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What causes attention deficit hyperactivity disorder?

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What causes attention deficit hyperactivity disorder?

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Attention deficit hyperactivity disorder (ADHD) affects around 1-3% of children. There is a high level of comorbidity with developmental and learning problems as well as with a variety of psychiatric disorders. ADHD is highly heritable, although there is no single causal risk factor and non-inherited factors also contribute to its aetiology. The genetic and environmental risk factors that have been implicated appear to be associated with a range of neurodevelopmental and neuropsychiatric outcomes, not just ADHD. The evidence to date suggests that both rare and multiple common genetic variants likely contribute to ADHD and modify its phenotype. ADHD or a similar phenotype also appears to be more common in extreme low birth weight and premature children and those exposed to exceptional early adversity. In this review, the authors consider recent developments in the understanding of risk factors that influence ADHD.
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Arch Dis Child 2012;97:260 –265 . do i:10.1136 /ar chd isc hil d-2 011-3 004 82260
Accepted 20 July 2011
Published Online First
7 September 2011
A B S T R A C T
Attention defi cit hyperactivity disorder (ADHD) af fects
around 1–3% of children. There is a high level of
comorbidity with developmental and learning problems
as well as with a variety of psychiatric disorders. ADHD
is highly heritable, although there is no single causal risk
factor and non-inherited factors also contribute to its
aetiology. The genetic and environmental risk factors
that have been implicated appear to be associated with
a range of neurodevelopmental and neuropsychiatric
outcomes, not just ADHD. The evidence to date
suggests that both rare and multiple common genetic
variants likely contribute to ADHD and modif y its
phenotype. ADHD or a similar phenotype also appears
to be more common in extreme low birth weight and
premature children and those exposed to exceptional
early adversity. In this review, the authors consider
recent developments in the understanding of risk factors
that infl uence ADHD.
Hyperkinetic disorder was fi rst described as a
syndrome in 1902 by George Still, a UK paedia-
trician. The disorder is characterised by develop-
mentally inappropriate hyperactivity, inattention
and impulsiveness. These symptoms must be
of early onset, present in more than one setting
and associated with impairment in functioning
(eg, peer relationships, educational achievement).
The current diagnostic terms of hyperkinetic dis-
order, used in the International Classifi cation of
Diseases, 10th revision (ICD-10) and attention
defi cit hyperactivity disorder (A DHD), adopted
by the Diagnostic and statistical manual of mental dis-
orders , fourth edition (DSM-IV) are similar but not
identical (see table 1 for DSM-IV criteria). ICD-10
has more strict criteria, with a threshold number
of symptoms in each of the domains of inatten-
tion, hyperactivity and impulsivity needed for
diagnosis. Prevalence rates overall in the UK vary
from 1.4% for hyperkinetic disorder
1 to 2.23%
2
for ADHD. Those with intellectual disability (ID)
and boys (3–4:1 male:female ratio) are more com-
monly affected.
Comorbidity is typical. ADHD commonly co-
occurs with specifi c and global developmental and
learning problems that include autistic spectrum
disorders (ASDs), diffi culties with speech and lan-
guage, motor co-ordination and reading, as well
as with a range of psychiatric disorders notably
oppositional defi ant disorder, conduct disorder
and tic disorders. Anxiety, depression and more
rarely bipolar affective disorder can also compli-
cate the clinical presentation. Longitudinal stud-
ies show that ADHD symptoms and impairment
often persist into adult life and are associated with
increased risk of antisocial behaviour and sub-
stance misuse,
3 poor educational attainment and
workplace performance, unemployment, friend-
ship diffi culties and social problems.
4
CAUSES OF ADHD
ADHD, like other common medical and psychiat-
ric disorders (eg, asthma, schizophrenia), is infl u-
enced by multiple genes, non-inherited factors and
their interplay.
