Why following instructions is essential for treatment success (and why this is really difficult)

 

Clara Hausmann, Mental mHealth Lab / Chair of Applied Psychology, Karlsruhe Institute of Technology



When visiting your doctor due to a simple cold you’ve caught, you will probably get the following advice: Get a rest from work, stay in bed for a week, drink a lot of herbal tea and go for a slow walk once a day. Well, you might follow the advice as you’ve been told. But possibly, you can’t stand tea or you are currently under pressure to finish some urgent work and anyway, you don’t feel that bad anymore after one day in bed. The degree to which a patient correctly follows medical advice is called compliance.

            Compliance is also an important term in the psychological and medical research, we are conducting – especially in our ambulatory settings where patients are treated outside of the hospital. In contrast to doing research in very well controlled laboratory settings, embedding research into everyday life  avoids  a lot of methodological disadvantages. For example, participants’ behavior won’t be biased by the presence of a researcher or the artificial situation in the lab. Another great feature of ambulatory assessment lays within the opportunity to gather real time or near real time data. Participants will be regularly asked about their current state of mind, so researchers don’t have to take into account the inaccuracy of patients’ retrospective reports [1] .  Still, we are facing some difficulties when using ambulatory settings – reaching a good compliance is part of it.

            In the CoCA PROUD study, for instance, we are ambulatorily monitoring our ADHD-diagnosed participants’ mental and physical state. Therefore, they are equipped with a smartphone and a small activity sensor. Participants keep an eDiary, by fulfilling repeated questionnaires on the smartphone while the activity sensor on their wrists measures physical activity. Meanwhile, they will take part in some non-pharmalogical interventions (daily physical exercise training or bright light therapy), which promise to alleviate some core symptoms of ADHD and it’s comorbidities such as depression.

            In this study, „compliance“ is what we call the percentage of prompts, that were answered, in order to fulfill the eDiary. All in all, participants receive four prompts per day, including questions about their current mood, social context and ADHD symptomatology. Furthermore, we can analyze how often the sensor was worn. Additionally, checking for the compliance during the interventions allows us to calculate how much time was spend on actively carrying out the instructions (e.g. doing strengthening and aerobic exercises).

In general, we aim to reach a good compliance. The more our participants contribute, the better the quality of data and the understanding of ADHD can be. However, one can imagine that general facts of life such as situational distraction or simple forgetting can be a hindrance for participants, to answer prompts [2].  Apart from this, researchers must be aware, that ambulatory assessment is inherently disruptive to participants’ daily lives. For instance, the activity trackers that participants wear are quite big, and getting daily prompts from the eDiary can be a real nuisance. The art lies in the design of the research: It is unquestionably essential to find a good balance between participants’ expenditure in time and energy and the amount and quality of data collected [3]. In order to find this balance, we’re always first testing the research study on ourselves to check for the feasibility, comfort, and ease of participation.

            Besides that, there are specific challenges for participants diagnosed with ADHD. For instance, the tendency to show irregularities in the day-and-night-rhythm might not always match the time of the smartphone prompts, that are sent in regular intervals. Furthermore, some patients tend to have problems in keeping their belongings organized. Especially for young patients, it might be challenging to keep the phone both charged and on their person. Inattention and lack of concentration as core symptoms of ADHD, are additional burdens to the conscientious and constant work on the questionnaires. Particularly young patients are expected to be quickly bored by the repeated questions, incoming day by day.

            We encounter those difficulties in multiple ways. An important tool is the smartphone’s chat function. Participants can easily reach a contact person and vice versa. Hence, individual or technical problems can be detected and solved quickly. In order to facilitate the start, we send reminding and motivating messages during the first four days of the measurement. To keep participants’ motivation high, they receive daily feedbacks, visualizing how they have performed when exercising.

            Taken as a whole, compliance, whether good or not, provides a lot of important information about the quality of the intervention. A treatment can only be considered as promising and helpful, when patients are able and motivated to include it into their daily lives. Therefore, the combination of ambulatory assessment and compliance monitoring gives us a realistic idea of a treatment’s actual feasibility and – in the consequence – it’s quality.

