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November 29, 2021
Sweden has a national single-payer health insurance system that includes virtually the entire population. It also has a system of national registers that track every resident from birth to death. That makes it possible to conduct nationwide population studies with a very high degree of precision and reliability.
In addition, one of the national registers is the Swedish Twin Register. Tracking all twins in the population enables studies to evaluate the degree to which observed associations may be attributable to genetic influences and to familial confounding. The twin method relies on the different levels of genetic relatedness between monozygotic ("identical") twins, who are genetically identical, and dizygotic ("fraternal") twins, who share on average half of their genetic variation (as do ordinary full siblings).
A Swedish team of researchers identified 42,582 Swedish twins born between 1959 and 1985, and who were, therefore, adults by the time of the study (20-47 years old). Of these, 24,872 (three out of five) completed a web-based survey with 1,300 questions covering lifestyle and mental and physical health. Out of this group, 17,999 provided information on ADHD symptoms and food frequency.
Self-reported ADHD symptoms came from nine inattention components and nine hyperactivity/impulsivity components, covering the 18 DSM- IV symptoms of ADHD.
The food frequency questionnaire included 94 food items, with the following frequency categories: never, 1-3 times/month, 1-2 times/week, 3-4 times/week, 5-6 times/week, 1 time/day, 2 times/day, 3 times/day.
In the raw data, the two subtypes of ADHD exhibited very similar associations. Both had significant associations with unhealthy diets. Both were more likely to be eating foods high in added sugar, and neglecting fruits and vegetables while eating more meat and fats.
After adjusting for the degree of relatedness of twins (whether monozygotic or dizygotic) and controlling for the other ADHD subtype, the associations remained statistically significant for inattention, but diminished to negligible levels or became statistically non-significant for hyperactivity/impulsivity.
Even for persons with inattention symptoms, adjusted correlations were small (never exceeding r = 0.10), with the strongest associations being for overall unhealthy eating habits (r = 0.09), eating foods high in added sugar (r = 0.10) or high in fat (r = 0.05), and neglecting fruits and vegetables (r = 0.06). All other associations became statistically non-significant.
For persons with hyperactivity/impulsivity symptoms, the only associations that remained statistically significant - but at tiny effect sizes - were unhealthy dietary patterns (r = 0.04) and consumption of foods high in added sugar (r = 0.03).
The further genetic analysis, therefore, focused on the strongest associations, between ADHD subtypes on the one hand, and unhealthy dietary patterns and eating foods high in added sugar on the other hand. The heritability estimates (the fraction of phenotypic covariance explained by genetic influences) were 44%, 40%, and 37% for inattention and high-sugar food, inattention and unhealthy dietary patterns, and hyperactivity/impulsivity and high-sugar food, respectively.
When examining only differences between pairs of monozygotic("identical") twins, the correlations became stronger for inattention, rising to r = 0.12 for unhealthy eating habits and r = 0.13 for consumption of foods high in added sugar. For hyperactivity/impulsivity symptoms, the association with unhealthy eating habits was weaker, and the association with consumption of foods high in added sugar became statistically insignificant.
The authors concluded, "we identified positive associations between self-reported trait dimensions of ADHD and intake of seafood, high-fat food, high-sugar food, high-protein food, and an unhealthy dietary pattern, and negative associations with consumption of fruits, vegetables, and a healthy dietary pattern. However, all the associations are small in magnitude. These associations were stronger for inattention compared to hyperactivity/ impulsivity. This pattern of associations was also reflected at the etiological level, where we found a slightly stronger genetic correlation between inattention with dietary habits and hyperactivity/impulsivity with dietary habits. Non-shared environmental influences also contributed to the overlap between ADHD symptom dimensions and consumption of high-sugar food and unhealthy dietary pattern. However, shared environmental influences probably contributed relatively little to the associations between ADHD symptoms and dietary habits. ... significant MZ twin intraplate differences also provided support for a potential causal link between inattention and dietary habits.
Lin Li, Mark J. Taylor, Katarina Bälter, Ralf Kuja-Halkola, Qi Chen, Tor-Arne Hegvik, Ashley E. Tate, Zheng Chang, Alejandro Arias-Vásquez, Catharina A. Hartman, Henrik Larsson, "Attentiondeficit/hyperactivity disorder symptoms and dietary habits in adulthood: A large populationbased twin study in Sweden," American Journal of Medical Genetics (2020) Vol.183, Issue 8, 475-485, https://doi.org/10.1002/ajmg.b.32825.
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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