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July 4, 2021
Our genes are very important for the development of mental disorders-including ADHD, where genetic factors capture up to 75% of the risk. Until now, the search for these genes had yet to deliver clear results. In the 1990s, many of us were searching for genes that increased the risk for ADHD because we know from twin studies that ADHD had a robust genetic component. Because I realized that solving this problem required many DNA samples from people with and without ADHD, I created the ADHD Molecular Genetics Network, funded by the US NIMH. We later joined forces with the Psychiatric Genomics Consortium (PTC) and the Danish psych group, which had access to many samples.
The result is a study of over 20,000 people with ADHD and 35,000 who do not suffer from it - finding twelve locations (loci) where people with a particular genetic variant have an increased risk of ADHD compared to those who do not have the variant. The results of the study have just been published in the scientific journal Nature Genetics, https://www.nature.com/articles/s41588-018-0269-7.
These genetic discoveries provide new insights into the biology behind developing ADHD. For example, some genes have significance for how brain cells communicate with each other, while others are important for cognitive functions such as language and learning.
Our study used the genome-wide association study (GWAS)methodology because it allowed us to discover genetic loci anywhere on the genome. The method assays DNA variants throughout the genome and determines which variants are more common among ADHDvs. control participants. It also allowed for the discovery of loci having very small effects. That feature was essential because prior work suggested that, except for very rare cases, ADHD risk loci would individually have small effects.
The main findings are:
A) we found 12 loci on the genome that we can be certain harbor DNA risk variants for ADHD. None of these loci were traditional candidate genes' for ADHD, i.e., genes involved in regulating neurotransmission systems that are affected by ADHD medications. Instead, these genes seem to be involved in the development of brain circuits.
B) we found a significant polygenic etiology in our data, which means that there must be many loci(perhaps thousands) having variants that increase the risk for ADHD. We will need to collect a much larger sample to find out which specific loci are involved;
We also compared the new results with those from a genetic study of continuous measures of ADHD symptoms in the general population. We found that the same genetic variants that give rise to an ADHD diagnosis also affect inattention and impulsivity in the general population. This supports prior clinical research suggesting that, like hypertension and hypercholesteremia, ADHD is a continuous trait in the population. These genetic data now show that the genetic susceptibility to ADHD is also a quantitative trait comprised of many, perhaps thousands, of DNA variants
The study also examined the genetic overlap with other disorders and traits in analyses that ask the questions: Do genetic risk variants for ADHD increase or decrease the likelihood a person will express other traits and disorders. These analyses found a strong negative genetic correlation between ADHD and education. This tells us that many of the genetic variants which increase the risk for ADHD also make it more likely that a person will perform poorly in educational settings. The study also found a positive correlation between ADHD and obesity, increased BMI, and type-2 diabetes, which is to say that variants that increase the risk of ADHD also increase the risk of overweight and type-2 diabetes in the population. This work has laid the foundation for future work that will clarify how genetic risks combine with environmental risks to cause ADHD. When the pieces of that puzzle come together, researchers will be able to improve the diagnosis and treatment of ADHD.
Executive function impairment is a key feature of ADHD, with its severity linked to the intensity of ADHD symptoms. Executive function involves managing complex cognitive tasks for organized behavior and includes three main areas: inhibitory control (suppressing impulsive actions), working memory (holding information briefly), and cognitive flexibility (switching between different mental tasks). Improving executive functions is a critical objective in the treatment of ADHD.
Amphetamines and methylphenidate are commonly used to treat ADHD, but can cause side effects like reduced appetite, sleep problems, nausea, and headaches. Long-term use may also lead to stunted growth and cardiovascular issues. This encourages the search for non-invasive methods to enhance executive function in children with ADHD.
Neurological techniques like neurofeedback and transcranial stimulation are increasingly used to treat children with neurodevelopmental disorders. Neurofeedback is the most adopted method; it is noninvasive and aims to improve brain function by providing real-time feedback on brainwave activity so participants can self-regulate targeted brain regions.
The systematic search and meta-analysis examined children and adolescents aged 6–18 with ADHD. It included randomized and non-randomized controlled trials, as well as quasi-experimental studies that reported statistical data such as participant numbers, means, and standard deviations. Studies were required to use validated measures of executive function, including neurocognitive tasks or questionnaires. They also had to have control groups.
A meta-analysis of ten studies (539 participants) found a small-to-medium improvement in inhibitory control after neurofeedback training, with no publication bias and minimal study heterogeneity*. Long-term treatment (over 21 hours) showed benefits, while short-term treatment did not. However, publication bias was present in the long-term treatment studies and was not addressed.
A meta-analysis of seven studies with 370 children and adolescents found a small-to-medium improvement in working memory after neurofeedback, with no publication bias overall but high heterogeneity. A dose-response effect was observed: treatments over 21 hours showed benefits, while shorter ones did not. However, publication bias was present in the long-term treatment studies and was not addressed.
The study team also looked at sustained effects six months to a year after conclusion of training. Meta-analysis of two studies totaling 131 participants found a sustained small-to-medium improvement in inhibitory control, with negligible heterogeneity. Meta-analysis of three studies combining 182 participants found a sustained medium improvement in working memory, with moderate heterogeneity and no sign of publication bias.