5 There is no single cause of ADHD
and exposure to a risk factor does not necessar-
ily result in disorder. This means that any given
risk factor will only be observed in a proportion of
cases and will also be found in those who are unaf-
fected. Also, risk factors that contribute to the ori-
gins of ADHD might not necessarily be the same
as those that infl uence its course and outcomes.
A further complexity is that genetic factors can
exert indirect risk effects through interplay with
environmental factors. Genes can alter sensitiv-
ity to environmental risks (gene–environment
interaction), for example, environmental toxins or
psychosocial adversity.
6 Inherited factors can also
infl uence the probability of exposure to certain
environmental risks (gene–environment correla-
tion; see later). This means that environ mental
and genetic risk effects cannot be considered as
entirely distinct.
G E N E T I C S
Evidence of an inherited contribution to ADHD
There is robust evidence from a wide range of
study designs of a strong inherited contribu-
tion to ADHD. Family studies have consistently
found higher rates of ADHD (twofold to eightfold
increased risk)
7 in parents and siblings of affected
probands compared with relatives of unaffected
controls. Twin studies have shown that monozy-
gotic twin pairs have much higher concordance
rates for ADHD than dizygotic twin pairs
8 and
adoption studies have also found increased rates of
ADHD in the biological parents of ADHD adopt-
ees compared with both the adoptive parents of the
probands and with the parents of controls without
ADHD (eg, Sprich et al
9 ). Mean heritability esti-
mates are around 79%.
10 However, heritability is
not 100%, suggesting non-inherited factors also
contribute.
ADHD also appears to share an inherited liabil-
ity with other neurodevelopmental and psychiatric
problems, notably ASDs, developmental coordi-
nation problems,
10 reading ability,
11 IQ,
12 conduct
and mood problems.
13
14 These fi ndings suggest the
same inherited and familial risks can result in the
manifestation of different clinical phenotypes.
Searching for ADHD susceptibility genes
The high heritability of ADHD has fuelled efforts
to identify susceptibility genes. As is the case for
1 Department of Psychological
Medicine and Neurology,
Cardiff University School of
Medicine, Cardiff, UK
2 MRC Centre in
Neuropsychiatric Genetics and
Genomics, Cardiff Universit y,
Cardiff, UK
Correspondence to
Anita Thapar, Child and
Adolescent Psychiatry Section,
Department of Psychological
Medicine and Neurology,
Cardiff University, School of
Medicine, Heath Park, Cardiff,
CF14 4XN, UK;
t h a p a r @ c f . a c . u k
What causes attention defi cit hyperactivity disorder?
A n i t a T h a p a r , 1,2 M i r i a m C o o p e r , 1, 2 R a c h e l J e f f e r i e s , 1, 2 E v a n g e l i a S t e r g i a k o u l i 1,2
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Arch Dis Child 2012;97:260 –265 . do i:10.1136 /ar chd isc hil d-2 011-3 004 82 261
other complex disorders, molecular genetic studies of ADHD
have so far main ly been based on examining common DNA
variation (the common disease–common variant hypoth-
esis). This was originally investigated using candidate gene
approaches, in which assumptions about the pathophysiology
of the disorder are made, and more recently with ‘hypothesis-
free’ genome wide association studies (GWAS), in which the
frequencies of thousands of single nucleotide polymorphisms
(SNPs) across the genome are compared between cases and
controls.
15 There is also emerging interest in the contribution
of rare genetic variants to ADHD.
Examining specifi c genes of interest: candidate gene
association studies
There is a very large volume of literature on candidate genes
reported to be associated with A DHD, but only a few have con -
sistently withstood replication ( table 2 ) and meta-analyses.
The most robust evidence of association with ADHD has
been shown for a dopamine D4 receptor gene ( DRD4 ) variant.
This receptor binds both dopamine and norepinephrine and
there is a f unctional polymorphism (variable number tandem
repeatVNTR) in exon III of the gene that has been exten-
sively studied. The seven-repeat allele of this polymorphism
ha s been found to be assoc iated wit h ADH D in dif ferent met a-
analyses.
