ADHD: The Scientific Evidence

ADHD’s genetic link

 

A team of University scientists have revealed the first direct genetic link to attention deficit/hyperactivity disorder (ADHD).

The study, published in The Lancet, found that children with ADHD were more likely to have small segments of their DNA duplicated or missing than other children.

It also found significant overlap between these segments, known as copy number variants (CNVs), and genetic variants implicated in autism and schizophrenia, proving strong evidence that ADHD is a neurodevelopmental disorder – in other words, that the brains of children with the disorder differ from those of other children.

"We hope that these findings will help overcome the stigma associated with ADHD," according to Professor of Child and Adolescent Psychiatry Anita Thapar, School of Medicine, who led the study.

"Too often, people dismiss ADHD as being down to bad parenting or poor diet. As a clinician, it was clear to me that this was unlikely to be the case. Now we can say with confidence that ADHD is a genetic disease and that the brains of children with this condition develop differently to those of other children,” she added.

ADHD is one of the most common mental health disorders in childhood, affecting around one in 50 children in the UK. Children with ADHD are excessively restless, impulsive and distractible, and experience difficulties at home and in school. Although no cure exists for the condition, symptoms can be reduced by a combination of medication and behavioural therapy.

The condition is highly heritable – children with ADHD are statistically more likely to also have a parent with the condition and a child with an identical twin with ADHD has a three in four chance of also having the condition.

Until now there has been no direct evidence that the condition is genetic and there has been much controversy surrounding its causes, which some people have put down to poor parenting skills or a sugar-rich diet.

The University team analysed the genomes of 366 children, all of whom had been given a clinical diagnosis of ADHD, against over 1,000 control samples in search of variations in their genetic make-up that were more common in children with the condition.

 

 

"Children with ADHD have a significantly higher rate of missing or duplicated DNA segments compared to other children and we have seen a clear genetic link between these segments and other brain disorders," explains Dr Nigel Williams, School of Medicine.

"These findings give us tantalising clues to the changes that can lead to ADHD,” he added.

The researchers found that rare CNVs were almost twice as common in children with ADHD compared to the control sample – and even higher for children with learning difficulties. CNVs are particularly common in disorders of the brain.

There was also significant overlap between CNVs identified in children with ADHD and regions of the genome which are known to influence susceptibility to autism and schizophrenia. Whilst these disorders are currently thought to be entirely separate, there is some overlap between ADHD and autism in terms of symptoms and learning difficulties. This new research suggests there may be a shared biological basis to the two conditions.

The most significant overlap was found at a particular region on chromosome 16 which has been previously implicated in schizophrenia and other major psychiatric disorders and spans a number of genes including one known to play a role in the development of the brain .

"ADHD is not caused by a single genetic change, but is likely caused by a number of genetic changes, including CNVs, interacting with a child's environment," explains Dr Kate Langley, School of Medicine.

"Screening children for the CNVs that we have identified will not help diagnose their condition. We already have very rigorous clinical assessments to do just that,” she added.

The research was funded by the Wellcome Trust, with additional support from Action Medical Research, the Medical Research Council and the European Union.

Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, which has supported Professor Thapar's work for ten years, said: "These findings are testament to the perseverance of Professor Thapar and colleagues to prove the often unfashionable theory that ADHD is a brain disorder with genetic links.

“Using leading-edge technology, they have begun to shed light on the causes of what is a complex and often distressing disorder for both the children and their families."

 

 

Behavioural rewards 'work like drugs' for ADHD

New findings by Professor Chris Hollis of Nottingham University

 

A Nottingham University team measured brain activity as children played a computer game, offering extra points for less impulsive behaviour.

Their findings, published in Biological Psychiatry, could mean lower doses of drugs such as Ritalin in severe cases.But they warn teachers and parents may often struggle to give instant rewards.

Estimates vary, but it is believed that up to 5% of children in the UK have some form of attention-deficit hyperactivity disorder (ADHD).

This can lead to behavioural problems including impulsive actions, fidgeting and poor attention span, and can affect a child's academic and social progress.

Our study suggests that both types of intervention may have much in common in terms of their effect on the brain   Professor Chris Hollis, Nottingham University

In severe cases, stimulant drugs such as Ritalin, which act on parts of the brain associated with attention and behaviour, can be given.

In addition, parents are often asked to try to influence the child's actions directly by rewarding positive behaviour and making sure that there are negative consequences if a child behaves badly.