 

References:

[1] Trull, T. J., & Ebner-Priemer, U. W. (2013). Ambulatory Assessment. Annual review of clinical psychology, 9, 151–176. doi:10.1146/annurev-clinpsy-050212-185510 

[2] Piasecki et al. (2007). Assessing Clients in Their Natural Environments With Electronic Diaries: Rationale, Benefits, Limitations, and Barriers. Psychological Assessment,19(1), 25-43. doi:10.1037/1040-3590.19.1.25


[3] Carpenter, R. W., Wycoff, A. M., & Trull, T. J. (2016). Ambulatory assessment: New adventures in characterizing dynamic processes. Assessment, 23(4), 414–424. https://doi.org/10.1177/1073191116632341


 

Is it safe to use ADHD medications during pregnancy?

“Should I discontinue stimulants when I am pregnant?” “Is it harmful to my developing baby if I take ADHD medications during my pregnancy?” “What are the risks both to me and my baby if my ADHD goes untreated?” “What is the best way to manage my ADHD during pregnancy?” – For women with ADHD who become pregnant, especially those with moderate or severe ADHD symptoms, the next few months are filled with questions. One important decision for the pregnant women and their clinician is whether to remain on or cease their ADHD medication treatment before or during pregnancy, or while breastfeeding. Unfortunately, there is no clear ADHD treatment guidelines for pregnant women, which further complicates these decisions. Therefore, there is a need for high-quality evidence to support guidelines for the use of ADHD medication during pregnancy.

Given that, it is unethical to include pregnant and breastfeeding women in clinical trials, evidence-based guidelines need to rely on findings from naturalistic studies. So, what does the available findings from naturalistic studies tell us?  

In our newly published paper in CNS Drugs (https://doi.org/10.1007/s40263-020-00728-2), we conducted a systematic review to synthesize all available evidence regarding the safety of ADHD medication use while pregnant, with a focus on how these studies have handled the influence of confounding, which may bias the estimates from observational studies.

We identified eight cohort studies that estimated adverse pregnancy-related and offspring outcomes associated with exposure to ADHD medication during pregnancy. These studies varied a lot in data sources, type of medications examined, definitions of studied pregnancy-related and offspring outcomes etc. Overall, there was no convincing evidence for an association between maternal ADHD medication use during pregnancy and adverse pregnancy and offspring outcomes. Some studies suggested a small increased risk of low Apgar scores, preeclampsia, preterm birth, miscarriage, cardiac malformations, admission to a NICU, and central nervous system (CNS)-related disorder, but other available studies failed to detect similar associations. Because of the limited number of studies and inadequate confounding adjustment, it is currently unclear whether these small associations are due to a causal effect of prenatal exposure to ADHD medication or confounding.

In conclusion, the current evidence does not suggest that the use of ADHD medication during pregnancy results in significant adverse consequences for mother or offspring. However, the data are too limited to make an unequivocal recommendation. Therefore, physicians should consider whether the advantages of using ADHD medication outweigh the potential risks for the developing fetus according to each woman’s specific circumstances.

More information here:

Li, L., Sujan, A.C., Butwicka, A. et al. Associations of Prescribed ADHD Medication in Pregnancy with Pregnancy-Related and Offspring Outcomes: A Systematic Review. CNS Drugs (2020). https://doi.org/10.1007/s40263-020-00728-2

Authors:

Lin Li, MSc, PhD student in the School of Medical Science, Örebro University, Sweden.

Henrik Larsson, PhD, professor in the School of Medical Science, Örebro University and Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Sweden.

The notorious evening chronotype and my master’s thesis

Almost every person, healthy or not, suffers from occasional problems with sleep and circadian rhythm. In the modern days of 24/7 smartphone use and transcontinental flights, our internal body clock is having a hard time adjusting to the external cues. For the persons suffering from mental health issues, their impaired sleep cycle can be one of the cornerstone problems of daily living. Sleep problems have been confirmed to be a first symptom, consequence, or even a cause of such psychiatric conditions as major depression, bipolar disorder, ADHD, autism, substance abuse, and even aggressive behaviour. Their strong relations, however, have not been studied systematically and broadly just yet.

Why study the circadian rhythm?