16
18 The latest meta-analysis shows signifi cant asso-
ciation of small effect size,
19 although there is also evidence of
substantial heterogeneity across studies.
Another dopamine receptor gene, DR D5 , has also been con-
sistently implicated. A microsatellite genetic marker located
close (18.5 kb) but out side the gene region has also been found to
be associated with A DHD in several meta-analyses,
19 although
again with evidence of moderate heterogeneit y across studies.
The dopamine transporter gene ( DAT1) was originally con-
sidered the most likely ADHD candidate gene because it is
responsible for the reuptake of dopamine in the presynaptic
cleft,
20 inhibited by stimulants and also because the DAT1
knockout mouse exhibits hyperactivity and defi cits in inhibi-
tory behaviour.
21 In the most recent meta-analysis,
19 signifi -
cant evidence of association was found with the 480-bp allele
of the most commonly studied polymorphism (a VNTR in
the 3’ untranslated region (UTR) region of the gene) as well as
with other polymorphisms in the same gene. The substantial
heterogeneity reported could be the result of multiple poly-
morphisms in this gene increasing risk to ADHD or gene–en-
vironment interact ion between the 3’ U TR VNT R and prenatal
factors, such as maternal alcohol consumption
22 or maternal
smoking during pregnancy,
23 although these associations have
not been widely replicated.
The gene encoding catechol O methyl transferase ( COMT ),
which catalyses the degradation of dopamine, has also been
studied extensively in A DHD. A functional polymorphism in
the gene, which results in a valine–methionine transition and
affects enzyme activity, has been the focus of many genetic
studies. Neither meta-analysis
19 nor pooled analysis
17 has
found any evidence of association with ADHD. There is how-
ever evidence that COMT could have a modifying effect on the
ADHD phenotype rather than increase the risk of the disorder
itself. The COMT val/val genotype (associated with greater
enzyme activity) was found to be associated with antisocial
behaviour in patients with ADHD,
24 then replicated in two
independent populations as well as shown in a pooled analy-
sis.
25 The association fi nding has been subsequently replicated
in other studies and the link with antisocial behaviour appears
to be mediated through impaired social understanding.
26 This
association is specifi c to antisocial behaviour in ADHD because
it has not been observed with antisocial behaviour alone.
25
26
Searching across the genome for common genetic risk
variants: GWAS
Candidate gene association studies were relatively successful
for ADHD compared with other neuropsychiatric/develop-
mental disorders. However, GWAS ndings for ADHD are
still at an early stage, with no common gene variant having
Table 1 DSM-IV criteria for attention defi cit hyperactivit y disorder
Criteria can be met in either or bo th domains: for inatte ntive type, hyperactive -
impulsive type or combined type
Inattention Hyperactivity impulsivity
At least six of the following
symptoms
At least six of the following symptoms
Fails to sustain attention in t asks or
play activities
Often fi dgets wi th hands or squir ms in
seat
Often fails to follow throug h on
instructions from others
Dif culty re maining seated when
required
Often avoids tasks th at require
sustained men tal ef fort
Runs about or clim bs on things
excessively in situat ions when it is
inappropriate
Often easil y distr acted Exhibits a persistent pat tern of motor
activ ity (al ways on the go)
Often loses things that are necessa ry
for tasks or activitie s
Oft en noisy in playing or dif cu lty en gag-
ing quie tly in leisure ac tivities
Appears not to listen to what is be ing
said to him/h er
Dif culty waiting in t urns in games or
group situations
Fails to p ay attention t o details, or
makes careles s mista kes
Often blur ts out answers before ques-
tions have been co mpleted
Often forgetfu l in daily activi ties Often interrupt s or intrudes on others
Oft en has diffi culty or ganising tasks
and activities
Often talks excessi vely
