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The missing pieces of the ADHD puzzle: inflammation, neurotrophin and cortisol?

Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder with a global prevalence rate of 5–10%. ADHD presents with symptoms such as inattention, hyperactivity and impulsivity.

A child with ADHD often has difficulty sitting still in class, is easily distracted by noises or actions of other classmates, and they are often unable to complete tests or assignments on time. Moreover, the inattention and hyperactivity may result in a slip in academic grades, in frequent conflict with peers, or in increased parent-child conflicts.

I am a child and adolescent psychiatrist and neuroscientist working with the Stress, Psychiatry and Immunology Laboratory (the team who brought you the Inspire the Mind blog), as well as the China Medical University Hospital in Taiwan. I am interested in understanding the mechanisms behind ADHD, so that we can develop treatments that are specifically targeting the relevant brain systems in ADHD.

This blog is about our recent study published in the scientific journal Brain Behavior and Immunity about the imbalance of the different systems, including hypothalamus-pituitary-adrenal (HPA) axis, inflammation and neurotrophins in ADHD. If you are interested in nutrition and mental health, please also read my previous blogs, More Fish, Better Attention? It Really Depends and Diet and Exercise for Melancholy: A Throwback to The 18th Century; and, though unrelated to this topic, I also wrote a blog on When Hip-Hop Meets Psychiatry.

First of all, let me provide a brief introduction to ADHD.

There are generally 3 subtypes of ADHD classified according to the presentations of the symptoms. The inattentive subtype is when the child mainly has problems concentrating on homework, is forgetful of personal belongings or things needed for daily activities, and often procrastinates on tasks that require concentration. The hyperactive-impulsive subtype is when the child is restless during a lecture, exhibits a large amount of energy, is unable to sit through a class, often interrupts others during conversation and games, and cuts in lines. And lastly, the combined subtype is when the child exhibits the symptoms of both inattentive and hyperactive-impulsive subtypes and usually has higher aseverity of symptoms than the other two subtypes.

ADHD also has high comorbidity with other psychiatric disorders, including anxiety, depression, and substance use disorder, meaning that they often go hand in hand. Thus, recent studies have focused on investigating the root mechanisms causing ADHD, in the hope of preventing the development of other psychiatric comorbidities that may develop during the course of ADHD.

The ‘dopamine deficit theory’, has long been proposed as a possible mechanism in ADHD. Dopamine is a type of neurotransmitter that is important to both our body and brain and will affect our mood, attention, motivation and movement.

It has been reported that people with ADHD tend to have a much higher concentration of dopamine transporters (DAT) in the brain and so dopamine is removed too quickly from brain cells. And the imbalance of dopamine results in the manifestation of inattention, hyperactivity and impulsivity symptoms in ADHD. However, the ‘dopamine deficit theory’, seems only to provide a partial explanation for ADHD.

More recent studies have pointed to the involvement of several biological systems in the mechanisms leading up to ADHD: one of them is inflammation.

Interestingly, this theory is further supported by medical observations, since children with ADHD often present with other disorders associated with chronic inflammation, including atopic dermatitis (otherwise known as eczema), allergic rhinitis (inflammation in the nose which causes symptoms like the runny nose we see with the common cold) and autoimmune diseases (diseases where your immune system mistakenly attacks the body).

Inflammation is the protective reaction caused by our body when we are trying to fight off foreign invaders such as bacteria and viruses, and to heal injuries. However, prolonged inflammation may be harmful in the long run in that it will leave our bodies in a constant state of alertness and has negative impact on our tissues and organs.

Other proposed mechanisms include the dysregulation of the HPA axis (reflecting on the levels of cortisol) and the imbalance of neurotrophins (nutrients for brain cells).

The HPA axis is responsible for our fight or flight response. For example, when we see a lion ready to attack us during our hike, our brain and body will process the information for us to make a decision on whether to fight the lion head-on with the tree branch next to our feet or to run for our lives.

Neurotrophins, on the other hand, are the nutrients that help to stimulate and control the growth of new brain cells from brain stem cells.

Cortisol, inflammation, and brain development

An additional amount of cortisol, also known as the stress hormone, will be released into our bloodstreams when we are under great stress or engage in situations that will elicit the fight or flight response.

Cortisol and inflammation have been shown to have a great impact on general growth and cognitive development in children.

Previous research showed that those children with relatively high or low levels of cortisol, when compared with children with a normal range of cortisol levels, tend to have poorer cognitive function, such as attention. Too high or too low levels of cortisol may be ‘toxic’ for our brains, especially to the areas important for cognitive function.

On the other hand, a lack of cortisol will prevent our body from absorbing the nutrients that are crucial for cognitive development. It has also been shown that too low of a cortisol level has also been positively associated with novelty-seeking behaviours, such as activities that are new and challenging for the children, and sometimes risky.

Moreover, chronic inflammation of our bodies has also been associated with inflammation of our minds, which may further affect the developing brain. There is a study showing that chronic inflammation in children has a negative impact on social cognition and facial recognition, and these are deficits, such as being unable to pick up social clues at a dinner party, or being unable to recognize familiar faces, that are commonly observed in children with ADHD.

Previous studies have usually only examined the association between ADHD and one of the three systems- HPA axis, inflammation or neurotrophins- aforementioned, but not all of them. Moreover, the results of the existing research have been mixed, where some children with ADHD show dysregulation of some of the systems, and some do not. Thus, our study investigates on the imbalance of all three systems in children with ADHD.

ADHD has lower cortisol and BDNF and higher inflammatory biomarkers

In our study, we examined 98 children all aged 6 to 18 years, diagnosed with ADHD, and 21 children, aged 6 to 18, without ADHD. We compared the cortisol levels in saliva, and blood inflammatory biomarkers (such as high sensitivity C-reactive protein, or hs-CRP) and brain-derived neurotrophic factors (BDNF), a type of neurotrophin, between the two groups. BDNF tend to help the survival of the existing brain cells and encourage the growth of new brain cells, and is important for brain development and long-term memory.

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.

In our study, we found that children with ADHD have lower salivary cortisol levels at bedtime. Moreover, we also found that children with ADHD have higher levels of inflammatory biomarkers, in this case, measured by hs-CRP, and lower levels of BDNF, than children without ADHD.

The missing pieces to the ADHD puzzle ~ inflammation, neurotrophin and cortisol?

Our study not only supports the role of inflammation in ADHD, but it also suggests that normalising stress hormones such as cortisol may offer another treatment direction for ADHD. Moreover, the lower levels of brain nutrients such as BDNF in ADHD also indicate that BDNF may be a potential biomarker in this disorder.

In sum, children with ADHD may have a broader biological dysfunction than just in the brain, and future treatment aims should focus on specific mechanisms including anti-inflammation, nourishing the brain cells, and normalising cortisol actions in ADHD.


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