Dr Duncan Manders (Consultant Child & Adolescent and Intellectual Disabilities Psychiatrist, Royal Hospital for Sick Children, Edinburgh, UK) opened Week 1 of the 12th Meeting of Minds and set the stage for an interactive and thought-provoking meeting. He acknowledged how, under normal circumstances, the Meeting of Minds would host between 400‒500 delegates live in a major European city, but in the current, far from normal, circumstances, this year’s meeting had to be conducted virtually. However, he hoped it may reach even more delegates globally, with >2500 delegates already registered.

ADHD: dimension, disease or disorder?

Moderator: Dr Duncan Manders (Consultant Child & Adolescent and Intellectual Disabilities Psychiatrist, Royal Hospital for Sick Children, Edinburgh, UK)

Professor Stephen Faraone (The State University of New York Upstate Medical University, Syracuse, NY, USA) opened the first plenary session by reflecting on the gradual evolution of ADHD over the past 40 years of his research, from a categorical entity to a dimensional disorder.

Epidemiological evidence

Professor Faraone described epidemiological evidence that supports ADHD as a dimensional disorder. Symptom scores on the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviours (SWAN) scale in a population-representative sample of 2143 adolescents demonstrated a normal distribution, suggesting most people in the population have some ADHD symptoms. Furthermore, there was no distinction between scoring 4, 5 or 6 on the symptom scale (high-extreme, symptomatic) and having ADHD.1 Professor Faraone explained that plotting intelligence scores would also show a normal distribution, but those with intellectual disabilities would create a clear, distinct cluster at the low end of intelligence, unlike shown here in ADHD scores. Similar observations were made in the adult population, across both males and females, in the normal distribution of Adult ADHD Self-Report Scale (ASRS) scores and the lack of distinction between scores of individuals with or without ADHD.2

Genetic evidence

Evidence from genetic studies was then summarised by Professor Faraone. His own research of 37 twin studies from around the world revealed a mean ADHD heritability of 74%.3 Of these 37 studies, those that looked at ADHD diagnoses, supporting ADHD as a category, showed a heritability of ~74%. Studies that looked at ADHD as a symptom count in the population, similar to the previous studies,1,2 also showed a heritability of ~74%. Professor Faraone suggested this showed a similarity in ADHD heritability between a diagnostic, categorical perspective and a continuous trait perspective. Professor Faraone then explained how they found an underlying polygenic risk for ADHD in this study and that these variants form a normal distribution in the population. From a decile of this normal distribution, it can be observed that ADHD risk increases with the polygenic risk score; those in the highest 10% of polygenic risk have a 5-fold increased risk for ADHD.4 Professor Faraone concluded from this study that the underlying risk for ADHD is essentially continuous on a polygenic risk score scale. However, he also stated that the polygenic risk score is a very weak predictor of who does and does not have ADHD, and cannot be used for clinical diagnosis. Nevertheless, he explained that the finding of a significant polygenic background confirms predictions from previous twin studies, which suggested that the diagnosis of ADHD was the extreme of a quantitative trait.5,6 Another study in 7000 adolescents found that polygenic risk score indexes one’s risk for ADHD based on DNA assays; Professor Faraone suggested that this was further evidence that the risk of ADHD is continuous in the population.7 He also described the nearly identical genetic correlation (0.97) between the ADHD Psychiatric Genomic Consortium (PGC) project computed polygenic risk for ADHD as a diagnosed disorder and the Early Lifecourse & Genetic Epidemiology (EAGLE)/Queensland Institute of Medical Research (QIMR) computed polygenic risk for ADHD as a dimension in the population.4

Risk factors and brain networks

Professor Faraone presented environmental risk factors for ADHD, based on his clinical opinion and experience, which included:

  • Prenatal exposure to valproate, acetaminophen
  • Maternal hypertension, preeclampsia
  • Low birth weight
  • Iron/vitamin D deficiency
  • Exposure to toxicities
  • Family stress
  • Abuse and neglect
  • Severe deprivation.

He explained that most cases of ADHD are caused by the accumulation of genetic and environmental risk factors, each of small effect. Professor Faraone then discussed the impact of genetic and environmental risks on brain networks in ADHD. He revised the roles of the fronto-striatal and fronto-parietal networks in the manifestation of ADHD symptoms.8 Then, he explained the dynamic switching and coordination of brain networks in attention, and how individuals with ADHD show small or absent anti-correlations between the default mode network and the cognitive control network, as well as lower connectivity within the default mode network and cognitive and motivational loops of the fronto-striatal circuits.9

Clinical implications

In the final part of this session, Professor Faraone presented the clinical implications of a dimensional model of ADHD. In his clinical opinion and experience, viewing ADHD as a dimension reduces diagnostic controversies by:

  • Developing probabilistic predictions for ADHD in the same way that thresholds are established for other dimensional traits such as blood pressure, cholesterol and weight
  • Eliminating a proliferation of subtypes
  • Reducing overdiagnosis
  • Including subthreshold ADHD in the model.

He explained how subthreshold cases milder than full ADHD cases show more psychiatric comorbidity, school failure, neuropsychological impairment, substance use and psychosocial impairment compared with controls.10 Additionally, a lack of difference between subthreshold and full ADHD on scores of behaviour problems has also been found.11 Therefore, Professor Faraone concluded that, in his opinion, subthreshold ADHD should be taken just as seriously as full ADHD. The diagnostic issues for subthreshold adult ADHD, in Professor Faraone’s clinical opinion, included: the difficulty of retrospective recall; less severe ADHD; history of supportive home and school environments; self-medication; subthreshold cases with many symptoms; and the low sensitivity of the Diagnostic and Statistical Manual of Mental Disorders – 5th Edition (DSM-5TM) due to lack of criteria for emotional dysregulation and executive dysfunction.

