In studies about treatment for children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD), it is important to use valid and reliable instruments to measure effects. A valid instrument can measure a difference in symptoms before and some time after the treatment has started. Usually questionnaires for parents and teachers are used.

In the TRACE project, currently running in the Netherlands, we are looking at the effectiveness of a dietary intervention versus care as usual, for children diagnosed with ADHD in the age group of 5-12 year old. In addition to the standard questionnaires, there is an observation instrument called the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS). This instrument was added in the TRACE project as an objective measurement for changes in behavior.

DB-DOS, ADHDThe DB-DOS was originally developed to measure disruptive behavior disorders (DBD) in preschoolers1. This way, treatment effects are not only measured in an indirect way, through information of caregivers, but also in a direct observation in the clinical setting. However, the age range of the children in the TRACE project is different from the preschoolers the DB-DOS was originally intented for. That’s why the TRACE project added several tasks to the original DB-DOS, to make sure it elicits disruptive behaviours, as well as hyperactivity and impulsivity, and to make it suitable for older children. During the current trial we try to find out if the DB-DOS is also a valid measurement for older children, aged 5-12 years.

The DB-DOS uses three different interactional contexts: parent-child context, examiner-child context and parent-examiner-child context. Children will be asked to complete different tasks. Some are rather boring, or frustrating, to see if this may elicit attention problems, hyperactivity, impulsive behaviour or disruptive behaviors. The DB-DOS contains, for example, some tasks which can evoke anger or sadness and some tasks where children get the chance to cheat. The reaction of the child is observed from behind a one-way screen. The observation lasts about 60 minutes and afterwards the observed behavior is scored by the examiner through a coding system. With more evidence-based instruments, mental health problems can be targeted more efficiently and reliably.

Our final goal is earlier interventions which prevent mental health problems in these children getting more severe and spreading through other domains such as school, work, or social contacts.

We will keep you posted about the results of the DB-DOS in the TRACE project!

REFERENCE
1 Bunte, T. L., Laschen, S., Schoemaker, K., Hessen, D. J., Van der Heijden, P. G. M., & Matthys, W. (2013). Clinical Usefulness of Observational Assessment in the Diagnosis of DBD and ADHD in Preschoolers. Journal of Clinical Child & Adolescent Psychology, 42(6), p.p. 749-761.
http://dx.doi.org/10.1080/15374416.2013.773516

 

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Recently, the idea that gastrointestinal microbiota are able to affect host behaviour is gaining momentum and it is based on studies conducted with animal models but also in humans with neurological disorders. However, the mechanisms that underlay this complex interplay between gut, brain and microbiota are not completely understood. Here we discuss recent findings on how microbial products could potentially affect the gut-brain axis.

Intestinal microbiota grow through the fermentation of undigested carbohydrates that end up in the large intestine. It was shown that absence of microbes or disruption of the microbiota, led to increased populations of impaired microglia cells in mice. Microglia cells are the primary effector cells for immune signalling to the central nervous system. The presence of a complex microbiota community, was shown to be essential for proper microglia maturation and function [1].

The main products of microbial fermentation in the gut are; acetate, propionate and butyrate, collectively known as short chain fatty acids(SCFA’s). Their beneficial role in human physiology have been well described, and recently evidence suggests that these molecules are able to cross blood brain barrier [2]. Moreover, gut microbiota have been associated with the brain barrier integrity. Mice raised in absence of bacteria are reported to have reduced brain barrier integrity. Once colonized with either a butyrate or an acetate/propionate producing bacteria, significant improvements were reported in the barrier [3]. Notably the integrity of the blood-brain barrier from the germ free mice was able to be restored through the oral administration of butyrate.

Gut_Microbes and Mental HealthSCFA’s are among the molecules having the privilege to cross the blood brain barrier and access the brain directly, their role should be studied in detail.

Recent studies also demonstrate that gut microbes regulate levels of intestinal neurotransmitters. The enteric nervous system interacts with a plethora of neurotransmitters (more than 30 have been identified so far.) Actually, the bulk of serotonin production ~90%, a neurotransmitter associated with mood and appetite is located in the gut. Specialized cells known as enterochromaffin cells are the main serotonin producers in the gut. In the absence of intestinal microbiota gastrointestinal serotonin levels are depleted. However, they can be restored by the addition of a specific spore forming consortium of intestinal bacteria. Specific bacterial metabolites have been reported to mediate this effect [4].

