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Attention-Deficit/Hyperactivity Disorder (ADHD), characterized by a persistent pattern of inattention and/or hyperactivity/impulsivity, is one of the most commonly diagnosed behavioral disorders in childhood. Its worldwide-pooled prevalence is estimated at about 5%; impairing symptoms of ADHD may persist in adulthood in as many as 65% of cases. Because of inattention, hyperactivity, and/or impulsivity and their frequent co-occurrence with co-morbid conditions, individuals with ADHD are at risk for academic and work failure, low self-esteem, family conflict, poor peer relationships, and involvement with the criminal justice system. Therefore, ADHD imposes a huge burden on the society.

Despite being one of the most studied disorders in child psychiatry, the causes of ADHD have not yet been fully elucidated, likely due to its heterogeneity (i.e. different risk factors in different subgroups of patients).

The present project aimed to elucidate the role of iron deficiency as a possible risk factor for ADHD, at least in a subgroup of individuals with the disorder. Iron is an essential trace metal, which plays a central role in a multitude of biological processes, including many essential brain functions. It has been showed that iron deficiency, the most common single nutrient disorder in the world, is associated with long lasting effects on the brain which may underlie low intelligence scores and decreased learning performance. Research conducted prior to this project addressed the role of iron deficiency as a possible contributing factor for ADHD. Such studies used a measure of peripheral (i.e. in the body rather than in the brain) iron by means of serum ferritin levels and provided mixed findings. Indeed, because the blood-brain barrier prevents the direct entry of peripheral iron in the brain, how well peripheral iron indices correlate with central (i.e. brain) iron content is still unclear. We reasoned that, since it is brain iron that is expected to impact neuronal functions underlying ADHD symptoms, the assessment of brain iron would provide more meaningful insight than the measure of peripheral iron. Therefore, our project was carried out to better understand possible alterations in brain iron, as well as its effects, in children with ADHD.

The first part of the project, conducted at the Institute for Pediatric Neuroscience, New York Child Study Center, New York University, NY, USA, aimed to assess peripheral and brain iron levels in a sample of 25 children with ADHD (aged 8-12 years) and in a age and gender-matched comparison group. Brain iron was estimated with a novel technique (named multiple field correlation) developed by a group of engineers and radiologists formerly at the New York University. In this sample, it was found that children with ADHD presented with significantly lower estimated iron in some brain regions (caudate nucleus, globus pallidus) compared to children with typical development. Of note, serum ferritin levels did not differ in the two groups. These results carry important consequence from the scientific and public health standpoint. They suggest that further research on iron in ADHD should focus on brain iron, rather than on serum ferritin levels. If replicated, these results also provide a rationale for future studies assessing early interventions of iron supplementation in infancy (or during pregnancy) as a way to prevent ADHD, at least in a subgroup of children who may present later on with this disorder. Such studies may provide insight on the causal role of brain iron deficiency in ADHD, that we could not test in our study given its correlational design.

The second part of the project was carried out at the Child Neuropsychiatry Unit, Department of Life Sciences and Reproduction, Verona University, Verona, Italy. Overall, this study aimed to assess the possible relation between low brain iron levels and alterations in brain functioning not only during the day, but also during night sleep, in children with ADHD. Indeed, it has been reported that a poor quality of sleep may impact cognitive functions. Therefore, we were particularly interested in assessing a possible correlation between low brain iron levels and sleep alterations. More specifically, the aim of the study was to evaluate the relationship between brain iron levels and parameters of the electroencephalogram (EEG) and somatosensory evoked potentials (to assess the correlation between low brain iron levels and alterations in central and peripheral nervous system functioning), as well as of the polysomnography (to gain insight on possible correlation between low brain iron and alterations in sleep). We analysed a sample of 20 children with ADHD and sleep disorders. Whereas we did not find any significant correlation between brain iron levels and parameters from the EEG and somatosensory evoked potentials, we did find a significant correlation between brain iron levels and number of periodic movements in sleep. Since periodic limb movements in sleep fragment sleep architecture, it is possible that brain iron deficiency lead to a disruption of sleep, which contributes to cognitive deficits during the daytime, thud aggravating ADHD symptoms. However, the correlational nature of our study suggests but cannot prove the causal role of iron deficiency in contributing to sleep alterations. Interestingly, once again we found that peripheral iron (measured by serum ferritin levels) was not correlated with any assessed parameter from the EEG, polysomnography or evoked potentials. The results of the study carried out at Verona University support further studies aimed at assessing the effects of early iron supplementation as a way to improve not only daytime ADHD symptoms, but also the quality of sleep, which in turns may impact on daytime functioning.

Overall, the results of out study suggest that brain iron deficiency may be involved in ADHD, at least in a subsample of cases, that we estimate at about 15%. This subsample of children with ADHD may benefit from early iron supplementation as a strategy to improve their symptoms. Considering the prevalence of ADHD (about 5%), 15% of the entire population of children with ADHD translates to a significant number of children that may benefit from iron supplementation worldwide.

For further information, please contact: Dr. Samuele Cortese,