Professor Faraone summarised that for both adults and adolescents, ADHD symptoms occur as a dimension in the population, and subthreshold ADHD requires caution and clinically informed decision. He suggested that neurodiversity should be more acknowledged rather than the disease/disorder framework in which ADHD may be considered a disability, in the way that those with disabilities can function in some environments or with accommodations.12 Expanding on this, he stated how neurodiversity is already well acknowledged in popular culture (e.g. Google has ~2,490,000 results for ‘neurodiversity’) and so academia has fallen behind. In Professor Faraone’s opinion, this new perspective for research and clinical care for ADHD reframes the disorder as a disability, is consistent with the dimensional model of ADHD, does not stigmatise the diagnosis of ADHD and reduces controversies about overdiagnosis.

Professor Faraone: “We need to think of ethical and non-stigmatising language and concepts to help us think about people who are different”

Clinical Hot Topic 1: Behavioural and brain states in ADHD

Professor Joseph Sergeant (Emeritus Professor of Clinical Neuropsychology, Vrije University, Amsterdam, The Netherlands) set the scene of his presentation by stating that individuals with ADHD have non-optimal behavioural and brain states. In other words, their actual brain state typically does not match the required task or condition state needed to perform the task at an optimal level.

Activity and sleep

Professor Sergeant presented results from various research studies that investigated brain states of individuals with ADHD and their ability to perform tasks. The initial study he presented examined differences in motor activity levels between hyperactive boys (n=12) and age-matched controls (n=12).13 The results showed that hyperactive boys were consistently more active compared with the control group.13 This finding was particularly evident post-lunch where there was typically a dip in motor activity levels in the control group; however, activity levels in hyperactive boys increased during this time period and remained high for the rest of the afternoon.13 In particular, in specific tasks such as reading and mathematics, the boys who were hyperactive had higher activity levels but lower performance compared with the control group, suggesting that higher activity does not mean higher performance.13

Professor Sergeant went on, using different study details, to exemplify that this hyperactivity is outwith the control of the individual with ADHD. For example, in a study that investigated sleep issues in adults with ADHD, it was noted that individuals with ADHD suffered from more sleep issues such as loud snoring, restless legs and periodic limb movements than individuals without ADHD.14 In a separate study, when the brain states of adults with ADHD during sleep were compared with individuals without ADHD who had undergone total sleep deprivation, it was noted that different areas of the brain were hypoactivated.15 In other words, while both groups suffered from sleep deprivation, it affected their brains in different ways.15 An explanation for this finding is that individuals with ADHD have a delayed circadian rhythm phase compared with individuals without ADHD.16 Professor Sergeant then described how this form of sleep deprivation lowers daytime task performance, sleep-associated memory consolidation in individuals with ADHD and ability to perform sustained attention tasks.17,18

The effects of exercise on ADHD performance

Professor Sergeant moved on to describe results from studies that investigated how physical exercise affects ADHD performance.19,20 Results from one of the studies highlighted that exercise is likely to have a significantly positive effect on functional outcomes in individuals with ADHD (g=0.627).19 Another study, which examined magnetic resonance imaging (MRI) data of preadolescent children after acute aerobic exercise, highlighted that executive functioning and motor skills improved in individuals with ADHD.20 However, there was not a significantly prolonged improvement in these functional outcomes in individuals with ADHD.19,20 Professor Sergeant suggested that, in his opinion, this may be an avenue for future research and therapeutic intervention.

The effects of event rate on ADHD performance

As described by Professor Sergeant, the event rate is the rate of two signals coming after one another in the brain. The event rate is highly important for the speed and efficiency of processing: the slower the signal, the higher the efficiency and speed of processing information. Professor Sergeant highlighted MRI data from a study that investigated the effects of event rates in adults with ADHD.21 These data suggested that the slower the condition, the more efficient individuals with ADHD were at processing the information.21

Emotional lability in individuals with ADHD

Professor Sergeant stated that there is a clear relationship between emotional lability and ADHD (d=0.95 and g=1.2) and there may be a gender difference between how females and males with ADHD react emotionally.22,23

The effects of mind wandering in ADHD

Professor Sergeant next noted that there is a relationship between mind wandering and ADHD. He suggested that mind wandering is linked to the default mode network (automatic thought processes). Professor Sergeant also noted that it is yet to be determined which parts of the brain are activated in the default mode network and which are not in individuals with ADHD.

How are all the brain states linked in individuals with ADHD?

Professor Sergeant highlighted that exercise has an effect on both emotional lability (reducing anxiety and depressive symptoms) and symptoms of ADHD.24 Furthermore, he noted that current research has shown that mind wandering and emotional lability can predict ADHD symptom severity. In addition, mind wandering, emotional lability and sleep quality are all linked and contribute to the symptomatology of adulthood ADHD. For example, mind wandering can lead to emotional lability, which can increase the severity of ADHD symptoms, and poor sleep quality can exacerbate mind wandering, leading to ADHD symptoms.25

Professor Sergeant then moved on to highlight data from studies which suggested that micro-states within the brains of individuals with ADHD predict that an error is about to occur in all neuro-psychological tasks.26,27 In other words, an error is not simply down to motivational factors, but occurs because the brain of an individual with ADHD is not functioning correctly.26,27 Additionally, Professor Sergeant presented evidence that there is more default-mode variability in the brains of individuals with ADHD, and this leads to a reduction in task performance compared with a normal brain: default-mode activity variability is reduced in order to achieve optimal task performance.28 However, ADHD medication is able to reduce default-mode variability in individuals with ADHD and so bring their task performance in line with individuals without ADHD.28 Furthermore, individuals with higher ADHD scores have lower functional connectivity between the fronto-parietal network and the right ventral visual cortex and so have higher mind-wandering scores.29

Professor Sergeant concluded his presentation by saying that behavioural states influence brain states and vice versa in ADHD, causing lapses of attention and decrement in attentional processing. In his opinion, Professor Sergeant noted that ADHD medication is able to positively influence both the brain and behavioural states; therefore, improving attentional performance and ADHD symptomatology.