Other intestinal microbiota have been reported also to regulate the levels of the GABA neurotransmitter. Reduced levels of GABA have been associated with anxiety, panic disorder and depression. Bacterial GABA producers have been known to exist for years but it was not until 2016 that a gut bacteria was identified as GABA consumer [5]. For example, decreased levels of bacterial GABA producers were identified in a human cohort of depressed individuals. Studies in mice reinforce these findings. Intervention with the lactic acid bacteria Lactobacillus rhamnosus (JB-1) in healthy mice reduced anxiety related symptoms (accompanied by a reduction in the mRNA expression of GABA receptors in the Central Nervous System.) Lactic acid producing bacteria have also been reported to produce GABA in several food products such as kimchi, fermented fish and cheese [6].

Collectively, our gut microbiota encodes for ~100 times more genes than the human genome. The potential for some of these microbial genes to produce compounds able to interact with the nervous system and regulate critical pathways implicated in the gut brain axis is realistic and worth being explored.

Authors Prokopis Konstanti, MSc and Clara Belzer, PhD are working in the Department of Molecular Ecology, Laboratory of Microbiology, Wageningen University, Netherlands.

Footnotes

  1. Erny, D., et al., Host microbiota constantly control maturation and function of microglia in the CNS. Nature neuroscience, 2015. 18(7): p. 965-977.
  2. Joseph, J., et al., Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Frontiers in Neuroscience, 2017. 11(155).
  3. Braniste, V., et al., The gut microbiota influences blood-brain barrier permeability in mice. Science translational medicine, 2014. 6(263): p. 263ra158-263ra158.
  4. Yano, J.M., et al., Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell, 2015. 161(2): p. 264-276.
  5. P. Strandwitz, K.K., D. Dietrich, D. McDonald, T. Ramadhar, E. J. Stewart, R. Knight, J. Clardy, K. Lewis; , Gaba Modulating Bacteria of the Human Gut Microbiome. 2016.
  6. Dhakal, R., V.K. Bajpai, and K.-H. Baek, Production of gaba (γ – Aminobutyric acid) by microorganisms: a review. Brazilian Journal of Microbiology, 2012. 43(4): p. 1230-1241.

 

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In every classroom approximately two children are diagnosed with Attention Deficit Hyperactivity Disorder (ADHD). They struggle with attention problems and hyperactive and impulsive behavior. This has negative consequences for these children. For example, they can have difficulties learning, it puts them at risk for other psychiatric problems, and it can cause parent-child relationship problems. Therefore, children with ADHD do need some sort of treatment for optimizing the quality of their lives.

After psycho-education to the child, parents and teacher, medication is often the first choice of treatment because it is evidence-based. However, there is a growing group of parents that do not wish to medicate their child. They are concerned about the side and long-term effects. Thus, these parents seek other treatment. That is where they get stuck: which other effective treatments are available?

In order to develop new treatments, there is a growing field of research focusing on risk factors for ADHD symptoms. One of these risk factors that has been studied increasingly is nutrition. Nutrition plays a role in physical well-being, but could also play a role in psychological well-being and cognitive functioning. Consequently, dietary treatments could be an alternative treatment for children with ADHD. There is a long history of research in nutrition, but there is not enough evidence yet about the (cost-)effectiveness to implement dietary treatments in clinical health care.

Elimination DietSo far, studies examining the effectiveness of a so-called elimination diet showed the strongest effects (1). The aim of an elimination diet is to find out which products trigger ADHD symptoms. However, results of these studies are inconclusive because of several limitations. First, outcome measurements used in these studies were not objective. Second, studies suffered from a sample bias towards highly motivated and educated parents. Third, underlying mechanisms are still unknown. Fourth, long-term effects are unknown. Moreover, it is unknown if an elimination diet is more effective in reducing ADHD symptoms than a healthy diet based on the World Health Organization (WHO) guidelines (2).

We thought: can we take into account these limitations and examine the effectiveness of two dietary treatments? This resulted in the TRACE study: ‘Treatment of ADHD with Care as usual versus an Elimination diet’ (TRACE) study. This is the first study to determine the short- and long-term effectiveness and cost-effectiveness of two dietary treatments as initial addition to care as usual as a treatment trajectory for children with ADHD.

We will substantially improve upon previous studies by implementing the intervention in non-commercial mental health centers, including blinded and objective measurements, and comparing two dietary treatments with care as usual. Also, understanding the biological effects could inform clinicians to potential markers and targets for preventative or individualized treatment. For this reason, we also examine the underlying biological mechanisms (e.g. mechanisms in the gut and brain) of dietary treatments (TRACE-BIOME and TRACE-MRI studies). We collect blood, stool and saliva samples.

The TRACE study is a two arm randomized control trial: participants are randomized to either an elimination diet or a healthy diet. The comparator arm includes children who are being treated with care as usual. Currently, we included in each dietary treatment arm about half of the targeted participants (N=81 in each dietary group). In the care as usual group, we included about one third of the targeted participants (N=60).