Additional criteria requir ed: Onse t before the age of 7 years, f unctional impairment,
impair ment present in more than one set ting
DSM-IV, Diagnostic and statistical manual of menta l disorders, fourth edition
Table 2 Candidate genes associated with ADHD selecting the most
consistently replicated fi ndings
Gene Polymorphism OR PConsistency
DRD4 7-repeat allele of
VNT R in exon III
1.27 <0.00001 Replicated in four
meta-analyses/
pooled analyses
DRD5 148 -b p mic ro sa t-
ellite repeat
1.22 0.000095 Replicated in four
meta-analyses/
pooled analyses
DAT1 480-bp VNTR in
3’ UTR
1.1 0.002 Replicated in t wo
meta-analyses/
pooled analys es, did
not replicate in four
SNAP25 T1065G 1.15 0.03 Replicated in two
meta-analyses
but not s ame
polymorphism
COMT and
antisocial
behaviour in
ADHD
Val158Met poly-
morphism
2.82 <0.01 Replicated in three
large independent
samples
Reported OR and p v alue are from Gizer et al meta-analysis 19 apar t from CO MT , for
which OR and p value are take n from L angley et al . 26
ADHD, attention defi cit hyper activity disorder; COMT, catechol -O-methyltrans-
ferase; DAT1, dopamine trans porter gene; DRD4, dopa mine D4 recepto r gene;
DRD5, dopamine D5 recept or gene; SNAP25, synaptosomal-associate d protein of
25 kD; UTR, unt ranslated region; VN TR, variable n umber tandem re peat.
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yet been identifi ed.
27 The same has been true for autism. The
lack of genome-wide signifi cant results may be because of
the large sample sizes required. Because of the heavy mul-
tiple testing burden and the small effect sizes expected, tens
of thousands of cases and controls are likely to be required,
as has been shown in other complex disorders such as dia-
betes.
28 None of the four published GWAS of ADHD has
achieved genome-wide signifi cant results.
29
32 A meta-analy-
sis of these studies that included 2064 parent–child trios, 896
cases and 2455 controls had a best p value of 1.2×10
−6 and no
SNP reached genome-wide signifi cance (p=5×10
−8 ).
33
Although these results appear disappointing, it has to
be remembered that ADHD GWAS studies are still in their
infancy. Apart from sample sizes, which are clearly important,
there is the issue of sample heterogeneity, which has also been
highlighted by meta-analyses of candidate gene studies
19 and
can make collaboration and replication of signifi cant results
diffi cult.
27 Another view is that disorders such as ADHD and
autism may be better explained by the effect of rare genetic
variants.
The contribution of rare genetic variants: chromosomal
anomalies, genetic syndromes and copy number variants
A number of different chromosomal anomalies including
abnormalities in the number of chromosomes (notably sex
chromosome aneuploidies) and chromosomal structure as well
as some single gene disorders have been found to be associ-
ated with higher rates of ADHD. Fragile X syndrome, tuber-
ous sclerosis and several microdeletion syndromes including
Smith Magenis and Velocardiofacial (VCFS; 22q11 microdele-
tion) syndromes are associated with ADHD (more commonly
inattentive type). They are also associated with other neurode-
velopmental and psychiatric disorders (eg, ASD, psychosis in
VCFS). However routine screening in those without ID does
not appear to be indicated.
34
35
Copy number variants (CNVs) are a type of chromosomal
struct ural variant. These DNA segments va ry in size between
people and can be either duplications, when there is a gain
of DNA, or deletions, when there is a loss of DNA. They are
part of t he normal variation of t he human genome.
36 Large
(>500 kb), rare (<1% frequency) duplications and deletions
have been implicated in the aetiology of neurodevelopmental
disorders, such as autism,
37 schizophrenia and ID.
38 Studies
that have examined rare CNVs of all sizes in ADHD have
not found an increased rate of deletions or duplications in
cases
39
40 but have found CNVs to be enriched for neurode-
velopmental genes. In a UK study that focused on large, rare
CNVs in ADHD (410 cases and 1156 controls), there was a
signi cantly i ncreased rat e i n c ases compared w it h controls.