Professor Sergeant: “Behavioural states are quite clearly related not only to ADHD but also to the brain states seen in an individual with ADHD”

Clinical Hot Topic 2: Enduring neurobiological consequences of abuse and neglect

Professor Akemi Tomoda (Professor of Research Center for Child Mental Development, University of Fukui, Fukui, Japan) presented data from various studies on the long-term effects of childhood trauma. She opened the presentation by saying that many abused people often suffer from serious mental health disorders even if they are not subjected to life-threatening cruelty.30 Childhood exposure to traumatic stress is a major risk factor for later psychopathology such as aggression, delinquency and drug abuse, as well as psychiatric difficulties such as depression and anxiety.30

Professor Tomoda presented statements surrounding developmental trauma disorder related to childhood trauma and how it can manifest itself. For example, ADHD-like hyperactivity and destructive behavioural disorder may appear in childhood, whereas post-traumatic stress disorder (PTSD) and dissociation symptoms may appear in adolescence and complicated PTSD may occur in adulthood.31 Next, Professor Tomoda proposed the hypothesis that childhood maltreatment can act as a stressor that produces changes in brain development and therefore sets in motion future psychiatric disorders. She noted that, so far data have shown that childhood maltreatment leads to the amygdala (the centre of emotion) becoming overstimulated, which leads to excess cortisol release causing developmental brain damage.32

Verbal abuse

Professor Tomoda presented data from a study conducted by her research group using the Parental Verbal Aggression Scale.33 This study included adults who had experienced childhood verbal abuse (n=21, mean [standard deviation (SD)] age 21.2 [2.4] years) and a control group who had not (n=19, mean [SD] age 21.1 [1.9] years).33 Compared with the controls, those who had experienced verbal abuse as a child had a 14% increase in grey matter volume in the left superior temporal gyrus (maternal verbal abuse, p=0.006; paternal verbal abuse, p=0.013).33 The adverse effect of verbal abuse was the reduction in the number of axons that constitute the arcuate fasciculus, which plays a role in language.34

Harsh corporal punishment

Professor Tomoda went on to present data from another study from her research group, which investigated the effects of harsh corporal punishment on brain development.35 This study included 23 participants (mean [SD] age, 21.7 [2.2] years) who had been repeatedly exposed to harsh corporal punishment but had no history of sexual or significant physical abuse and 22 age-matched controls (mean [SD] age, 21.7 [1.8] years).35 Results of the study showed that there was a 19.1% reduction in grey matter volume in the medial prefrontal cortex,35 which Professor Tomada highlighted could affect memory, attention and behaviour.

Witnessing domestic violence

Professor Tomoda next stated that children who witness domestic violence can experience a decline in intellectual ability and vocabulary comprehension.36-38 Professor Tomoda presented results from her own data, which suggested that there was approximately a 6.1% reduction in the size of the visual cortex (which processes visual information) in adults who had witnessed domestic violence as a child (n=22, mean [SD] age, 21.8 [2.4] years) compared with an unaffected control group (n=30, mean [SD] age, 21.6 [2.1] years).39 Additionally, there was a noted difference in variability in right lingual volume between duration of exposure to interparental physical aggression and duration of exposure to interparental verbal aggression (3.2% versus 19.8%).39

Overall, Professor Tomoda stated that varying forms of childhood maltreatment lead to different brain developmental issues. In short, childhood verbal abuse can deform the visual cortex, harsh corporal punishment may lead to atrophy of the prefrontal cortex, and witnessing interparental domestic violence can cause the visual cortex to shrink.33,35,39

Professor Tomoda concluded her presentation with the following take-home messages:

  • Childhood maltreatment is associated with marked effects on brain morphology, function and circuitry.
  • Childhood maltreatment is associated with altered processing in a variety of brain regions including the ventromedial prefrontal cortex and sensory cortices.
  • The nature or magnitude of the effect of altered processing depends to a substantial degree on type and timing of maltreatment during developmental sensitive periods.
  • Diminished ability to regulate emotions and accurately convey their intentions to others, as well as increased interoceptive awareness and self-referential thinking are hallmarks of childhood maltreatment. These are likely adaptive alterations designed to reduce distress and to help individuals reproduce and survive in what appears to be a malevolent world.

A difference between the environment someone is adapted for and the environment they live in can manifest as psychopathology.

