWAS (however, some of them are underpowered) for all these phenotypes from the Psychiatric Genomics Consortium (https://www.med.unc.edu/pgc/results-and-downloads), and maps of signals of different types of positive selection in the human genome for different human populations (http://hsb.upf.edu/). However, since the GWAS have been conducted in individuals of recent European ancestry, the authors focus on European populations. Out of the five phenotypes analyzed, the authors identified signals of polygenic adaptation in ASD and SCZ-associated alleles with incomplete (i.e. it has not reached fixation) selection in European populations. Next, they analyzed genetic correlation of ASD with some other phenotypes (http://ldsc.broadinstitute.org/) and concluded that ASD is related to several advantageous traits: years of schooling, college completion, childhood intelligence and opennessto experience. Based on these results, the authors hypothesize that ASD alleles present beneficial effects with respect to cognitive ability, a feature under selective pressure.
It is unclear whether the absence of statistically significant results for the other phenotypes is due to the lack of power of the GWAS for detecting associations due to low sample size of the studies, lack of power of the applied boosting statistics for detecting polygenic selection or to true lack of selective advantage of these phenotypes. In the case of ADHD, several hypotheses have been proposed to explain the high prevalence of the phenotype in current populations (see https://www.ncbi.nlm.nih.gov/pubmed/27530703). GWAS with larger sample sizes and the use of more powerful selective tests will be required in order to properly test these hypotheses.
Health and fitness apps enable researchers, physicians, sport specialists and healthcare practitioners to maximize health and gather data from large numbers of people (Savage, 2015). Nowadays, the apps have the potential to reach nearly all populations, regardless of gender or ethnicity, even for those who have limited access to healthcare. Another remarkable point is that smartphones allow to perform assessments without be physically present on specific location.
Smartphones made to measure
In this context, several apps are being validated for obtaining data of sports performance and public health issues. In this context, The MyHeart Counts Cardiovascular Health Study is a very good example (McConnell et al., 2017). In this study physical activity was recorded through the motion coprocessor chip of the smartphone. The motion chip was able to include triaxial accelerometer, gyroscope, compass and barometer. Fitness was measured with the 6-minute walk test and final time was registered by the app. Sleep patterns were also registered by the motion chip. MyHeart Counts has demonstrated the feasibility, large-scale and real world assessment of physical activity, fitness and sleep using a smartphone in more than 40.000 people. Smartphones are definitely made to measure!
Apps for measuring fitness
More specifically, apps offer a large potential on fitness assessment, making it inexpensive, easier, accessible, feasible and last leading a laboratory into the pocket.
In fact, considering the importance reached by physical fitness as a powerful indicator not only of sport performance, but also and mainly as a maker of current and future health/disease, it is relevant to known about the currently available apps allowing assessment of the main health-related physical fitness components. An example is My Jump, which has been developed by Balsalobre-Fernandez, Glaister, & Lockey (2015) for measuring vertical jump height. Vertical jump is the most common field test to evaluate lower limb power in various populations and it has been recognized as an important tool to quantify neuromuscular fatigue.
In this sense, we have recently reviewed the apps for measuring the main health-related fitness components available in Google Play and App Store (unpublished material). Therefore, we have concluded some important points: 1- All validated apps conducted under research conditions have been developed for App Store; 2- Course-Navette field-test has been the most use for apps aiming to estimate aerobic capacity; 3- Regarding the muscular strength component most of the apps has been designed to calculate the maximum repetition; 4- Few apps are available to measure velocity and agility; 5- The flexibility category is the one that contains more scientifically validated apps.
Take home message
If you are planning to use an app to measure your fitness, you should pay attention to the following recommendations:
If you have a Smartphone you have a lab in your pocket.
Demand scientifically validated apps.
Check out the ratings and user reviews of the apps.
Take a look to security aspects.
Adrià Muntaner-Mas, Antonio Martínez-Nicolás and Francisco B. Ortega
Dept. Physical Education and Sports, Faculty of Sports Sciences, University of Granada, Spain.
Balsalobre-Fernandez, C., Glaister, M., & Lockey, R. A. (2015). The validity and reliability of an iPhone app for measuring vertical jump performance. Journal of Sports Sciences, 33(15), 1–6.
McConnell, M. V., Shcherbina, A., Pavlovic, A., Homburger, J. R., Goldfeder, R. L., Waggot, D., … Ashley, E. A. (2017). Feasibility of Obtaining Measures of Lifestyle From a Smartphone App. JAMA Cardiology, 2(1), 67.
Savage, N. (2015). Mobile data: Made to measure. Nature, 527(7576), S12–S13.
For all the German followers, I would like to recommend current contributions by Prof. Andreas Reif, University of Frankfurt am Main, Germany: The online-accessible article was published in the Frankfurter Allgemeine Zeitung and the related interview can be found on the pages of the HR.After a contribution to reading, one for listening, now another to watch: The lecture on the adult ADHD by Prof. Reif at the Hertie Foundation.
Although some people view the impulsivity and inattentiveness of ADHD adults as a normal trait, these symptoms have adverse consequences, which is why doctors consider ADHD to be a disorder. The list of adverse consequences is long and now we can add another: broken bones. A recent study by Komurcu and colleagues examined 40 patients who were seen by doctors because of broken bones and forty people who had not broken a bone. After measuring ADHD symptoms in these patients, the study found that the patients with broken bones were more impulsive and inattentive than those without broken bones. These data suggest that, compared with others, adults with ADHD symptoms put themselves in situations that lead to broken bones. What could those situations be? Well, we know for starters that ADHD adults are more likely to have traffic accidents. They are also more likely to get into fights due to their impulsivity. As a general observation, it makes sense that people who are inattentive are more likely to have accidents that lead to injuriers. When we don’t pay attention, we can put ourselves in dangerous situations. Who should care about these results? ADHD patients need to know about this so that they understand the potential consequences of their disorder. They are exposed to so much media attention to the dangers of drug treatment that it can be easy to forget that non-treatment also has consequences. Cognitive behavior therapy is also useful for helping patients learn how to avoid situations that might lead to accidents and broken bones. This study also has an important message for administrators how make decisions about subsidizing or reimbursing treatment for ADHD. They need to know that treating ADHD can prevent outcomes that are costly to the healthcare system, such as broken bones. For example, in a study of children and adolescents, Leibson and colleagues showed that healthcare costs for ADHD patients were twice the cost for other youth, partly due to more hospitalizations and more emergency room visits. Do these data mean that every ADHD patient is doomed to a life of injury and hospital visits? Certainly not. But they do mean that patients and their loved ones need to be cautious and need to seek treatments that can limit the possibility of accidents and injury.
Komurcu, E., Bilgic, A. & Herguner, S. (2014). Relationship between extremity fractures and attention-deficit/hyperactivity disorder symptomatology in adults. Int J Psychiatry Med 47, 55-63.
Leibson, C. L., S. K. Katusic, et al. (2001). “Use and Costs of Medical Care for Children and Adolescents With and Without Attention-Deficit/Hyperactivity Disorder.” Journal of the American Medical Association 285(1): 60-66.