Circadian rhythm is our inner clock that regulates a lot of important processes in the human body, including the sleep/wake cycle, the release of hormones and even the way we process medicines. This clock is run by the brain region called the hypothalamus, which piles up a protein called CLK (referring to “clock”), during the daytime. CLK, in turn, activates the genes which make us stay awake, but also gradually increases the creation of another protein called PER. When we have a lot PER, it turns off CLK production and makes us ready to sleep. As CLK is getting lower, this causes a decrease in PER, so that the process starts again with elevating CLK waking us up. This cycle happens at around 24-hour intervals and is greatly influenced by so-called zeitgebers, or time-givers, like light, food, noise and temperature. When our retina neurons catch light waves, the suprachiasmatic nucleus in our brain stops the production of the hormone called melatonin that induces sleep and starts producing noradrenaline and vasopressin instead to wake us. This is the exact reason why you cannot fall asleep after watching a movie at night.

PER
Figure 1. The smart protein CLK wakes us up and its friend PER gets us to sleep.

Sometimes our body clock fails to function, as in the case of jetlag when we feel bad after changing a time zone or social jetlag when we have to start work early at 8 am. It can go as far as a circadian rhythm disorder meaning you have either a delay or advancement of sleep phases or an irregular or even non-24-hour daily activities preference. However, in the general population, a small variation in the rhythm is quite normal and is usually referred to as a chronotype. It defines your preference of when to go to sleep and do your daily activities and is divided into 3 distinct versions. The radical points of these variations include a morning chronotype, or “larks”, who go somewhat 2-3 hours ahead of the balanced rhythm, and an evening chronotype, or “owls”, who are a little delayed. The larks feel and function better during the first half of the day and go to bed rather early, while the owls prefer to work in the evenings and go to bed and wake up naturally late. The third chronotype is the in-between, balanced version of these two.

arjan-stalpers-itBTNoD1PpA-unsplash
Figure 2. The ‘owls’ seem to have questionable personalities and suffer from psychiatric conditions more often!

What’s my study about?

Previous research has shown that many psychopathologies are linked to an evening circadian preference. For my master thesis research, I am investigating whether we can identify specific profiles in sleep and circadian rhythm problems that are linked to specific mental health problems. There was even a curious study where researchers linked the Dark Triad personalities, which include people with tendencies for manipulation, lack of empathy, and narcissism, to the evening chronotype. Maybe this leaves some evidence for the famous quote that “evil does not rest”. However, there’s a great variation in sleep duration and perceived quality of sleep in patients with various diseases. We hope to divide such persons into more or less accurate groups with a sleep profile that would predict and aid the correct diagnosis of one or the other mental health condition.

The psychopathologies are included in our study as so-called dimensions, which look at each psychiatric syndrome not as with a norm/pathology cut-off but rather as a continuum of symptoms severity. This approach allows us to see if the sleep/circadian profile we identify refers to mental health in general or can be a distinguished part of a certain psychiatric condition. It might be that all dimensions, like depression and autistic spectrum disorders, have an evening chronotype and some non-specific sleep problems. Alternatively, we might find out that a person with symptoms of depression would sleep more or less than average and go to bed later, whereas a person with anxiety would go to sleep later as well but wake up at night very often despite an average summed up sleep duration.

The circadian rhythm changes throughout a lifetime from an early to an evening chronotype towards adolescence and then gradually shift back to the earlier preference with older age. Across the whole lifespan people constantly face varying quality of night sleep. Moreover, each psychiatric condition has a particular age of onset and sometimes changes its character with time. These are the reasons why our study will also look at how the sleep/circadian profiles change within the development phases from children (4-12 years) to adolescents (13-18) to adults (19-64) to the elderly (≥65) and if they affect males and females differently.

Why would it matter?

Should we discover distinct links between the profiles of sleep/circadian problems and certain conditions, other studies can then look into whether these profiles could be the reasons behind developing a mental health condition. It’d be interesting to finally learn what is a chicken and an egg in each profile-disease relation. For instance, should we really treat ADHD patients with melatonin and bright-light lamps instead of stimulants?

sabri-tuzcu-KHBvwAnWFmc-unsplash
Figure 3. Maybe if we adopt a typical cat’s lifestyle, we get less mental health problems. 🙂

Dina Sarsembayeva is a neurologist and a research master’s student at the University of Groningen. She is using the data from the CoCa project to learn if the chronotypes and sleep problems can be turned into profiles to predict specific psychiatric conditions.