41
This rate was especially high in those with ADHD and ID
but was not restricted to this group. Restricting analysis to
those without ID, this study also reported an overlap of CNVs
found i n A DH D w ith both autism and schizophrenia, further
strengthen ing the notion of ADHD being a neurodevelop-
mental disorder.
41
ENVIRONMENTAL RISK FACTORS
Inherited factors are not the only explanation of ADHD.
Although there are a number of environmental risk factors
that are associated with A DHD ( table 3 ), identif ying which of
these are causal is challenging. This is because many observed
associations m ight arise as a result of sy mptoms/disorder i n the
child or the parent (reverse causation eg, peer rejection, fam-
ily adversity,
42 low socioeconomic status
43 or head injury),
44
Table 3 Environmental factors repor ted to be associated with ADHD
Mater nally r elate d prenatal risks Alcoh ol in pregnancy
Smoking in pregnancy
Drug use in pregnancy
Mater nal stress in pregnancy
Mater nal health in pregnanc y (obesit y)
Pregnancy and birth c omplic ations Bl eeding in pregnancy
Protracted/complicated delivery
Prematurity/low birth weight/intrauterine
growth restriction
Low APGAR score
External agents Infections
Expo sure to lead and ot her toxi ns eg, PCB
Nutritiona l factors
Psychosocial adversities
ADHD, attention defi cit hyperactivit y disorder; PCB, polychlorinated biphenyl.
Figure 1 Mother’s genes can in uence ADHD as well as exposure to
c e r t a i n e n v i r o n m e n t a l f a c t o r s .
or from unmeasured confounders that can include inherited
factors (see gure 1 ).
45 Interestingly, time trends studies have
shown no increase in the population rate of A DHD over time,
although identifi cation has increased.
46 Cross-national studies
have not yet found consistent evidence of lower ADHD rates in
certain countries. These fi ndings contrast with data on child-
hood behavioural problems for which rates have risen in the
last 50 years
46
47 and vary geographically. These results sug-
gest that for ADHD there are more likely to be multiple envi-
ronmental risks, each of small effect, with the overall burden
of these risks remaining similar over time and between coun-
tries. Some of these risk effects might be modifi ed by genetic
infl uences (gene–environment interaction). Environmental
risks can also alter gene function through tissue-speci c epi-
genetic mechanisms. For example, animal studies have dem-
onstrated how adverse early rearing has an impact on stress
responses through such mechanisms and that these biological
changes can be transmitted to subsequent generations.
48
Maternal smoking, alcohol, drug use and stress/anxiety
in pregnancy
Clinical and epidemiological associations show a consis-
tent association (OR=2.39)
49 and dose–response relationship
between prenatal exposure to maternal cigarette smoking
(maternal reports and urinar y cotinine levels) and offspring
ADHD. Although biologically plausible, because smoking
is known to have an effect on physiological processes that
may create risks relevant to the origins of ADHD, it is dif-
cult to adequately control for familial and social confounds
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in observational designs. Recent studies suggest that the asso-
ciation with A DHD (but not with lower birth weight) may
wholly or substantially represent familial and inherited con-
founds (gene–environment correlation).
50
51
Alcohol is a known teratogen and prenatal exposure to
heavy maternal drinking can cause foetal alcohol syndrome,
the behavioural aspects of which include symptoms of inat-
tention and hyperactivity. However, associations between less
extreme alcohol use i n pregnanc y and offspring A DHD/ADH D
symptoms are inconsistent.
52
53 Findings are also inconsistent
with regard to links with prenatal exposure to illicit drugs.
52
Maternal stress in pregnancy has also been reported to be
associated with offspring A DHD symptoms, although recent
work suggests that for ADH D (but not antisocial behaviour
or anxiety), this might also refl ect inherited links between
mother and child (gene–environment correlation) rather than
being causal.
