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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.
Many studies have shown that ADHD is associated with increased risks of suicidal behavior, substance misuse, injuries, and criminality. As we often discuss in our blogs, treatments for ADHD include medication and non-medication options, such as CBT (Cognitive Behavioral Therapy). While non-drug approaches are often used for young children or mild cases of ADHD, medications – both stimulants and non-stimulants – are common for adolescents and adults.
Global prescriptions for ADHD drugs have risen significantly in recent years, raising questions about their safety and effectiveness. Randomized controlled trials have demonstrated that medication can help reduce the core symptoms of ADHD. However, research from these trials still offers limited or inconclusive insights into wider and more significant clinical outcomes, such as suicidal behavior and substance use disorder.
An international study team conducted a nationwide population study using the Swedish national registers. Sweden has a single-payer national health insurance system, which covers nearly every resident, enabling such studies. The researchers examined all Swedish residents aged 6 to 64 who received their first ADHD diagnosis between 2007 and 2018. Analyses of criminal behavior and transport accidents focused on a subgroup aged 15 to 64, since individuals in Sweden must be at least 15 years old to be legally accountable for crimes or to drive.
The team controlled for confounding factors, including demographics (age at ADHD diagnosis, calendar year, sex, country of birth, highest education (using parental education for those under 25), psychiatric and physical diagnoses, dispensations of psychotropic drugs, and health care use (outpatient visits and hospital admissions for both psychiatric and non-psychiatric reasons).
Time-varying covariates from the previous month covered diagnoses, medication dispensations, and healthcare use. During the study, ADHD treatments licensed in Sweden included amphetamine, atomoxetine, dexamphetamine, guanfacine, lisdexamphetamine, and methylphenidate.
After accounting for covariates, individuals diagnosed with ADHD who received medication treatment showed better outcomes than those who did not. Specifically:
-Suicidal behaviors dropped by roughly 15% in both first-time and recurrent cases.
-Initial criminal activity decreased by 13%, with repeated offences falling by 25%.
-Substance abuse initiation declined by 15%, while recurring substance abuse was reduced
by 25%.
-First automotive crashes were down 12%, and subsequent crashes fell by 16%.
There was no notable reduction in first-time accidental injuries, and only a marginally significant 4% decrease in repeated injuries.
The team concluded, “Drug treatment for ADHD was associated with beneficial effects in reducing the risks of suicidal behaviours, substance misuse, transport accidents, and criminality, but not accidental injuries when considering first event rate. The risk reductions were more pronounced for recurrent events, with reduced rates for all five outcomes.”
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Background:
Pharmacotherapies, such as methylphenidate, are highly effective for short-term ADHD management, but issues remain with medication tolerability and adherence. Some patients experience unwanted side effects from stimulant medications, leaving them searching for alternative ADHD treatments. Alternative treatments such as cognitive training, behavioral therapies, psychological interventions, neurofeedback, and dietary changes have, so far, shown limited success. Thus, there is a critical need for non-pharmacological options that boost neurocognitive performance and address core ADHD symptoms.
First— What Are NIBS (Non-Invasive Brain Stimulation) Techniques?
Non-invasive brain stimulation (NIBS) techniques, including transcranial direct current stimulation (tDCS), transcranial random noise stimulation (tRNS), transcranial alternating current stimulation (tACS), and repetitive transcranial magnetic stimulation (rTMS) are generating growing attention within the scientific community.
NIBS techniques are methods that use external stimulation, such as magnets or electrical currents, to affect brain activity without any invasive procedures. In transcranial alternating current stimulation (tACS), for example, small electrodes are placed on the scalp of the patient, and a weak electrical current is administered.
The theory behind these techniques is that when a direct current is applied between two or more electrodes placed on specific areas of the head, it makes certain neurons more or less likely to fire. This technique has been successfully used to treat conditions like depression and anxiety, and to aid recovery from stroke or brain injury.
The Study:
Previous meta-analyses have produced conflicting indications of efficacy. A Chinese research team consisting of sports and rehabilitative medicine professionals has just published a network meta-analysis to explore this further, through direct comparison of five critical outcome domains: inhibitory control, working memory, cognitive flexibility, inattention, hyperactivity and impulsivity.
To be included, randomized controlled trials needed to have participants diagnosed with ADHD, use sham control groups, and assess ADHD symptoms and executive functions – such as inhibitory control, working memory, cognitive flexibility, inattention, hyperactivity, and impulsivity – using standardized tests.
A total of thirty-seven studies encompassing 1,615 participants satisfied the inclusion criteria. It is worth noting, however, that the authors did not specify the number of randomized controlled trials nor the number of participants included in each arm of the network meta-analysis.
Furthermore, the team stated, “We checked for potential small study effects and publication bias by conducting comparison-adjusted funnel plots,” but did not share their findings. They also did not provide information on outcome variation (heterogeneity) among the RCTs.