Further reading

  1. Walker, W. H., Walton, J. C., DeVries, A. C. & Nelson, R. J. Circadian rhythm disruption and mental health. Transl. Psychiatry 10, (2020).
  2. Logan, R. W. & McClung, C. A. Rhythms of life: circadian disruption and brain disorders across the lifespan. Nature Reviews Neuroscience vol. 20 49–65 (2019).
  3. Jones, S. G. & Benca, R. M. Circadian disruption in psychiatric disorders. Sleep Med. Clin. 10, 481–493 (2015).
  4. Taylor, B. J. & Hasler, B. P. Chronotype and Mental Health: Recent Advances. Curr. Psychiatry Rep. 20, (2018).

On a coalmine and an MRI scanner – Is it fun, participating in DELTA?

About two and a half years ago, Dr. Emma Sprooten started the DELTA project. In DELTA, acronym for Determinants of Long-term Trajectories in ADHD, she investigates factors that contribute to the difference in (severity of) symptoms and impairment in people who were diagnosed with ADHD as a child. Previously, these adults participated in a study called NeuroImage when they were a child. We asked them if they were willing to participate one more time in this study. In the coming three weeks, we will post three blogs about the project. This is blog 1.

2019. Somewhere in autumn. Trees have become all shades of brown, yellow and red. We pass forests while driving on a German highway, all the way from Holland. After a while, the landscape changes from the colored forest to an industrial town. It is grey and gloomy, packed with old-fashioned industry buildings. Soon, the navigation sends us into an even more surreal place. We find ourselves surrounded by rusty brown pipes in a place that feels like an abandoned factory. If we would not know better, we would begin to feel a bit worried about what could happen here… 

What brings us here in this desolate area? To put it short, a bunch of people who were diagnosed with ADHD during their childhood, and a hypermodern 7 Tesla MRI scanner. Over ten years ago, as children, our participants first came in together with their parents and siblings. They played games, were interviewed and got an MRI scan, that was presented to them as ‘ a picture of the inside of your brain’. Now, we are repeating these measurements for a third time, with an upgrade from 3 Tesla to 7 Tesla MRI, allowing even more detailed pictures of their brains.

For scientists it is extremely valuable that people are willing to take part in this research. This is one of the few cohorts in the world in which people with ADHD are followed up for such a long time. It makes it possible to investigate which factors influence the different clinical trajectories that ADHD can take:. We are now testing people for already a third time in the NeuroImage project, that started in 2009. The current follow-up is called the DELTA project. More on the content of the project in our third blog. 

Next week, we’ll give you a peek into what a participant experiences during a test day in Essen. 

If you cannot wait to get some information on NeuroImage, see: https://www.ru.nl/donders/vm-site/collaborations/projects/neuroimage/

For a peak into Zollverein, the world heritage site where the 7 Tesla scanner is located, see: https://www.zollverein.de/zollverein-unesco-world-heritage-site/ The photo at the top of this post shows a detail of the coal mine at Zollverein.

“No I do not have ADHD, I am just busy!”, but still very interesting for genetic studies!

Do you sometimes find it difficult to pay attention? Can you be very disorganized at times, or very rigid and inflexible? Although difficulties with attention, organization and rigidity are symptoms of psychiatric disorders, these traits are not unique to people with a diagnosis. And that is very useful for studying the genetics of psychiatric disorders.

Being easily distracted, liking things to go in a certain way, having a certain order in the way you do things, these might all be things you recognize yourself (or someone you know) in, while you (or they) are not diagnosed with any psychiatric disorder. We actually know that many of these symptoms are indeed found in a range in the general population, with some people showing them a lot, some a little and some not at all. If these symptoms are also present in people without a diagnosis then why should we only study people with a diagnosis to learn more about the biology of symptom-based disorders?

Many psychiatric disorders, like attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are disorders that ‘run in the family’. Using family-based and genetic studies it was found that they are actually highly heritable. However the underlying genetic risk factors turned out to be difficult to find. Enormous samples sizes (comparing more than 20 000 people with the disorder to even more individuals without the disorder) were needed to robustly find just a few genetic risk factors, although we know that many more genetic factors contribute. Even though these disorders are highly prevalent, collecting genetic data on psychiatric patients for research is still challenging. Using population-based samples – that include all varieties of people from the general population – can be a good alternative to reach large sample sizes for powerful genetic studies.