Research has suggested that, unlike in non-ADHD children, these incentives and disincentives only work well if delivered on the spot, as opposed to later in the day or week.

The Nottingham team wanted to look at the effects of this "behaviour therapy" in the brain of the child.

They devised a computer game in which children had to "catch" aliens of a certain colour, while avoiding aliens of a different colour.

The game was designed to test the children's ability to resist the impulse to grab the wrong sort of alien.

To test whether incentives made a difference, in one variant of the game the reward for catching the right alien was increased fivefold, as was the penalty for catching the wrong one.

Lower doses

Activity in different parts of the brain was monitored using an electroencephalogram (EEG).

They found that the incentives helped the children perform better at the game, although not to the same extent as the child's normal dose of Ritalin.

However, the EEG revealed that both were "normalising" brain activity in the same regions.

Professor Chris Hollis, who led the research, said that the combination of drugs and incentives produced the best results, and might mean children with ADHD could take lower doses of drugs while maintaining control of their behaviour.

He said: "Although medication and behaviour therapy appear to be two very different approaches of treating ADHD, our study suggests that both types of intervention may have much in common in terms of their effect on the brain.

"Both help normalise similar components of brain function and improve performance."

However, he conceded that it might not always be practical to use behavioural therapy.

"We know that children with ADHD respond disproportionately less well to delayed rewards - this could mean that in the 'real world' of the classroom or home, the neural effects of behavioural approaches using reinforcement and rewards may be less effective."

 

ADHD is accepted as a valid diagnosis by the UK's National Institute for Health and Clinical Excellence (NICE - the body responsible for providing evidence-based health promotion and treatment guidelines).

There is a growing base of evidence helping us to understand the causes of the condition, but gaps in the science of ADHD mean that there is as yet no biological way to diagnose the condition and behavioural observations are key.

This page gives a brief overview of the background to the condition and of the areas of research that are helping us to understand the causes.
A Brief History of ADHD

Although ADHD is often thought of as a recently-identified condition, stimulant medication was being being prescribed for for its symptoms as early as the 1930s.

First scientific thoughts were that the condition was caused by brain damage following trauma such as encephalitis or difficult birth.  There was no evidence for this, however, and these neurological interpretations were put aside as large epidemiological studies looked into the causes of children's behaviour problems.

Studies showed that the key traits of impulsivity, hyperactivity and inattention appeared in much higher numbers amongst children referred to psychiatrists than in the population as a whole.  In the 1980s, the American Psychiatric Association started to focus on describing the problems at a behavioural level.

In the US, moderate to severe levels were recognised and given the name  ‘Attention Deficit Hperactivity Disorder' - ADHD.  In Europe, only extreme levels were recognised, under the name ‘hyperkinetic disorder'.  The term ‘ADD' has also been used to describe the condition without the hyperactive element.  Currently, ADHD is the widely-accepted term.

Under US diagnostic criteria, three sub-types are available:  Primarily inattentive, primarily hyperactive, and combined.  Under World Health Organisation criteria, all three traits have to be present for an ADHD diagnosis to be given.

ADHD traits are often found alongside other mental health problems including depression, anxiety and bi-polar disorder.  Learning difficulties such as dyslexia can also be present.  The confounding effects of these must be evaluated in every case.

ADHD Science:  Research Areas

In recent years brain imaging has shown links between ADHD and brain functioning, and biological investigations are indicating links with molecular genetics.  There are also a number of important environmental factors.  The following is a brief review of each of these topics.
Brain Functioning

An important focus for research is the field known as ‘executive functioning'.  Whilst there is still some debate about exactly how this is defined, it is generally understood to mean the processes that include planning, organisation, maintaining a mental set, selective attention, motivation and self control.  People with poor executive functioning find it difficult to direct their behaviour towards goals, to regulate their behaviour, and to understand consequences.

A review of 83 cognitive experimental studies on executive functioning (Wilcutt et al, 2005) found that groups of people with ADHD had significant deficits in executive functioning.

The neural mechanisms underlying executive function are not yet clearly understood.  A key question is whether impairments are directly linked to a deficit in brain processes or whether they are secondary to more general processes.

There has also been some work on non-executive functions.  A meta-analysis (Alderson et al, 2007) showed, for example, slower stop signal reaction times amongst groups of people with ADHD, and also that individuals with ADHD had more variable reaction times than those without.