Results:
Ultimately, none of the interventions produced significant improvements in ADHD symptoms, whether in inattention symptoms or hyperactivity/impulsivity symptoms. Likewise, none of the interventions produced significant improvements in inhibitory control. Some tDCS interventions enhanced working memory and cognitive flexibility, but details about trial numbers and participants were missing. The team concluded, “none of the NIBS interventions significantly improved inhibitory control compared to sham controls. … In terms of working memory, anodal tDCS over the left DLPFC plus cathodal tDCS over the right DLPFC … and anodal tDCS over the right inferior frontal cortex (rIFC) plus cathodal tDCS over the right supraorbital area ... were associated with significant improvements compared to sham stimulation. For cognitive flexibility, only anodal tDCS over the left DLPFC plus cathodal tDCS over the right supraorbital area demonstrated a statistically significant benefit relative to sham. ... Compared to the sham controls, none of the NIBS interventions significantly improved inattention. ... Compared to the sham controls, none of the NIBS interventions significantly improved hyperactivity and impulsivity.”
How Should We Interpret These Results?
In a word, skeptically.
If one were to read just the study’s abstract, which states, “The dual-tDCS and a-tDCS may be considered among the preferred NIBS interventions for improving cognitive function in ADHD”, it might seem that the takeaway from this study is that this combination of brain stimulation techniques might be a viable treatment option for those with ADHD. Upon closer inspection, however, the results do not suggest that any of these methods significantly improve ADHD symptoms. Additionally, this study suffers from quite a few methodological flaws, so any results should be viewed critically.
Background:
Despite recommendations for combined pharmacological and behavioral treatment in childhood ADHD, caregivers may avoid these options due to concerns about side effects or the stigma that still surrounds stimulant medications. Alternatives like psychosocial interventions and environmental changes are limited by questionable effectiveness for many patients. Increasingly, patients and caregivers are seeking other therapies, such as neuromodulation – particularly transcranial direct current stimulation (tDCS).
tDCS seeks to enhance neurocognitive function by modulating cognitive control circuits with low-intensity scalp currents. There is also evidence that tDCS can induce neuroplasticity. However, results for ADHD symptom improvement in children and adolescents are inconsistent.
The Method:
To examine the evidence more rigorously, a Taiwanese research team conducted a systematic search focusing exclusively on randomized controlled trials (RCTs) that tested tDCS in children and adolescents diagnosed with ADHD. They included only studies that used sham-tDCS as a control condition – an essential design feature that prevents participants from knowing whether they received the active treatment, thereby controlling for placebo effects.
The Results:
Meta-analysis of five studies combining 141 participants found no improvement in ADHD symptoms for tDCS over sham-TDCS. That held true for both the right and left prefrontal cortex. There was no sign of publication bias, nor of variation (heterogeneity) in outcomes among the RCTs.
Meta-analysis of six studies totaling 171 participants likewise found no improvement in inattention symptoms, hyperactivity symptoms, or impulsivity symptoms for tDCS over sham-TDCS. Again, this held true for both the right and left prefrontal cortex, and there was no sign of either publication bias or heterogeneity.
Most of the RCTs also performed follow-ups roughly a month after treatment, on the theory that induced neuroplasticity could lead to later improvements.
Meta-analysis of four RCTs combining 118 participants found no significant improvement in ADHD symptoms for tDCS over sham-TDCS at follow-up. This held true for both the right and left prefrontal cortex, with no sign of either publication bias or heterogeneity.
Meta-analysis of five studies totaling 148 participants likewise found no improvement in inattention symptoms or hyperactivity symptoms for tDCS over sham-TDCS at follow-up. AS before, this was true for both the right and left prefrontal cortex, with no sign of either publication bias or heterogeneity.
The only positive results came from meta-analysis of the same five studies, which reported a medium effect size improvement in impulsivity symptoms at follow-up. Closer examination showed no improvement from stimulation of the right prefrontal cortex, but a large effect size improvement from stimulation of the left prefrontal cortex.
Interpretation:
It is important to note that the one positive result was from three RCTs combining only 90 children and adolescents, a small sample size. Moreover, when only one of sixteen combinations yields a positive outcome, that begins to look like p-hacking for a positive result.
In research, scientists use something called a “p-value” to determine if their findings are real or just due to chance. A p-value below 0.05 (or 5%) is considered “statistically significant,” meaning there's less than a 5% chance the result happened by pure luck.
When testing twenty outcomes by this standard, one would expect one to test positive by chance even if there is no underlying association. In this case, one in 16 comes awfully close to that.
To be sure, the research team straightforwardly reported all sixteen outcomes, but offered an arguably over-positive spin in their conclusion: “Our study only showed tDCS-associated impulsivity improvement in children/adolescents with ADHD during follow-ups and anode placement on the left PFC. ... our findings based on a limited number of available trials warrant further verification from large-scale clinical investigations.”
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