Taking together the fact that psychiatric-like symptoms are also, to a certain degree, present in the general population, and the fact that genetic studies can benefit from large(r) sample sizes to find genetic associations, it can be very interesting to study psychiatric-like traits in population-based samples. This is indeed what happened in the field of psychiatric genetics. The first proof-of-concept studies were able to show an astonishing overlap in genetic factors of more than 90% between ADHD and ADHD symptoms in the general population. Our own research group was able to show that certain autistic traits, like rigidity, indeed share a genetic overlap with ASD and that genes that were previously linked to ASD show an association to autistic traits in the population. These results show that genetic factors involved in disorder-like traits are overlapping with genetic factors involved in the clinical diagnosis, and therefore can indeed be used to study the biology of psychiatric disorders.

So next time you feel distracted/rigid/disorganized, don’t get discouraged, but consider signing up for a genetic study. Science might need you!

Janita Bralten is a postdoctoral researcher at the department of Human Genetics in the Radboud university medical center, Nijmegen, the Netherlands. Her research focusses on the genetics of psychiatric disorders.

Further reading:

Bralten J, van Hulzen KJ, Martens MB, Galesloot TE, Arias Vasquez A, Kiemeney LA, Buitelaar JK, Muntjewerff JW, Franke B, Poelmans G. Autism spectrum disorders and autistic traits share genetics and biology. Mol Psychiatry. 2018 May;23(5):1205-1212.

Middeldorp CM, Hammerschlag AR, Ouwens KG, Groen-Blokhuis MM, Pourcain BS, Greven CU, Pappa I, Tiesler CMT, Ang W, Nolte IM, Vilor-Tejedor N, Bacelis J, Ebejer JL, Zhao H, Davies GE, Ehli EA, Evans DM, Fedko IO, Guxens M, Hottenga JJ, Hudziak JJ, Jugessur A, Kemp JP, Krapohl E, Martin NG, Murcia M, Myhre R, Ormel J, Ring SM, Standl M, Stergiakouli E, Stoltenberg C, Thiering E, Timpson NJ, Trzaskowski M, van der Most PJ, Wang C; EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium; Psychiatric Genomics Consortium ADHD Working Group, Nyholt DR, Medland SE, Neale B, Jacobsson B, Sunyer J, Hartman CA, Whitehouse AJO, Pennell CE, Heinrich J, Plomin R, Smith GD, Tiemeier H, Posthuma D, Boomsma DI. A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts. J Am Acad Child Adolesc Psychiatry. 2016 Oct;55(10):896-905.

If you are interested in joining a scientific study see for example:

https://www.ru.nl/donders/vm-site/proefpersonen/engelse-versies-centers/participants/donders-centre-cognition-en/

or

https://www.impactadhdgenomics.com/patienten/nl/deelnemen (Dutch only)

Pay Attention to ADHD – Podcast with prof. Stephen Faraone

Professor Stephen Faraone – professor in Psychiatry at SUNY Upstate University and expert on ADHD – was interviewed by dr. Therese Markow for the podcast series ‘Critically Speaking’. In this podcast they discuss myths about ADHD and the scientific evidence that debunks these myths. Stephen Faraone explains why it is so important to diagnose and treat ADHD early. He also explains why ADHD is often undiagnosed in girls, and why sometimes adults are diagnosed with ADHD who have not sought treatment earlier in their life.

Critically Speaking is a podcasts series hosted by dr. Therese Markow who interviews experts to discuss in plain language complex issues that concern our health, society and planet.

You can listen to the podcast here: http://criticallyspeaking.libsyn.com/002-pay-attention-adhd-with-dr-stephen-faraone

 

Can virtual reality help in the treatment of ADHD?

Virtual-reality (VR) can be defined as an interactive computer-generated experience that can be similar to the real world or fantastical1. For instance, in a VR environment, a person is able to virtually live in the artificial world by looking and moving around it, as well as interacting with virtual characters or items2. Nowadays there are different kinds of VR environments, mainly used for entertainment purposes (e.g. video-games) or professional training (e.g. aviation, military training etc.)3. VR tools usually  range from a headset  (head-mounted displays with a small screens in front of the eyes), to proper full-scale rooms with bigger screens and special equipment  to increase the augmented reality experience.

Virtual reality head-mounted display. Image by Gerd Altmann from Pixabay.