The pattern of findings suggests that those with ADHD suffer from a wider impairment of attentional and cognitive processing rather than just difficulties with regulating their behaviour.

Further clues on brain functioning come from neuro-imaging studies.  A meta analysis (Dickstein et al, 2006) indicated that ADHD groups had reduced activation in some brain regions but hyperactivity in others.

Pliszka et al (2006 ) compared neuro-imaging results between children with ADHD who had been treated with drugs and those who had not, and found no difference on most measures.

A systematic meta analysis of brain structural changes (Valera et al, 2007) found that ADHD participants showed reductions in brain volume - but studies did not distinguish between those who had taken medication and those who had not.

Dopamine has long been suspected to be a critical part of the picture.  Dopamine is a neurotransmitter - a chemical which relays, amplifies, and modulates signals between neurons.  There is a strong body of research showing that it is involved in the control of movements, and that it is key to learning how to associate stimuli with rewards, reinforcement, and motivation.  Either too much or too little dopamine can cause impairment in different ways - accurate regulation is vital.

A PET brain scan study (Volkow et al, 2009) showed differences in the potential to respond to dopamine amongst those participants with ADHD.
Genetics

Twin studies show a clear genetic element in ADHD.  If one identical twin has the condition, then the other appears twice as likely to have it as a non-identical sibling - assuming they have experienced the same environmental influences.  In addition, Sprich et al (2000) found that biological parents of children with ADHD are more likely to have ADHD than adoptive parents, and more likely to have the condition than the parents of children without ADHD.

At the molecular level, specific genetic variants associated with small increases in the risk for ADHD have been identified within the dopamine D4 receptor gene and close to the D5 receptor gene (Li et al, 2006).  The level of risk is similar to that for genetic influences in common conditions such as diabetes - it isn't sufficient to cause the condition but could contribute a small increase to the overall risk.
Diet

McCann et al (2007) confirmed that artificial colours and sodium benzoate were linked to increased short-term levels of ADHD symptoms in children both with and without the condition, but that there was no indication of a long-lasting effect.

A link between ADHD and long chain polyunsaturated fatty acids (PUFA) has been suggested, but it's not possible to take this idea further at the moment because there is no consensus on the physiological significance of PUFA measurements.

Some children do demonstrate extreme reactions to certain foods, both natural and artificial, and may be helped by medically-supported exclusion diets.

 

Environment

The following factors that adversely affect brain development before birth and in early childhood have been linked with the risk of ADHD:

* Maternal smoking in pregnancy (Linnet et al, 2003)
* Alcohol consumption in pregnancy (Mick et al, 2002)
* Heroin use during pregnancy (Ornoy et al, 2001)
* Foetal oxygen deprivation, brain injury, exposure to toxins, and zinc deficiency (Toren et al, 1996).

These risk factors don't act in isolation, but interact with each other and with other risk factors including genetic susceptibility.

Pre-natal maternal stress has been shown to increase the risk of various developmental disorders including ADHD symptoms, emotional and cognitive problems, anxiety and language delay (Talge et al, 2007).  This link isn't specific to ADHD, and the mechanisms are not yet understood.

It has also been established that early adversity increases the risk of ADHD. Studies of children who have survived deprivation in institutional care (Roy et al, 2000) found that they showed persistent problems with inattention and hyperactivity.  Maltreatment, in particular sexual abuse, has been found to lead to higher levels of ADHD (Famularo et al,1992, McLeer et al ,1994). The mechanisms for this may include a failure to develop cognitive and emotional control at the appropriate stage.

Disruptive family life and parenting difficulties are more common amongst the families of children with ADHD, but there is no evidence to suggest that this is a cause of ADHD rather than an effect.  In addition, the fact that there is a genetic link tells us that many parents of ADHD children may themselves have undiagnosed ADHD, so making it harder for them to manage their children.

Conclusion

Research consistently shows that those with ADHD have differences in brain function, structure and performance on neuro-cognitive tests.  However, the differences from control subjects aren't universal, and don't apply to all those with a clinical diagnosis.

It is not yet known whether the biological and psychological factors are parts of a common pathway, independent contributions to multiple causes, or simply co-existing with no direct causal role.

Diagnosis continues therefore to be on the basis of behavioural observation, but we are confident that ongoing research will lead to a better understanding of ADHD and bring about new ways of helping those with the condition to achieve their full potential.

You can find a more in-depth discussion of the points covered here in the NICE Guidelines for ADHD Treatment.

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