54 In summary, with the exception of the extreme
phenotype of foetal alcohol syndrome, the evidence that
maternally related cigarette and substance use and stress in
pregnancy play a major causal role in ADHD remains equivo-
cal, although many of these factors are clearly detrimental for
other offspring outcomes.
Low birth weight and prematurity
Most studies, including meta-analyses of premature and/
or low birth weight children, fi nd evidence of an association
with ADHD (relative risk of 2.64 for ADHD in premature
children)
55 and ADHD symptoms/attentional problems.
56
The risk appears to be strongest for extreme prematurity and
very low birth weight in relation to inattention symptoms
and ADHD inattentive subt ype.
57
58 Some preliminary stud-
ies also suggest the likely importance of intrauterine growth
restriction (small for gestational age).
59
60 However it is not
known whether low birth weight and/or prematurity and
other associated pre/perinatal risks (see table 3 ) are risk mark-
ers of ADHD or whether they are causal. The fi ndings at least
suggest the need for heightened awareness of possible ADHD
in very premature/low birth weight children.
Toxins and diet
Specifi c environmental exposures that seem to have relevance
to the ADHD phenotype include organic pollutants (eg, pes-
ticides, polychlorinated biphenyl (PCBs)) and lead. These may
damage cognitive and neural systems known to be implicated
in ADHD.
61
Associations between organophosphate pesticide exposure
and ADHD have been investigated cross-sectionally,
62 and
prospectively (eg, Eskenazi et al , Marks et al , Rauh et al
63
65 )
using assessments of prenatal and postnatal (childhood) uri-
nary organophosphate metabolites and umbilical cord plasma
levels of pesticides.
PCBs are a large group of toxic manufactured organic com-
pounds that were previously mass produced. Both human
and animal studies have examined the effect of PCB expo-
sure on neurobehavioural outcomes similar to those affected
in ADHD, and these have found evidence of impairments in
working memory, response inhibition and cognitive fl exi-
bility.
66 A recent prospective study also found a positive
association between low-level prenatal PCB exposure and
ADHD-type behaviour in middle childhood, with a dose–re-
sponse relationship.
67 Both human and animal studies of lead
exposure have shown similar impairments in executive func-
tions and attention, with cognitive fl exibility, vigilance and
alertness being most reliably affected.
66 There is also emerging
evidence from several studies that lead could be implicated in
ADHD even at low levels, but causality cannot be assumed
from the evidence to date. Similarly, further work is needed
to draw fi rm conclusions about how important pesticides and
PCBs are as causes of ADHD.
Dietary constituents that have been studied in relation to
ADH D symptom s include sugar, a rtifi cial food colourings, zinc,
iron, magnesium and omega-3 fatty acids. There is no convinc-
ing evidence yet that diet plays a major causal role in A DHD.
However, a separate issue relates to using dietary change to
modify symptoms. Overall, the value of the studies looking
at diet and A DHD are limited by small sized trials, subjective
measures of outcome and varied protocols for intervention, and
on this basis there has been inadequate evidence to suggest
that dietar y manipulation can ameliorate ADHD symptoms
in children.
68 However, a recent randomised controlled trial of
a restricted elimination diet based on high or low IgG foods
suggests a benefi cial effect of a restricted elimination diet on
ADHD and oppositional de ant disorder symptoms.
69
Psychosocial adversity
Adverse social and family environments such as low parental
education, social class, poverty, bullying/peer victimisation,
negative parenting, maltreatment and family discord are asso-
ciated with ADHD. However, the designs used so far have not
been able to show that these are defi nite causes of ADHD. For
example, longitudinal and treatment studies suggest that nega-
tive mother/son
70 and peer relationships arise in response to
child ADHD symptoms. This contrasts with fi ndings for child
antisocial behaviour/conduct disorder in which a variety of
designs including treatment trials have consistently found that
adverse social and family environments are causal. However,
psychosocial factors might modify ADHD expression espe-
cially in those who are genetically susceptible, for example
by infl uencing comorbidities such as conduct disorder, depres-
sion symptoms and level of impairment. This needs further
investigation.