We hope to finish inclusion around January 2020.   am really looking forward to the results and hope to share this with you in a couple of years! If you have any questions, feel free to contact us via trace@karakter.com

References:

(1) Nigg, J. T., Lewis, K., Edinger, T., & Falk, M. (2012). Meta-analysis of attention-deficit/hyperactivity disorder or attention-deficit/hyperactivity disorder symptoms,         restriction diet, and synthetic food color additives. Journal of the American Academy of Child & Adolescent Psychiatry, 51(1), 86-97. https://doi.org/10.1016/j.jaac.2011.    10.015 . Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321798/

(2) Izquierdo Pulido, M. L., Ríos Hernández, A., Farran, A., & Alda, J. Á. (2015). The role of  diet and physical activity in children and adolescents with ADHD. Recent Advances in Pharmaceutical Sciences V, 2015, Research Signpost. Chapter 4, p. 51-64.  Link: http://diposit.ub.edu/dspace/bitstream/2445/67543/1/T_1444299316Munozv%204.pdf

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As described in my previous blog post (Nutrition, Gut Microbiota and Behavior, 4th of April), I will investigate the association between nutrition, gut microbiota and behavior. One of the main focuses within my research is to investigate the association between early life nutrition, gut microbiota development and inhibitory control within toddlers and pubertal children.

The first 1000 days of life (starting from conception) were shown to be a critical window for child development. In this phase, nutritional intake of the infant can stimulate the body and brain towards a healthy development, also known as nutritional programming1. Hence, early life nutrition, i.e. breastfeeding, can exert a major influence on infant development and thus future behavior. Breast milk contains many beneficial components such as sugars, immune factors and bacteria which are difficult to process in bottle formulas. Thus, exclusive breastfeeding is recommended until six months of age in the Netherlands.breastfeeding and early nutrition

Several studies have looked at the association between infant breastfeeding duration and future executive functioning. (Executive functions are cognitive processes in the brain that contribute to regulating thoughts and behaviors. Executive functions can be roughly divided into three core functions, namely: inhibitory control, working memory, and cognitive flexibility. Inhibitory control, which can be interpreted as the opposite of impulsivity, is necessary to suppress impulses.) Two studies found positive associations with breastfeeding duration and executive functioning in childhood2,3. However, some studies have found no associations between infant breastfeeding and future executive functioning 4,5. These studies have examined general executive functioning and mainly focussed on attention, and not inhibitory control. Furthermore, different ages and populations were examined which makes it difficult to draw firm conclusions about the association between breastfeeding duration and future executive functioning. Thus, it is of particular interest whether inhibitory control is association with breastfeeding duration.

In addition, previous literature has focused mostly on duration of breastfeeding, while the composition of breast milk is also of major importance. Breastmilk contains many nutrients that are finely attuned to the needs of the infant. It contains biologically active compounds which have diverse roles, among others guiding the development of the infant’s intestinal microbiota6. Breast milk also contains specific sugars, also known as human oligosaccharides, which have been shown to influence the types of microbiota colonizing in the infant gut7. This may potentially be associated with impulsive behaviour8. Thus, in addition to examining breastfeeding duration in relation to inhibitory control, I will also examine the breastmilk composition in relation to inhibitory control.

  1. Agosti, M., Tandoi, F., Morlacchi, L. & Bossi, A. Nutritional and metabolic programming during the first thousand days of life. La Pediatr. Medica e Chir. 39, (2017).
  2. Hayatbakhsh, M. R., O’Callaghan, M. J., Bor, W., Williams, G. M. & Najman, J. M. Association of Breastfeeding and Adolescents’ Psychopathology: A Large Prospective Study. Breastfeed. Med. 7, 480–486 (2012).
  3. Julvez, J. et al. Attention behaviour and hyperactivity at age 4 and duration of breast-feeding. Acta Paediatr. 96, 842–847 (2007).
  4. Belfort, M. B. et al. Infant Breastfeeding Duration and Mid-Childhood Executive Function, Behavior, and Social-Emotional Development. J. Dev. Behav. Pediatr. 37, 43–52 (2016).
  5. Groen-Blokhuis, M. M. et al. A prospective study of the effects of breastfeeding and FADS2 polymorphisms on cognition and hyperactivity/attention problems. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 162, 457–465 (2013).
  6. Andreas, N. J., Kampmann, B. & Mehring Le-Doare, K. Human breast milk: A review on its composition and bioactivity. Early Hum. Dev. 91, 629–635 (2015).
  7. Lewis, Z. T. et al. Maternal fucosyltransferase 2 status affects the gut bifidobacterial communities of breastfed infants. Microbiome 3, 13 (2015).

 

 

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