Professor Tomoda: “I hope science of the human mind will progress on the basis that development of child mental [health] problems and brain function are studied from the viewpoint of trauma and attachment”

The brain: neurochemistry of behaviour, emotion and cognition

Moderator: Dr Duncan Manders (Consultant Child & Adolescent and Intellectual Disabilities Psychiatrist, Royal Hospital for Sick Children, Edinburgh, UK)

Professor David Nutt (Edmond J. Safra Professor of Neuropsychopharmacology / Director of the Neuropsychopharmacology Unit in the Division of Brain Sciences, Imperial College London, London, UK) first presented a short introduction to the variety of neurotransmitters that are located within the brain, particularly focusing on dopamine and noradrenaline. Professor Nutt indicated that dopamine is involved in movement control, motivation, reward and reinforcement.40-42 Dopamine receptor agonism aids in the production of a positive mood, increased attention and concentration, while antagonism relates to a negative mood, decreased attention and concentration.43 Professor Nutt indicated that noradrenaline has a variety of effects, which range from regulation of mood and attention in the prefrontal cortex, mediation of motor movements in the cerebellum and control of blood pressure in the spinal cord.40

Professor Nutt: “We use that ability of noradrenaline antagonism to dampen anxiety and promote sleep in a treatment for PTSD”

The ADHD brain and the relevance of its neurochemical pathways

Moderator: Dr Duncan Manders (Consultant Child & Adolescent and Intellectual Disabilities Psychiatrist, Royal Hospital for Sick Children, Edinburgh, UK)

Professor David Nutt then presented data and information of the neurochemical pathways and the effects of stimulants in the brains of individuals with ADHD. He highlighted a study that examined brain activity in several regions of the brain in boys with ADHD compared with unaffected controls. The study noted that various regions of the brain, such as the basal ganglia and the prefrontal cortex, were underactive in boys with ADHD due to lack of dopamine release. However, treatment with the stimulant methylphenidate increased activity to normal levels by enhancing dopamine release.44

Professor Nutt went on to describe a theory of the mechanism of ADHD.40 Typically, in normal situations, the ventral tegmental area (origin of dopaminergic cell bodies) of the brain activates the prefrontal cortex, which in turn inhibits the basal ganglia and so provides a balanced effect between activity and attention.40 However, in individuals with ADHD there is a dopamine deficiency and so reduced activation of the prefrontal cortex leads to inattention.40 Additionally, deficiencies in dopamine cause the basal ganglia to be abnormally active, therefore leading to excessive activity in individuals with ADHD.40 However, treatment with stimulants allows for normal processes to resume through enhanced dopamine release.40

Professor Nutt described how prefrontal cortex noradrenaline (thought to mediate attention, behaviour and concentration) is also involved in ADHD.40 Professor Nutt noted that there are two types of drugs that target noradrenaline. The first drug is atomoxetine, a noradrenaline reuptake blocker, which increases the availability of noradrenaline in the prefrontal cortex and so increases attention and concentration in individuals with ADHD.45 However, Professor Nutt stated that it takes several weeks for atomoxetine to build up in the system and thus to have an effect on noradrenaline levels. The second drug is a noradrenaline agonist, guanfacine, which acts on the postsynaptic and presynaptic neurones. Professor Nutt stated that the effect of guanfacine on individuals with ADHD is postsynaptic stimulation, which facilitates attention and behavioural control.

Next, Professor Nutt presented results from a study which used the radio label 11C-methylreboxetine to image noradrenaline transport sites within the thalamus using positron-emission tomography (PET).46 A reduction of the radiolabel was observed when the individual was treated with the stimulant methylphenidate. Professor Nutt suggested that this is consistent with the idea that stimulants not only work on dopamine levels but also increase noradrenaline levels. Extrapolation of the dose-response curve provided evidence of a dose-response relationship between methylphenidate and 11C-methylreboxetine levels. Doses of methylphenidate >20 mg correlated with a reduction in radiolabelling, which suggested increase transport of noradrenaline.46 Professor Nutt concluded by stating that this effect of stimulants on increasing noradrenaline transport from the thalamus to the prefrontal cortex is part of the benefits of stimulant use for treatment of ADHD.46

Professor Nutt: “PET imaging allows us for the first time look at the release of neurotransmitters”

Clinical Hot Topic 3: Can genetics inform our ADHD clinical practice?

Dr Diane McIntosh (Clinical Assistant Professor, University of British Columbia, Vancouver, Canada) began by explaining that heterogeneity and inter-individual differences are a hallmark of neurodevelopmental disorders such as ADHD.8,47 In her session, she outlined the genetic evidence for ADHD as a neurodevelopmental disorder.

Heritability and ADHD

Dr McIntosh stated that ADHD is of high heritability; twin studies of diagnosis or symptom counts found a heritability of around 0.8.3 Furthermore, over 30 twin studies have reached consensus estimates of a heritability of 70‒80% throughout the lifespan.48,49 It has been concluded that environmental risks do not increase the likelihood of ADHD between siblings: it is largely genetic.50 Dr McIntosh added to this that family and twin studies have shown that ADHD can have genetic overlap with other conditions, including conduct disorder51 and another highly heritable disorder, bipolar disorder.52 Dr McIntosh went on to recap the mechanisms behind heritability, to introduce the concept of single nucleotide polymorphisms (SNPs) and their involvement in affecting a gene’s function. She described how SNPs can act as biological markers, to locate genes associated with disease and predict the risk of developing that disease.53 Dr McIntosh explained that developing ADHD actually involves polygenic inheritance, where a number of different genes are involved with a cumulative effect.