One exception is exposure to extreme early deprivation.
A study of Romanian orphans adopted in the UK found a
deprivation-speci c inattentive and overactive pattern of
behaviour.
71 It remains to be examined whether a similar pat-
tern of defi cits arises in response to less extreme adversit y.
C O N C L U S I O N
In summary, there is strong evidence of an inherited contri-
bution to ADHD, although non-inherited factors that likely
include environmental risks and chance events (including de
novo genetic changes) are also important. There is no single
cause of ADHD and the risk factors that have been identifi ed
so far appear to be non-specifi c. That is, risks such as chro-
mosomal microdeletions (eg, VCFS), large, rare CNVs, extreme
low birth weight and prematurity appear to affect a range of
different neurodevelopmental and psychiatric phenotypes.
Genetic risks likely also include multiple common gene vari-
ants of small effect size that have yet to be identi ed, with
the possible exception of a few dopaminergic genes. With the
costs of DNA sequencing dropping, there is likely to be an
increasing focus on identifying rare genetic variants, including
structural variants such as CNVs and other rare mutations
with larger risk effects.
Despite the rapid advances in genetics, there is still a need
for further research into environmental risks. Although many
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factor s are associat ed with AD HD, differen t designs are n eeded
to test which are causal.
45 T he strongest evidence relates to the
links between ADHD/ADHD-like behaviours and relatively
rare extreme adversities, specifi cally extreme prematurity,
very low birth weight, foetal alcohol syndrome and a pat-
tern of behaviours associated with institut ional deprivation in
the early years. Less is k nown about risk factors that modify
ADHD outcomes. One exception is the association bet ween
COMT and antisocial behaviour in ADHD that is well repli-
cated now and highlights that behavioural problems in those
with A DHD may have different origins to behavioural prob-
lems in general.
Cumulatively, the available evidence goes some way
towards highlighting groups who are at higher risk; specifi -
cally those who have a family history of ADH D and/or neu-
rodevelopmental or learning problems, and those who have
been exposed to the environmental adversities described ear-
lier. However, none of these risks, including the genetic ones,
provide tests or biomarkers of ADHD. It is hoped that, in the
future, improved identi cation of ADHD risk factors and path-
ways will increase our understanding of the as yet unknown
pathogenesis of ADHD and pave the way for improving diag-
nosis and treatment.
A c k n o w l e d g e m e n t s Ongoing ADHD research supported by the Wellcome Trust.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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... Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neuropsychiatric condition characterized by age-inappropriate inattention and hyperactivity/ impulsivity [1,2]. Generally, children with ADHD perform worse than their typically developing peers in reaction time variability, intelligence/achievement, vigilance, working memory, and response inhibition [2], which can have a negative impact on their lives, families, and society. ...
... Technically, MRI studies reporting brain networks in ADHD can be divided into the following three subcategories: (1) functional connectivity networks (FCNs), which explore the correlation of regional functional MRI (fMRI) signals, suggesting a less-optimized topological organization [7,8]; (2) white matter connectivity networks (WMCNs), which are based on diffusion tensor imaging (DTI) and have also been used to investigate the structural networks in ADHD [9,10]; (3) morphological brain networks (MBNs), which rely on structural T1-weighted MRI sequences and were constructed by calculating interregional morphological similarities [13]. Compared with FCNs and WMCNs, MBNs have the following advantages [14,15]: (1) easy to obtain imaging modality (T1-weighted image) in a clinic; (2) greater image quality (signal-tonoise ratio); (3) much simpler preprocessing pipeline and no need to remove the physiological noise; (4) relatively small movement artifact. Currently, population-based structural covariance networks (SCNs) are the most common MBNs [16][17][18]. ...
... The current study has some limitations. First, previous studies have reported the correlations between ADHD and obesity and/or family income, which also have a critical role in children's brain development [1,2]. In our study, we did not include all possible elements. ...