The team concluded, “NFT is an effective intervention for improving executive function in children with ADHD, specifically inhibitory control and working memory. This approach demonstrates a more pronounced impact on working memory when extended beyond 1000 min [sic], with inhibitory control following closely behind. Furthermore, the evidence suggests that NFT may have sustained effects on both working memory and inhibitory control. Given the relatively small number of studies assessing long-term effects and the potential for publication bias, further research is necessary to confirm these effects.”
Moreover, because 1) RCTs are the gold standard, and the meta-analyses combined RCTs with non-RCTs, and 2) data from neurocognitive tasks was combined with data from more subjective and less accurate questionnaires, these meta-analysis results should be interpreted with further caution.
*Heterogeneity refers to the rate of variation between individual study outcomes. High heterogeneity means that there was substantial variation in the results. When a meta-anaylysis has high heterogeneity, it suggests that the studies differ significantly in their populations, methods, interventions, or outcomes, making the combined result much less reliable.
Many news outlets have reported an increase – or surge – in attention-deficit/hyperactivity disorder, or ADHD, diagnoses in both children and adults. At the same time, health care providers, teachers and school systems have reported an uptick in requests for ADHD assessments.
These reports have led some experts and parents to wonder whether ADHD is being overdiagnosed and overtreated.
As researchers who have spent our careers studying neurodevelopmental disorders like ADHD, we are concerned that fears about widespread overdiagnosis are misplaced, perhaps based on a fundamental misunderstanding of the condition.
Discussions about overdiagnosis of ADHD imply that you either have it or you don’t.
However, when epidemiologists ask people in the general population about their symptoms of ADHD, some have a few symptoms, some have a moderate level, and a few have lots of symptoms. But there is no clear dividing line between those who are diagnosed with ADHD and those who are not, since ADHD – much like blood pressure – occurs on a spectrum.
Treating mild ADHD is similar to treating mild high blood pressure – it depends on the situation. Care can be helpful when a doctor considers the details of a person’s daily life and how much the symptoms are affecting them.
Not only can ADHD symptoms be very different from person to person, but research shows that ADHD symptoms can change within an individual. For example, symptoms become more severe when the challenges of life increase.
ADHD symptoms fluctuate depending on many factors, including whether the person is at school or home, whether they have had enough sleep, if they are under a great deal of stress or if they are taking medications or other substances. Someone who has mild ADHD may not experience many symptoms while they are on vacation and well rested, for example, but they may have impairing symptoms if they have a demanding job or school schedule and have not gotten enough sleep. These people may need treatment for ADHD in certain situations but may do just fine without treatment in other situations.
This is similar to what is seen in conditions like high blood pressure, which can change from day to day or from month to month, depending on a person’s diet, stress level and many other factors.
ADHD symptoms start in early childhood and typically are at their worst in mid-to late childhood. Thus, the average age of diagnosis is between 9 and 12 years old. This age is also the time when children are transitioning from elementary school to middle school and may also be experiencing changes in their environment that make their symptoms worse.
Classes can be more challenging beginning around fifth grade than in earlier grades. In addition, the transition to middle school typically means that children move from having all their subjects taught by one teacher in a single classroom to having to change classrooms with a different teacher for each class. These changes can exacerbate symptoms that were previously well-controlled. Symptoms can also wax and wane throughout life.
Psychiatric problems that often co-occur with ADHD, such as anxiety or depression, can worsen ADHD symptoms that are already present. These conditions can also mimic ADHD symptoms, making it difficult to know which to treat. High levels of stress leading to poorer sleep, and increased demands at work or school, can also exacerbate or cause ADHD-like symptoms.
Finally, the use of some substances, such as marijuana or sedatives, can worsen, or even cause, ADHD symptoms. In addition to making symptoms worse in someone who already has an ADHD diagnosis, these factors can also push someone who has mild symptoms into full-blown ADHD, at least for a short time.
The reverse is also true: Symptoms of ADHD can be minimized or reversed in people who do not meet full diagnostic criteria once the external cause is removed.
Clinicians diagnose ADHD based on symptoms of inattention, hyperactivity and impulsivity. To make an ADHD diagnosis in children, six or more symptoms in at least one of these three categories must be present. For adults, five or more symptoms are required, but they must begin in childhood. For all ages, the symptoms must cause serious problems in at least two areas of life, such as home, school or work.
Current estimates show that the strict prevalence of ADHD is about 5% in children. In young adults, the figure drops to 3%, and it is less than 1% after age 60. Researchers use the term “strict prevalence” to mean the percentage of people who meet all of the criteria for ADHD based on epidemiological studies. It is an important number because it provides clinicians and scientists with an estimate on how many people are expected to have ADHD in a given group of people.
In contrast, the “diagnosed prevalence” is the percentage of people who have been diagnosed with ADHD based on real-world assessments by health care professionals. The diagnosed prevalence in the U.S. and Canada ranges from 7.5% to 11.1% in children under age 18. These rates are quite a bit higher than the strict prevalence of 5%.