Mega-analytic studies

Dr McIntosh stated that one of the areas of research that will change medicine is the ability to analyse large amounts of data, called mega-analytics, which will further our understanding of heritability. The statistical handling of enormous and complex data sets can further our understanding of the heritability of common brain disorders.54 The large population-based cohort of the Child and Adolescent Twin Study in Sweden (CATSS) is an example of a large data set, the analysis of which has further validated the view that ADHD is principally a neurodevelopmental disorder, characterised by a potential persistence of profound cognitive, behavioural and psychosocial impairments throughout life.55,56 Dr McIntosh explained that the way that we can use genetics to understand heritability of ADHD is to use genome-wide association studies (GWAS). These studies look at the SNPs present in individuals with ADHD versus those without. If a particular SNP is very common in people with ADHD and not in those without ADHD, then it is suggested to be associated with the disorder.57 A GWAS published in 2019 had a significant impact on the world of ADHD, according to Dr McIntosh, through being able to identify 12 SNPs related to vulnerability to ADHD. This was an international collaboration that analysed ~10 million positions (loci) of the genomes of 55,374 individuals with ADHD from several countries. Due to the polygenic inheritance of ADHD, it was suggested that the more of the 12 SNPs you have, the more likely you are to develop, and probably to have increased severity of, ADHD.4

Heritability of adult ADHD

Previously when looking at heritability of adult ADHD, Dr McIntosh explained that only self-reports had been considered and the rate of heritability was lower (30‒40%), possibly due to the tendency of adults to underrate their own symptoms.58 Adult ADHD heritability was better estimated by family members providing information rather than the individual with ADHD themselves (80%) and by clinical diagnosis (72%).59,60 Dr McIntosh suggested that these findings show the heritability of ADHD remains stable during the transition from childhood to adulthood. In addition, the higher heritability for clinical diagnosis of adult ADHD confirms the suggestions from family studies that persistent ADHD is highly familial.3,61,62 Dr McIntosh then reminded the audience that ADHD changes throughout the lifespan. For example, she noted that ADHD may manifest with a different symptom set to that in the DSM criteria during adulthood, but still have significant impairing functions.

Genotype and phenotype of ADHD

Dr McIntosh explained the functional associations of some of the 12 SNPs discovered in the GWAS and their normal gene roles, which, interestingly, related to the manifestation of ADHD. For example, DUSP6 is a gene involved in the control of dopaminergic neurotransmission – the target of the most common ADHD pharmacological treatments.4 She reminded the audience that a genotype is different to a phenotype: a phenotype is the physical manifestation of characteristics that are determined by the genotype. This GWAS also identified genetic correlations of ADHD with other phenotypes. ADHD was positively correlated with variables such as major depression, obesity/body mass index and type II diabetes. These phenotypes are already known to be commonly associated with psychiatric disorders, including ADHD. ADHD was negatively correlated with variables including subjective wellbeing, childhood IQ, years of schooling and university completion. ADHD was also positively correlated with ever having smoked, number of cigarettes/day, lung cancer and number of children ever born, and negatively correlated with the age of first birth, relating to someone having a child before they are ready, perhaps due to impulsive behaviour.4 Dr McIntosh emphasised that, in her opinion, these data are of critical importance to draw the line between genotypic information received from large data sets and the phenotypes of individuals observed in clinical practice. She expanded further by saying that this study is a real game changer for ADHD to show people it is a neurodevelopmental disorder and does not just disappear when people are aged 18 years – it has a solid genetic basis.

Possible brain alterations in ADHD

Dr McIntosh continued her presentation by stating that research has also been able to clinically delineate and define where there is pathology in the brain associated with ADHD. These suspected factors influencing the persistence of ADHD into adulthood are processes that delay the development of brain networks.8 For example, it is known that the prefrontal cortex does not fully develop until early adulthood and is even more delayed in people with ADHD who may never catch up. A possible cause of this could be myelin dysfunction. There may be delayed or dysregulated myelination in people with ADHD, which could be a future therapeutic target.56 Finally, Dr McIntosh posed the question, ‘Why does ADHD persist into adulthood?’. She explained that ADHD is a circuitopathy: delayed development of fronto-striatal and limbic circuits leads to future impairment and alterations in neuroplasticity, disrupting brain maturation and causing the persistence of destructive cognitive and emotional impairments.56 She stated that we already know clinically that the phenotype of ADHD changes over time but now we have the biological evidence to back it up, through data such as from functional MRI. For instance, symptom recovery in ADHD was related to stronger integration of prefrontal regions in the executive control network, and the pattern and strength of resting-state functional connectivity across remittent ADHD, persistent ADHD and unaffected control groups potentially reflects the presence of compensatory neural mechanisms that aid symptomatic remission.63

Dr McIntosh: “[ADHD] is a neurodevelopmental disorder and doesn’t just suddenly disappear when you turn 18”

Clinical Hot Topic 4: ADHD as a risk factor for infection with COVID-19

Professor Iris Manor (Child & Adolescent Psychiatrist, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel) presented research she was involved in which investigated ADHD as a risk factor for COVID-19.64 She began by describing the symptoms of ADHD that she feels tends to increase the risk for viral transmission. These included:

  • Failure to give close attention to details or making careless mistakes
  • Not seeming to listen when spoken to directly
  • Not following through on instructions and being easily distracted
  • Difficulty in keeping materials and belongings in order
  • Losing things necessary for tasks or activities.