VR has been recently investigated as a potential treatment for different metal health problems or psychiatric disorders such as social anxiety4, specific phobias5, post-traumatic stress disorder (PTSD)6, or persecutory delusions7. The key assumption behind the use of VR tools in mental health practice, relies in the fact that, in VR settings, individuals can repeatedly experience and learn appropriate coping strategies in a controlled environment8,9. For instance, knowing that the exposure is not real, allows people to face difficult situations and learn therapeutic strategies which they can then adopt in the real world.

..but how those VR tools can be used for the treatment of ADHD?

Recent evidence shows that VR can help enhance some of the core therapeutic challenges of ADHD such as attention, problem solving and managing impulsive behaviours10. For example, using VR can create virtual scenarios that can reward and empower skills such as response inhibition and emotional control10. One of the most commonly used scenarios is the class-room environment, which can introduce life-like distractions to asses children’s behaviour in an ecologically-based setting 10-11. In this virtual environment children with ADHD may be more able to use the trial-and-error instructional strategies to train learning skills11. For instance, in these VR settings, children with ADHD can also learn strategies to use in the real world without experiencing failures due to their experiences at school, making them more willing to accept the private feedback of the VR teacher.

Although VR ca be potentially used in ADHD treatment, is still an experimental procedure that needs more research to assess its validity. Also, there are still some concerns regarding potential side effects of long-term VR exposure, such as headaches, seizures, nausea, fatigue, drowsiness, disorientation, apathy, and dizziness10. Overall, despite its therapeutic potential, more studies are needed to assess its long-term treatment efficacy as well as the efficacy of VR environments compared to other non-pharmacological treatments already available for ADHD.

Isabella Vainieri and Jonna Kuntsi

Isabella Vainieri is a PhD student at the Social, Genetic & Developmental Psychiatry Centre at King’s College London.

Jonna Kuntsi is Professor of Developmental Disorders and Neuropsychiatry at King’s College London.

References

  1. Burdea, Grigore C. and Philippe Coiffet. Virtual Reality Technology. John Wiley & Sons, 2017.
  2. Rizzo AA, Buckwalter JG, Neumann U. Virtual reality and cognitive rehabilitation: a brief review of the future. J Head Trauma Rehabil. 1997;12:1–15.
  3. Johnson D. Virtual environments in army aviation training; Proceedings of the 8th Annual Training Technology Technical Group Meeting; Mountain View (CA), USA. 1994.
  4. . Maples-Keller JL, Bunnell BE, Kim SJ, Rothbaum BO. The Use of Virtual Reality Technology in the Treatment of Anxiety and Other Psychiatric Disorders. Harv Rev Psychiatry. 2017;25(3):103–113.
  5. Roy S, Kavitha R. Virtual Reality Treatments for Specific Phobias: A Review. Orient.J. Comp. Sci. and Technol;10(1).
  6. Rizzo A’, Shilling R. Clinical Virtual Reality tools to advance the prevention, assessment, and treatment of PTSD. Eur J Psychotraumatol. 2017;8(sup5):1414560. Published 2017 Jan 16. doi:10.1080/20008198.2017.1414560
  7. Freeman, D., Bradley, J., Antley, A., Bourke, E., DeWeever, N., Evans, N., Černis, E., Sheaves, B., Waite, F., Dunn, G., Slater, M., & Clark, D. (2016). Virtual reality in the treatment of persecutory delusions. British Journal of Psychiatry, 209, 62-67.
  8. Sanchez-Vives M, Slater M. From presence to consciousness through virtual reality. Nat Rev Neurosci 2005; 6: 332–9
  9. Slater M, Rovira A, Southern R, Swapp D, Zhang J, Campbell C, et al. Bystander responses to a violent incident in an immersive virtual environment. PLoS One 2013; 8: e52766.
  10. Bashiri A, Ghazisaeedi M, Shahmoradi L. The opportunities of virtual reality in the rehabilitation of children with attention deficit hyperactivity disorder: a literature review. Korean J Pediatr. 2017;60(11):337–343.
  11. Bioulac S, Lallemand S, Rizzo A, Philip P, Fabrigoule C, Bouvard MP. Impact of time on task on ADHD patient’s performances in a virtual classroom. Eur J Paediatr Neurol. 2012;16:514–521

The cortex and ADHD: the second project of the ENIGMA-ADHD collaboration.