Some researchers claim that the difference between the diagnosed prevalence and the strict prevalence means that ADHD is overdiagnosed.
We disagree. In clinical practice, the diagnostic rules allow a patient to be diagnosed with ADHD if they have most of the symptoms that cause distress, impairment or both, even when they don’t meet the full criteria. And much evidence shows that increases in the diagnostic prevalence can be attributed to diagnosing milder cases that may have been missed previously. The validity of these mild diagnoses is well-documented.
Consider children who have five inattentive symptoms and five hyperactive-impulsive symptoms. These children would not meet strict diagnostic criteria for ADHD even though they clearly have a lot of ADHD symptoms. But in clinical practice, these children would be diagnosed with ADHD if they had marked distress, disability or both because of their symptoms – in other words, if the symptoms were interfering substantially with their everyday lives.
So it makes sense that the diagnosed prevalence of ADHD is substantially higher than the strict prevalence.
People who are concerned about overdiagnosis commonly worry that people are taking medications they don’t need or that they are diverting resources away from those who need it more. Other concerns are that people may experience side effects from the medications, or that they may be stigmatized by a diagnosis.
Those concerns are important. However, there is strong evidence that underdiagnosis and undertreatment of ADHD lead to serious negative outcomes in school, work, mental health and quality of life.
In other words, the risks of not treating ADHD are well-established. In contrast, the potential harms of overdiagnosis remain largely unproven.
It is important to consider how to manage the growing number of milder cases, however. Research suggests that children and adults with less severe ADHD symptoms may benefit less from medication than those with more severe symptoms.
This raises an important question: How much benefit is enough to justify treatment? These are decisions best made in conversations between clinicians, patients and caregivers.
Because ADHD symptoms can shift with age, stress, environment and other life circumstances, treatment needs to be flexible. For some, simple adjustments like classroom seating changes, better sleep or reduced stress may be enough. For others, medication, behavior therapy, or a combination of these interventions may be necessary. The key is a personalized approach that adapts as patients’ needs evolve over time.
Executive function impairment is a key feature of ADHD, with its severity linked to the intensity of ADHD symptoms. Executive function involves managing complex cognitive tasks for organized behavior and includes three main areas: inhibitory control (suppressing impulsive actions), working memory (holding information briefly), and cognitive flexibility (switching between different mental tasks). Improving executive functions is a critical objective in the management of ADHD.
Recent studies show that exercise interventions can enhance executive function in individuals with ADHD. Unlike traditional medications, which are costly and may cause side effects such as headaches, nausea, or growth issues, exercise can be incorporated into daily routines of children and adolescents without negative reactions.
Some studies report that aerobic exercise does not significantly improve executive function. However, most past reviews of aerobic exercise effects on executive function have focused on people without ADHD, with few examining interventions for children or adolescents with ADHD.
The Study:
A Chinese and South Korean study team conducted a systematic search of the peer-reviewed published literature to perform meta-analyses on randomized controlled trials (RCTs) specifically focused on aerobic exercise interventions for children and adolescents with ADHD.
All studies included were randomized controlled trials involving participants aged 6 to 18 years who had been clinically diagnosed with ADHD. The interventions consisted of various forms of aerobic exercise, while the control groups engaged in either non-exercise activities or daily routines. Each study was required to report at least one outcome measure with usable data for calculating the effect size on executive functioning.
The Results:
Meta-analysis of fifteen RCTs combining 653 children and adolescents with ADHD reported a medium to large effect size improvement in inhibitory control. There was no sign of publication bias, but wide heterogeneity (variation) in outcomes among studies.
Six to eight weeks of aerobic exercise produced modest improvements, with much greater gains seen after twelve weeks. Hour-long sessions were as effective as longer ones. Moderate intensity exercise proved more beneficial than vigorous intensity.
Meta-analysis of eight RCTs combining 399 children and adolescents with ADHD produced a medium effect size improvement in working memory. There was no sign of publication bias, and heterogeneity was moderate.
Once again, six to eight weeks of aerobic exercise produced modest improvements, with much greater gains seen after twelve weeks. Hour-long sessions were as effective as longer ones. But in this case moderate-to-vigorous intensity yielded the best results.
Meta-analysis of ten RCTs combining 443 children and adolescents with ADHD was associated with a medium to large effect size improvement in cognitive flexibility. There was no sign of either publication bias or heterogeneity. Neither the length of treatment, session time, or intensity affected the outcome.
The Take-Away:
The team concluded, “Our study indicates that aerobic exercise interventions have a positive impact with a moderate effect size on inhibitory control, working memory, and cognitive flexibility in children and adolescents with ADHD. However, the effectiveness of the intervention is influenced by factors such as the intervention period, frequency, session durations, intensity, and the choice between acute or chronic exercise. Specifically, chronic aerobic exercise interventions lasting 12 weeks or longer, with a frequency of 3 to 5 sessions per week, session durations of 60 min or more, and intensities that are moderate or moderate-to-vigorous, have the greatest overall effect… caution should be exercised when interpreting these findings due to the significant heterogeneity in inhibitory control and working memory.”
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