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ADHD —  Lost in tempo in cortisol rhythm and lost in balance in inflammation

I am a child and adolescent psychiatrist and neuroscientist working with the Stress, Psychiatry, and Immunology Laboratory (the team that bring you Inspire the Mind ), as well as the Mind-Body Interface Laboratory (MBI-Lab) at China Medical University Hospital in Taiwan. My research interests include nutritional psychiatric research in children and adolescents with a special focus on attention deficit hyperactivity disorder (ADHD) and omega-3 fatty acids. I have previously written about ADHD for InSPIre the mind, “More Fish, Better Attention? It Really Depends”, and “The missing pieces of the ADHD Puzzle: inflammation, neurotrophin, and cortisol?”. In this latest piece, I will discuss our recently published meta-analysis that looked at cortisol levels and inflammatory biomarkers in children with ADHD. You can read the full paper in Translational Psychiatry.

Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder with a global prevalence rate of 5–10%. Children with ADHD often present with symptoms such as inattention, hyperactivity, and impulsivity. They often have difficulty sitting still in class, are easily distracted by noises or actions of other classmates, and are often unable to complete tests or homework assignments on time. This inattention and hyperactivity can sometimes result in a slip in academic grades, in frequent fights with peers, or in constant quarrels with their parents. All of which may lead the individual to have increased feelings of stress, anxiety, ill-health and helplessness, and decreased communication with their parents.

ADHD has been linked with an imbalance of several biological systems, including the hypothalamus-pituitary-adrenal (HPA) axis and inflammation, however, what the science tells us so far has been inconsistent. Dysregulation of the HPA axis (reflected in the levels of cortisol) has been suggested to play a role in ADHD. The HPA axis is important for our survival in that it helps to decide whether we should fight or flight in the context of danger.

For example, when we see a bear ready to attack us during a hike, our brain and body will process the information for us swiftly and we make a decision in the moment whether to fight the bear head-on with the tree branch next to our feet or to run for our lives! Cortisol, also known as the stress hormone, will be released into our bloodstream when we are under great stress such as this, when we engage in situations that will elicit the fight or flight response. Interestingly, an inadequate amount of cortisol has been associated with poor cognitive development in children, and too little cortisol has also been associated with novelty-seeking behaviors (activities that may involve risk-taking in search for new experiences), commonly seen in children with ADHD.

Inflammation, on the other hand, is a result of the protective reaction of our body when we are trying to fight off foreign invaders, such as bacteria and viruses, and to heal injuries. However, prolonged inflammation or chronic inflammation may be harmful, leaving our bodies in a constant state of alertness. This has a negative impact on our tissues and organs, including the developing brain and cognitive function.

The state of inflammation in our body can be indicated by inflammatory biomarkers. Biomarkers are the biological molecules found in blood, other body fluids, or tissues that are signs s of a normal or abnormal process, or of a condition or disease, and can be used to see how well the body responds to a treatment for a disease or condition. For example, an increase or decrease in the levels of inflammation biomarkers (such as C-reactive protein (CRP) or interleukin-6 (Il-6)) may be used to tell us if our body has an imbalance in the inflammation process. Children with ADHD have also been suggested to have more comorbidities with chronic inflammatory diseases, such as allergic rhinitis and atopic dermatitis.

The results of the existing research on the levels of cortisol and inflammatory biomarkers have been mixed where some children with ADHD have lower levels while others have no difference in levels than typically developing children.

Our recently published meta-analysis examined the levels of cortisol (upon awakening, noon, 6 pm, and before bedtime) and inflammatory biomarkers (Interleukin-1β (IL-1β), IL-6, IL-10 and tumor necrosis factor-alpha (TNF-α)) across 19 studies in 916 children with ADHD and 947 typically developing children. In addition, we also looked at the cortisol levels collected at different time-points throughout the day to see if changes during the day have an effect on the cortisol levels in these children. In fact, cortisol levels tend to follow a pattern across the day, reaching its peak within an hour after waking and declining thereafter, until reaching the lowest point at approximately midnight.

Interestingly, we found that children with ADHD, when compared to typically developing children, have lower baseline cortisol levels (from both salivary and blood samples). This may further suggest the children with ADHD have an off-balanced HPA-axis to fight against stress. Children with ADHD also have lower morning cortisol levels, especially awakening cortisol levels, but not lower afternoon cortisol levels, than typically developing children.

This is exciting news, since, in the near future, a simple morning spit of saliva may perhaps be able to tell the difference between a child with ADHD and a typically developing child.

The finding of lower morning cortisol levels in children with ADHD suggests that there may be an altered diurnal rhythm of cortisol levels in children with ADHD, where children with ADHD require a longer time for their cortisol to peak in the morning. This may help explain why children with ADHD may feel more tired in the morning and have a harder time waking for activities like school.

We also found that children with ADHD have lower levels of inflammatory biomarkers, in this case, measured by TNF-α, than children without ADHD. This tells us that children with ADHD may have an imbalanced inflammation system.

Another interesting finding is that differences in the DNA sequences of the TNF-α gene have also been associated with attention measures in children with ADHD. A gene is the basic physical and functional unit of our heredity (the sum of all biological processes by which particular characteristics are transmitted from parents to their offspring) and is made up of DNA. Investigating TNF-α, as well as their genomic sequences should be an important consideration in future ADHD studies to clarify its role in ADHD.

Well, it seems that children with ADHD have an altered diurnal cortisol rhythm presented with a lower morning cortisol level measured in the salivary sample and an atypical manifestation of inflammation biomarker levels from our current research.

However, more research is needed to investigate how to recover the altered diurnal rhythm of cortisol levels and restore the balance to the inflammation system in children with ADHD, in order to improve their clinical symptoms and help them keep the balance in their lives.

I look forward to sharing more with you on the research findings on the association between the changes in cortisol levels and inflammatory biomarkers and ADHD treatments in the near future!


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