The hypothesis of this study was that the rate of ADHD among COVID-19-positive subjects would be significantly higher compared with those without ADHD, and that treatment with ADHD medications may moderate the rate of COVID-19 infection. To investigate this, the research group collected data from electronic health records of 14,022 people registered with Leumit Health Services between February and April 2020, who underwent at least one COVID-19 test. ADHD was diagnosed according to DSM-4/5 criteria and treated ADHD was defined as purchasing ≥3 ADHD medication prescriptions consecutively in the past year.64

Summarising the results, Professor Manor stated that 1416 people (aged 2 months–103 years) were positive for COVID-19. Compared with those who tested negative for COVID-19, those positive for COVID-19 were significantly more likely to be younger, male and have low-medium socioeconomic status (SES) (all p<0.001). Additionally, individuals positive for COVID-19 had significantly lower comorbidity of chronic lung disease (p<0.001), hypertension (p<0.001), dementia (p<0.001), diabetes mellitus (p=0.03) and depression or anxiety (p=0.042). However, these individuals had a significantly higher comorbidity of ADHD (p<0.001). Professor Manor went on to describe that there was a significant difference between the 230 out of 1416 individuals (16.2%) positive for COVID-19 who were diagnosed with ADHD and the 1469 out of 12,606 (11.7%) individuals who tested negative for COVID-19 who were diagnosed with ADHD (p<0.001). ADHD as a risk factor for COVID-19 had an adjusted odds ratio (OR) of 1.58 (p<0.001) and was lower than the risk factors of individuals aged <20 years (OR, 2.08; p<0.001) and low-medium SES (OR, 1.96; p<0.001) but higher than male gender (OR, 1.18; p<0.001).64

Professor Manor explained that among the 1699 individuals diagnosed with ADHD, 418 (24.6%) were defined as treated and 1281 (75.4%) were defined as untreated, meaning the ratio of treated to untreated was 1:3. She added that, of the medications purchased, 92.9% were stimulants. The adjusted OR for COVID-19 infection for treated versus untreated individuals with ADHD was lower for those treated (OR, 0.85; p=0.707) than untreated (OR, 1.68; p<0.001). Furthermore, the risk for COVID-19 was higher only in untreated individuals with ADHD compared with individuals positive for COVID-19 without ADHD.64

Professor Manor stated that the infection rate of COVID-19 was found to be 10.1% and those testing positive tended to be younger, male and from a lower SES group. She explained that the tendency toward a lower SES group could be explained by the higher density of the population in these strata leading to increased rates of transmission, which is consistent with other urban reports.65  She added that being of younger age had been poorly reported elsewhere at the time this study was conducted and is now more widely known. Professor Manor indicated that, in her opinion, there was no single good explanation for the association between male sex and risk for COVID-19. The researchers of this study suggested that perhaps there was an association between being male and exhibiting risky behaviours such as attending mass gatherings, and thus remaining non-compliant with social distancing measures.64

Next, Professor Manor summarised the medical and psychiatric factors and their association with COVID-19 infection. She summarised that diabetes mellitus, chronic obstructive pulmonary disorder, hypertension and dementia were not found to be linked to an elevated rate of infection, most probably due to the strict ‘stay at home’ restrictions particularly stressed in this vulnerable population.66,67 Schizophrenia, dementia, depression and anxiety were also not found to be linked to an elevated rate of infection. ADHD was the sole mental health problem that was identified to significantly increase the risk for COVID-19 infection, irrespective of other demographic and medical conditions. Professor Manor proposed that a possible explanation of this significant vulnerability may be the characteristics of ADHD such as hyperactivity and inattention, hypersensitivity, and difficulty in taking orders and being disciplined. She noted that the other tested psychiatric disorders did not have the same effect as ADHD, although they share some of its clinical characteristics, such as distractibility, inattention and impaired judgement.64 Treated individuals with ADHD had a significantly lower likelihood of being infected with COVID-19 compared with those untreated (adjusted OR, 0.63 [95% confidence interval, 0.42‒0.94; p<0.001]). Professor Manor explained that the significant effect of treatment observed strengthens the association between the specific characteristics of ADHD and it being a risk factor.64

The strengths of this research, as summarised by Professor Manor, were the large, real-world, population-based study design and the multivariate analysis of variables that may affect the likelihood for infection with COVID-19. She also listed the weaknesses of the study, which included a lack of data about the severity of ADHD symptoms due to these data not being available in the electronic health records; additionally, there were no data regarding the presenting symptoms and severity of COVID-19 infection. Professor Manor indicated that the latter would be the objective of their future investigations. Professor Manor concluded that untreated ADHD seems to constitute a risk factor for COVID-19 infection while pharmacotherapy seems to alleviate the effect. Therefore, it is suggested that people with ADHD should be considered as more vulnerable to COVID-19 infection, and pharmacotherapy should be considered as a measure to diminish the infection rate in people with ADHD.64 This was an important final note for Professor Manor, as she feared that parents of children with ADHD may perceive that their child no longer needs to take their ADHD medication during the pandemic due to not being at school.

Professor Manor: “ADHD was the sole mental health problem that was identified to increase significantly the risk for infection of COVID-19”

