“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.

Who is the average patient with ADHD?

Is there an ‘average ADHD brain’? Our research group (from the Radboudumc in Nijmegen) shows that the average patient with ADHD does not exist biologically. These findings were recently published in the journal. Psychological Medicine.

Most biological psychiatry research heavily relies on so-called case-control comparisons. In this approach a group of patients with for instance ADHD is compared against a group of healthy individuals on a number of biological variables. If significant group effects are observed those are related to for instance the diagnosis ADHD. This often results in statements such as individuals with ADHD show differences in certain brain structures. While our results are in line with those earlier detected group effects, we clearly show that a simple comparison of these effects disguises individual differences between patients with the same mental disorder.

Modelling individual brains

In order to show this, we developed a technique called ‘normative modelling’ which allows us to map the brain of each individual patient against typical development. In this way we can see that individual differences in brain structure across individuals with ADHD are far greater than previously anticipated. In future, we hope that this approach provides important insights and sound evidence for an individualized approach to mental healthcare for ADHD and other mental disorders.

Individual differences in ADHD

When we studied the brain scans of individual patients, the differences between those were substantial. Only a few identical abnormalities in the brain occurred in more than two percent of patients. Marquand: “The brains of individuals with ADHD deviate so much from the average that the average has little to say about what might be occurring in the brain of an individual.”

Personalized diagnosis of ADHD

The research shows that almost every patient with ADHD has her or his own biological profile. The current method of making a diagnosis of psychiatric disorders based on symptoms is therefore not sufficient, the authors say: “Variation between patients is reflected in the brain, but despite this enormous variation all these people get the same diagnosis. Thus, we cannot achieve a better understanding of the biology behind ADHD by studying the average patient. We need to understand for each individual what the causes of a disorder may be. Insights based on research at group level say little about the individual patient.”

Re-conceptualize mental disorders

The researchers want to make a fingerprint of individual brains on the basis of differences in relation to the healthy range. Wolfers: “Psychiatrists and psychologists know very well that each patient is an individual with her or his own tale, history and biology. Nevertheless, we use diagnostic models that largely ignore these differences. Here, we raise this issue by showing that the average patient has limited informative value and by including biological, symptomatic and demographic information into our models. In future we hope that this kinds of models will help us to re-conceptualize mental disorders such as ADHD.”

Further reading

Wolfers, T., Beckmann, C.F., Hoogman, M., Buitelaar, J.K., Franke, B., Marquand, A.F. (2019). Individual differences v. the average patient: mapping the heterogeneity in ADHD using normative models. Psychological Medicine, https://doi.org/10.1017/S0033291719000084 .

This blog was written by Thomas Wolfers and Andre Marquand from the Radboudumc and Donders Institute for Brain, Cognition and Behaviour in Nijmegen, The Netherlands. On 15 March 2019 Thomas Wolfers will defend his doctoral thesis entitled ‘Towards precision medicine in psychiatry’ at the Radboud university in Nijmegen. You can find his thesis at http://www.thomaswolfers.com