After the first project on subcortical brain volumes in ADHD, published in Lancet Psychiatry in 2017 , ENIGMA-ADHD now analysed cortical data of 2246 people with a diagnosis of ADHD and 1713 people without, aged between four and 63 years old.  The data came from 37 research groups from around the world. FreeSurfer (imaging software) parcellations of thickness and surface area of 34 cortical regions were compared between cases and controls in 3 separate age groups; children, adolescents and adults.

ENIGMAADHD2JPG

Subtle differences only in the group of children were found. The childhood effects were most prominent and widespread for the surface area of the cortex. More focal changes were found for thickness of the cortex. All differences were subtle and detected only at a group level, and thus these brain images cannot be used to diagnose ADHD or guide its treatment.

These subtle differences in the brain’s cortex were not limited to people with the clinical diagnosis of ADHD: they were also present – in a less marked form – in youth with some ADHD symptoms. This second finding results from a collaboration between the ENIGMA-ADHD Working Group and the Generation-R study from Rotterdam, which has brain images on 2700 children aged 9-11 years from the general population. The researchers found more symptoms of inattention to be associated with a decrease in cortical surface area. In a third study, using the NeuroImage data from Nijmegen and Amsterdam, familial effects on those regions that showed case-control differences were investigated.  Siblings of those with ADHD showed changes to their cortical surface area that resembled their affected sibling. This suggests that familial factors such as genetics or shared environment may play a role in brain cortical characteristics.

We identified cortical differences that are consistently associated with ADHD combining data from many different research groups internationally. We find that the differences extend beyond narrowly-defined clinical diagnoses and are seen, in a less marked manner, in those with some ADHD symptoms and in unaffected siblings of people with ADHD. This finding supports the idea that the symptoms underlying ADHD may be a continuous trait in the population, which has already been reported by other behavioural and genetic studies.’ In the future, the ADHD Working Group, which is led by Martine Hoogman and Barbara Franke from the Radboudumc in Nijmegen, hopes to look at additional key features in the brain- such as the structural connections between brain areas – and to increase the representation of adults affected by ADHD, in whom limited research has been performed to date.

Link to the article: Hoogman et al., Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples

To learn more about other projects that are carried out using ENIGMA-ADHD data, please also read the paper by Yanli Zhang-James and colleagues on bioRxiv. Here, the ENIGMA-ADHD data of the first and the second project were used to do prediction modelling.  

The ADHD Working Group is one of over 50 working groups of the ENIGMA Consortium, in which international researchers pull together to understand the brain alterations associated with different disorders and the role of genetic and environmental factors in those alterations. For more information about ENIGMA-ADHD please visit our website http://enigma.usc.edu/ongoing/enigma-adhd-working-group/ or contact Martine Hoogman martine.hoogman (at) radboudumc.nlenigma_300dpi

Epigenetic signature for attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is considered a complex disorder caused by underlying genetic and environmental risk factors. To make it even more complex, environmental factors can influence the expression of genes. This is called epigenetics.

Given the large proportion of the heritability of ADHD still to be explained, there is a growing interest in the epigenetic mechanisms that modulate gene expression. microRNAs (miRNA) are small parts in the human genome that do not code for genes, but instead regulate the expression of other genes by promoting the degradation or suppressing the translation of those target genes. miRNA therefore provide a means to integrate effects of genetic and environmental risk factors.

The human genome encodes more than 2500 different miRNAs, the majority of which are expressed in the brain. miRNAs are known to be involved in the development of the central nervous system and in many neurological processes including synaptic plasticity and synaptogenesis. Given the limited accessibility of the human brain for studying epigenetic modifications, miRNA profiling in peripheral blood cells is often used as a non-invasive proxy to study transcriptional and epigenetic biosignatures, and to identify potential clinical biomarkers for psychiatric disorders.

We recently investigated the role of microRNAs in ADHD at a molecular level, by conducting the first genome-wide integrative study of microRNA and gene expression profiles in blood of individuals with ADHD and healthy controls. We identified three miRNAs (miR-26b-5p, miR-185-5p and miR-191-5p) that have different expression levels in people with ADHD, compared to those without ADHD. When we investigated downstream miRNA-mediated mechanisms underlying the disorder this provided evidence that aberrant expression profile of these three miRNA may underlie changes in the expression of genes related with myo-inositol signaling. This mediates the biological response of a large number of hormones and neurotransmitters on target cells. We also found that these miRNAs specifically targeted genes involved in neurological disease and psychological disorders.

