Biomarker Research in ADHD: the Impact of Nutrition (BRAIN). An Open-label Trial to Investigate the Mechanisms Underlying the Effects of a Few-foods Diet on ADHD Symptoms in Children
Overview
- Phase
- N/A
- Intervention
- Not specified
- Conditions
- Attention Deficit-Hyperactivity Disorder
- Sponsor
- Wageningen University
- Enrollment
- 100
- Locations
- 1
- Primary Endpoint
- Change in ADHD symptom scores
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
Attention deficit hyperactivity disorder (ADHD) is the most common childhood behavioural disorder, causing significant impediment to a child's development. The exact aetiology of ADHD is still unknown. It is a complex disorder with numerous contributing (epi)genetic and environmental factors. Currently, treatment predominantly consists of behavioural and pharmacological therapy. However, medication use is associated with several side effects and concerns about long-term effects and efficacy exist. Therefore, there is considerable interest in the development of alternative treatment options.
Double-blind research investigating the effect of a few-foods diet (FFD) has demonstrated large improvements in ADHD symptoms. However, following an FFD requires great effort of both the child and parents. To make this treatment easier or potentially obsolete, it is important to understand how and in which children an FFD affects ADHD symptoms.
The investigators hypothesise that an FFD affects brain function and behaviour, including ADHD symptoms, via the complex network of communication between the microbiota, gut and brain, i.e. the MGB axis. The aim of this study is to identify potential mechanism(s) underlying the impact of an FFD on ADHD symptoms and to identify biomarkers that predict the response to the FFD.
100 boys with ADHD will follow the FFD for 5 weeks. After inclusion, all participants will start with a baseline period, during which they will maintain their regular diet. The baseline period ends at the end of week 2. Thereafter, participants will follow a 5-week FFD, preceded by a 1-week transition period. The FFD period ends at the end of week 8.
At the end of the baseline period (i.e. at the end of week 2) and at the end of the FFD (i.e. at the end of week 8), fMRI scans will be made, blood and buccal saliva will be collected, and stool and urine will be handed in. Children will do computer tasks and parents will complete questionnaires to monitor ADHD and physical complaints. All samples will be analysed by researchers blinded to behavioural responses to the FFD. To assess the impact of the FFD on brain function and the MGB axis, associations between ADHD behavioural changes and changes in other primary and secondary study outcomes will be analysed.
This study may lead to the identification of biomarkers that can predict the response to an FFD. Understanding which changes - induced by an FFD - lead to improvements in ADHD symptoms may provide new avenues for developing treatments. Ultimately, the findings may enable personalised intervention strategies based on an individuals' configuration of the MGB axis.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Meeting DSM-IV ADHD criteria
- •Aged 8 up to and including 10 years
- •Right-handed
- •Available to visit Wageningen University for 4 sessions (i.e. intake, screening, T1 and T2), of which 3 sessions including the child (screening, T1, T2)
- •Upon study start, fully understanding and agreeing to the study objectives and having dated and signed an informed consent to participate in the study, including permission that material will be used or archived for (epi)genetic testing
- •Willing to be informed about chance-findings that may have implications for the health of the child or his family, and approving of reporting this to the child's medical specialist or family's general physician.
- •If the child uses "over the counter" medication, e.g. laxatives, melatonin for sleeping problems or hay fever medication, parents are asked to share the information leaflet, and if necessary participants are asked to change to alternatives that are free of additives that may affect ADHD, e.g. laxatives free of artificial sweeteners, sugar and cacao.
Exclusion Criteria
- •Diagnosis Autism Spectrum Disorder
- •Diagnosis Developmental Coordination Disorder
- •Premature birth (\< 36 weeks) and/or oxygen deprivation during birth
- •Diagnosed chronic gastrointestinal disorder, i.e. inflammatory bowel disease, irritable bowel syndrome, celiac disease, non-celiac gluten-intolerance (gluten-sensitivity) or lactose-intolerance
- •Auto-immune disorder (e.g. diabetes mellitus type 1)
- •Vegetarian/vegan
- •Diagnosis dyslexia and/or dyscalculia
- •Following behavioural therapy
- •Use of ADHD medication
- •Use of systemic antibiotics, antifungals, antivirals or antiparasitics in the past six months
Outcomes
Primary Outcomes
Change in ADHD symptom scores
Time Frame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
ADHD symptoms will be scored using the 18-item ADHD rating scale, which is based on the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and consists of 9 items that assess inattention and 9 items that focus on hyperactivity and impulsivity.
Change in peripheral blood metabolite concentrations
Time Frame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
Global metabolite profiles will be examined in plasma (or alternatively serum) obtained from whole blood using mass-spectrometry profiling. Phenylalanine and tyrosine plasma levels represent primary outcomes.
Change in functional composition of the gut microbiota
Time Frame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
Metagenome profiling will be performed on stool samples, leveraging Illumina next-generation sequencing technology. Sequence read data will be used for abundance profiling of microbiota genes that encode enzymes directly involved in the production or degradation of the dopamine and noradrenaline precursors phenylalanine and tyrosine.
Change in neural activation patterns during execution of tasks
Time Frame: Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8)
Using fMRI, blood oxygen-level-dependent (BOLD) signal changes will be measured whilst performing cognitive tasks that assess inhibitory control and selective attention, i.e. a stop-signal task (response inhibition) and a Flanker task (response conflict and associated error monitoring). fMRI BOLD responses will be assessed between variable task-elements and performance. Region of interest (ROI; anatomically defined regions in the brain) analyses of the BOLD responses will be performed.
Secondary Outcomes
- Change in peripheral blood cell gene expression profiles(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in physical complaints(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in a panel of peripheral blood protein biomarkers related to immune, metabolic and neurological status(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in ADHD symptoms(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in whole brain neural activation patterns during the execution of tasks(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in DNA methylation profiles(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in executive function(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in stool frequency(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in stool type(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in metabolite profiles(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- DNA genotype(Before the FFD diet intervention (i.e. at the end of week 2))
- Change in whole brain functional connectivity at rest(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in taxonomic and functional composition of the gut microbiota(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in oppositional defiant disorder symptoms(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))
- Change in social behavioural problems(Before and at the end of the FFD intervention (i.e. at the end of week 2 and at the end of week 8))