  1. Greven CU, Merwood A, van der Meer JM, et al. The opposite end of the attention deficit hyperactivity disorder continuum: genetic and environmental aetiologies of extremely low ADHD traits. J Child Psychol Psychiatry 2016; 57: 523-531.
  2. Das D, Cherbuin N, Butterworth P, et al. A population-based study of attention deficit/hyperactivity disorder symptoms and associated impairment in middle-aged adults. PLoS One 2012; 7: e31500.
  3. Faraone SV, Larsson H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry 2019; 24: 562-575.
  4. Demontis D, Walters RK, Martin J, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet 2019; 51: 63-75.
  5. Larsson H, Asherson P, Chang Z, et al. Genetic and environmental influences on adult attention deficit hyperactivity disorder symptoms: a large Swedish population-based study of twins. Psychol Med 2013; 43: 197-207.
  6. Levy F, Hay DA, McStephen M, et al. Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study. J Am Acad Child Adolesc Psychiatry 1997; 36: 737-744.
  7. Li JJ. The positive end of the polygenic score distribution for ADHD: a low risk or a protective factor? Psychol Med 2019: 1-10.
  8. Faraone SV, Asherson P, Banaschewski T, et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers 2015; 1: 15020.
  9. Kenzie ES, Parks EL, Bigler ED, et al. The dynamics of concussion: mapping pathophysiology, persistence, and recovery with causal-loop diagramming. Front Neurol 2018; 9: 203.
  10. Kirova AM, Kelberman C, Storch B, et al. Are subsyndromal manifestations of attention deficit hyperactivity disorder morbid in children? A systematic qualitative review of the literature with meta-analysis. Psychiatry Res 2019; 274: 75-90.
  11. Biederman J, Fitzgerald M, Kirova AM, et al. Further evidence of morbidity and dysfunction associated with subsyndromal ADHD in clinically referred children. J Clin Psychiatry 2018; 79.
  12. Baron-Cohen S. Editorial Perspective: Neurodiversity – a revolutionary concept for autism and psychiatry. J Child Psychol Psychiatry 2017; 58: 744-747.
  13. Porrino LJ, Rapoport JL, Behar D, et al. A naturalistic assessment of the motor activity of hyperactive boys. I. Comparison with normal controls. Arch Gen Psychiatry 1983; 40: 681-687.
  14. Bjorvatn B, Brevik EJ, Lundervold AJ, et al. Adults with attention deficit hyperactivity disorder report high symptom levels of troubled sleep, restless legs, and cataplexy. Front Psychol 2017; 8: 1621.
  15. Saletin JM, Jackvony S, Rodriguez KA, et al. A coordinate-based meta-analysis comparing brain activation between attention deficit hyperactivity disorder and total sleep deprivation. Sleep 2019; 42.
  16. Coogan AN, McGowan NM. A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder. Atten Defic Hyperact Disord 2017; 9: 129-147.
  17. Prehn-Kristensen A, Göder R, Fischer J, et al. Reduced sleep-associated consolidation of declarative memory in attention-deficit/hyperactivity disorder. Sleep Med 2011; 12: 672-679.
  18. Helfer B, Bozhilova N, Cooper RE, et al. The key role of daytime sleepiness in cognitive functioning of adults with attention deficit hyperactivity disorder. Eur Psychiatry 2020; 63: e31.
  19. Vysniauske R, Verburgh L, Oosterlaan J, et al. The effects of physical exercise on functional outcomes in the treatment of ADHD: a meta-analysis. J Atten Disord 2020; 24: 644-654.
  20. Chen AG, Zhu LN, Yan J, et al. Neural basis of working memory enhancement after acute aerobic exercise: fMRI study of preadolescent children. Front Psychol 2016; 7: 1804.
  21. Kooistra L, van der Meere JJ, Edwards JD, et al. Preliminary fMRI findings on the effects of event rate in adults with ADHD. J Neurol Transm (Vienna) 2010; 117: 655-662.
  22. Graziano PA, Garcia A. Attention-deficit hyperactivity disorder and children’s emotion dysregulation: a meta-analysis. Clin Psychol Rev 2016; 46: 106-123.
  23. Beheshti A, Chavanon M-L, Christiansen H. Emotion dysregulation in adults with attention deficit hyperactivity disorder: a meta-analysis. BMC Psychiatry 2020; 20: 120.
  24. Zang Y. Impact of physical exercise on children with attention deficit hyperactivity disorders: evidence through a meta-analysis. Medicine (Baltimore) 2019; 98: e17980.
  25. Helfer B, Cooper RE, Bozhilova N, et al. The effects of emotional lability, mind wandering and sleep quality on ADHD symptom severity in adults with ADHD. Eur Psychiatry 2019; 55: 45-51.
  26. Brandeis D, van Leeuwen TH, Rubia K, et al. Neuroelectric mapping reveals precursor of stop failures in children with attention deficits. Behav Brain Res 1998; 94: 111-125.
  27. Pliszka SR, Liotti M, Woldorff MG. Inhibitory control in children with attention-deficit/hyperactivity disorder: event-related potentials identify the processing component and timing of an impaired right-frontal response-inhibition mechanism. Biol Psychiatry 2000; 48: 238-246.
  28. Mowinckel AM, Alnæs D, Pedersen ML, et al. Increased default-mode variability is related to reduced task-performance and is evident in adults with ADHD. Neuroimage Clin 2017; 16: 369-382.
  29. Vatansever D, Bozhilova NS, Asherson P, et al. The devil is in the detail: exploring the intrinsic neural mechanisms that link attention-deficit/hyperactivity disorder symptomatology to ongoing cognition. Psychol Med 2019; 49: 1185-1194.
  30. Teicher MH, Samson JA. Childhood maltreatment and psychopathology: a case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. Am J Psychiatry 2013; 170: 1114-1133.
  31. van der Kolk B, Roth S, Pelcovitz D, et al. Disorders of extreme stress: the empirical foundation of a complex adaptation to trauma. J Trauma Stress 2005; 18: 389-399.
  32. Seckl JR, Meaney MJ. Glucocorticoid “programming” and PTSD risk. Ann N Y Acad Sci 2006; 1071: 351-378.
  33. Tomoda A, Sheu Y-S, Rabi K, et al. Exposure to parental verbal abuse is associated with increased gray matter volume in superior temporal gyrus. Neuroimage 2011; 54 Suppl 1: S280-S286.