These findings show that epigenetic modifications through microRNAs play a role in ADHD, and provide novel insights into how these miRNA-mediated mechanisms contribute to the disorder. In the future, these miRNAs may be used as peripheral biomarkers that can be easily detected from blood, as is shown in the figure.

What´s next?

The mechanism through which miRNAs modify gene expression is complex and dynamic. Therefore, future studies are required to provide deeper insights into the epigenetic mechanisms underlying ADHD, and to identify specific molecular networks that may be crucial in the development of the disorder.

Further reading

Cristina Sánchez-Mora et al. Epigenetic signature for attention-deficit/hyperactivity disorder: identification of miR-26b-5p, miR-185-5p, and miR-191-5p as potential biomarkers in peripheral blood mononuclear cells, Neuropsychopharmacology, volume 44, pages 890–897 (2019).

https://www.nature.com/articles/s41386-018-0297-0

About the author

Cristina Sánchez-Mora is postdoctoral researcher at the Psychiatry, Mental Health and Addictions group at Vall d’Hebron Institut de Recerca (VHIR). Her research is part of the CoCA consortium that investigates comorbid conditions of ADHD

ADHD and cannabis use

It is not uncommon for individuals to suffer from two or more psychiatric disorders at the same time. The appearance of these disorders frequently follows a specific order, and one disorder may predispose to others, all of which in combination contribute to the worsening of the quality of life of the individuals who suffer them. This is usually associated with more severe symptoms and worse prognosis. In addition, making a diagnosis and applying personalized treatments becomes more challenging in this context. By investigating the genetic overlap between disorders, we gain better understanding of why the disorders frequently co-occur.

In mental health, substance use disorders often appear when there is another mental condition. This is the case for attention-deficit/hyperactivity disorder (ADHD) and substance use disorder, where individuals with ADHD are more likely to use drugs during their lifetime than individuals who do not have ADHD. In particular, cannabis is the most commonly used substance among individuals with ADHD, which can also lead to the use of other drugs and to the worsening of their symptoms. ADHD is one of the most common neurodevelopmental disorders, affecting around 5% of children and 2.5% of adults, and is characterized by attention deficit, hyperactivity and impulsivity. Both ADHD and cannabis use are conditions determined partly by environmental factors but where genetic factors also play an important role.

We recently investigated the genetic overlap between ADHD and cannabis use, and found that the increased probability of using cannabis in individuals with ADHD, can be, in part, due to a common genetic background between the two conditions. We identified four genetic regions involved in increasing the risk of both ADHD and cannabis use, which could point to potential druggable targets and help to develop new treatments. In addition, we confirmed a causal link between ADHD and cannabis use, and estimated that individuals with ADHD are almost 8 times more likely to consume cannabis than those who do not have ADHD. This evidence goes in line with a temporal relationship, where the ADHD appears in childhood and the use of cannabis during adolescent or adulthood. This suggests that having ADHD increases the risk of using cannabis, and not vice versa.

This research has only been possible thanks to large international collaborations by the Psychiatric Genomics Consortium (PGC), iPSYCH, and the International Cannabis Consortium (ICC), where the genomes of around 85 000 individuals were analysed.

Overall, these results support the idea that psychiatric disorders are not independent, but have a common genetic background, and share biological pathways, which put some individuals at higher risk than others. This will help to overcome the stigma of addiction and mental disorders. In addition, the potential of using genetic information to identify individuals at higher risk will have a strong impact on prevention, early detection and treatment.

Further reading

María Soler Artigas et al. Attention-deficit/hyperactivity disorder and lifetime cannabis use: genetic overlap and causality, Molecular Psychiatry (2019) – https://www.nature.com/articles/s41380-018-0339-3

About the author

María Soler Artigas is postdoctoral researcher at the Psychiatry, Mental Health and Addictions group at Vall d’Hebron Institut de Recerca (VHIR), also part of the Biomedical Research Networking Center in Mental Health (CIBERSAM). Her research is part of the CoCA consortium that investigates comorbid conditions of ADHD.