  34. Choi J, Jeong B, Rohan ML, et al. Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biol Psychiatry 2009; 65: 227-234.
  35. Tomoda A, Suzuki H, Rabi K, et al. Reduced prefrontal cortical gray matter volume in young adults exposed to harsh corporal punishment. Neuroimage 2009; 47 Suppl 2: T66-T71.
  36. Huth-Bocks AC, Levendosky AA, Semel MA. The direct and indirect effects of domestic violence on young children’s intellectual functioning. J Fam Violence 2001; 16: 269-290.
  37. Koenen KC, Moffitt TE, Caspi A, et al. Domestic violence is associated with environmental suppression of IQ in young children. Dev Psychopathol 2003; 15: 297-311.
  38. Ybarra GJ, Wilkens SL, Lieberman AF. The influence of domestic violence on preschooler behavior and functioning. J Fam Violence 2007; 22: 33-42.
  39. Tomoda A, Polcari A, Anderson CM, et al. Reduced visual cortex gray matter volume and thickness in young adults who witnessed domestic violence during childhood. PloS One 2012; 7: e52528.
  40. Stahl SM. Mood Disorders. In: Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th edition. Cambridge, UK: Cambridge University Press, 2013.
  41. Kandel ER. Principles of Neural Science. 5th edition. New York, NY; McGraw-Hill, 2013.
  42. Purves D, Augustine GJ, Chikaraishi DM, et al. Neuroscience. 3rd edition. Sunderland, MA: Sinauer Associates, Inc., 2004.
  43. Nutt D, Demyttenaere K, Janka Z, et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol 2007; 21: 461-471.
  44. Rubia K, Halari R, Mohammad AM, et al. Methylphenidate normalizes frontocingulate underactivation during error processing in attention-deficit/hyperactivity disorder. Biol Psychiatry 2011; 70: 255-262.
  45. Simpson D, Plosker GL. Atomoxetine: a review of its use in adults with attention deficit hyperactivity disorder. Drugs 2004; 64: 205-222.
  46. Hannestad J, Gallezot JD, Planeta-Wilson B, et al. Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry 2010; 68: 854-860.
  47. Coghill DR, Seth S, Matthews K. A comprehensive assessment of memory, delay aversion, timing, inhibition, decision making and variability in attention deficit hyperactivity disorder: advancing beyond the three-pathway models. Psychol Med 2014; 44: 1989-2001.
  48. Franke B, Faraone SV, Asherson P, et al. The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 2012; 17: 960-987.
  49. Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1313-1323.
  50. Burt SA. Rethinking environmental contributions to child and adolescent psychopathology: a meta-analysis of shared environmental influences. Psychol Bull 2009; 135: 608-637.
  51. Christiansen H, Chen W, Oades RD, et al. Co-transmission of conduct problems with attention-deficit/hyperactivity disorder: familial evidence for a distinct disorder. J Neurol Transm (Vienna) 2008; 115: 163-175.
  52. Faraone SV, Biederman J, Wozniak J. Examining the comorbidity between attention deficit hyperactivity disorder and bipolar I disorder: a meta-analysis of family genetic studies. Am J Psychiatry 2012; 169: 1256-1266.
  53. MedlinePlus. What are single nucleotide polymorphisms (SNPs)? Available at: https://medlineplus.gov/genetics/understanding/genomicresearch/snp/. Accessed October 2020.
  54. Anttila V, Bulik-Sullivan B, Finucane HK, et al. Analysis of shared heritability in common disorders of the brain. Science 2018; 360: eaap8757.
  55. Taylor MJ, Larsson H, Gillberg C, et al. Investigating the childhood symptom profile of community-based individuals diagnosed with attention-deficit/hyperactivity disorder as adults. J Child Psychol Psychiatry 2019; 60: 259-266.
  56. Lesch KP. Editorial: Can dysregulated myelination be linked to ADHD pathogenesis and persistence? J Child Psychol Psychiatry 2019; 60: 229-231.
  57. Genome Wide Association Studies Fact Sheet. Available at: https://www.genome.gov/about-genomics/fact-sheets/Genome-Wide-Association-Studies-Fact-Sheet. Accessed October 2020.
  58. Schultz MR, Rabi K, Faraone SV, et al. Efficacy of retrospective recall of attention-deficit hyperactivity disorder symptoms: a twin study. Twin Res Hum Genet 2006; 9: 220-232.
  59. Larsson H, Chang Z, D’Onofrio BM, et al. The heritability of clinically diagnosed attention deficit hyperactivity disorder across the lifespan. Psychol Med 2014; 44: 2223-2229.
  60. Chang Z, Lichtenstein P, Asherson PJ, et al. Developmental twin study of attention problems: high heritabilities throughout development. JAMA Psychiatry 2013; 70: 311-318.
  61. Franke B, Faraone SV, Asherson P, et al. The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 2012; 17: 960-987.
  62. Faraone SV. Genetics of adult attention-deficit/hyperactivity disorder. Psychiatr Clin North Am 2004; 27: 303-321.
  63. Francx W, Oldehinkel M, Oosterlaan J, et al. The executive control network and symptomatic improvement in attention-deficit/hyperactivity disorder. Cortex 2015; 73: 62-72.
  64. Merzon E, Manor I, Rotem A, et al. ADHD as a risk factor for infection with Covid-19. J Atten Disord 2020: 1087054720943271.
  65. Harvard Kennedy School. Demographic determinants of testing incidence and COVID-19 infections in New York City neighborhoods. Available at: https://www.hks.harvard.edu/publications/demographic-determinants-testing-incidence-and-covid-19-infections-new-york-city. Accessed October 2020.
  66. Centers for Disease Control and Prevention. People at increased risk and other people who need to take extra precautions. Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fneed-extra-precautions%2Fpeople-at-increased-risk.html. Accessed October 2020.
  67. State of Israel Ministry of Health. New Coronavirus guidance. Available at: https://www.health.gov.il/English/News_and_events/spokespersons_messages/pages/10032020_22.aspx. Accessed October 2020.