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Full-text available
To investigate the topological organization of individual-based morphological brain networks (MBNs) in attention-deficit/hyperactivity disorder (ADHD) children with different methods. A total of 60 ADHD children and 60 typically developing (TD) controls matched for age and gender were enrolled. Each participant underwent a structural 3D T1-weighted scan. Based on the inter-regional morphological similarity of GM regions, Kullback–Leibler-based similarity (KLS), Multivariate Euclidean Distance (MED), and Tijms’s method were used to construct individual-based MBNs, respectively. The between-group difference of global and nodal network topological profiles was estimated, and partial correlation analysis was used for further analysis. According to KLS and MED-based network, ADHD showed a decreased global efficiency (Eglob) and increased characteristic path length (Lp) compared to the TD group, while Tijms’s method-based network showed no between-group difference in global and nodal profiles. Nodal profiles were significantly decreased in the bilateral caudate, and nodal efficiency of the bilateral caudate was negatively correlated with clinical symptom severity of ADHD (P < 0.05, FDR-corrected) by the KLS-based network. Nodal betweenness was significantly decreased in the left inferior occipital gyrus and correlated with clinical symptom severity of ADHD (P < 0.05, FDR-corrected) by the MED-based network. ADHD was found to have a significantly less integrated organization and a shift to a “weaker small-worldness” pattern, while abnormal nodal profiles were mainly in the corpus striatum and default-mode networks. Our study highlights the crucial role of abnormal morphological connectivity patterns in understanding the brain maturational effects in ADHD and enriching the insights into MBNs at an individual level.
... Ha sido revelador descubrir la frecuencia del dolor en el acortamiento aquíleo pues aunque adelantada por otros autores (222) no se había precisado de forma tan detallada en MPI en pacientes de nuestro entorno (223). Verificamos en fin que el dolor en MPI coexiste con factores como la presencia de acortamientos musculares y la alta frecuencia de TDAH comórbido, sugiriendo que la marcha de puntas puede ser un indicador precoz de TDAH como ya se ha sugerido en otras patologías cognitivas de la infancia (221). Es por ello que proponemos desterrar para siempre la idea de abordar la MPI como una "patología menor", viendo tanto su repercusión funcional como la asociación con determinadas comorbilidades, al margen de que pueda (o no) desaparecer espontáneamente (224). ...
Preprint
Idiopathic toe walking (ITW) is a gait abnormality featured by voluntary adoption of gait patterns without heel strike, generally in the absence of shortening of triceps surae. It is very heterogeneous and several hypotheses concerning its etiopathogenesis exist. Currently, diagnosis is based on the exclusion of other disorders. Children with ITW may show other comorbidities and clinical problems that lead to outpatient consultations with orthopedics or physical medicine. This work focuses on the improvement of the clinical characterization and the gait assessment of children with ITW. It also evaluates the efficacy of physiotherapy and the combination of physical therapy with botulinum toxin (BTx) and the gait changes in children with ITW after BTx. This dissertation focuses on 4 key objectives: The first objective was to provide a clinical description of a group of patients with ITW throughout a pediatric physical therapy consultation. Patients who were referred due to toe walking during the time of the study, were systematically evaluated through systematic examination and a screening tool called "Toe Walking Tool" (TWT). Out of all the patients seen (100), 77 were diagnosed of ITW. Pain, Achilles shortening measured by Silfverskjoldt's maneuver and symptoms of attention deficit disorder with or without hyperactivity were assessed. Around 4 out of 10 evaluated patients, showed subacute-chronic pain with a significant impact on their daily life. We also observed that Achilles' shortening was greater in older patients. Knee flexor shortenings were also found. ADHD diagnosis was frequent comorbidity in this sample. The second objective consisted of creating an algorithm for clinical management, the definition of a standardized protocol for physiotherapy, and the clinical evaluation of the results after their implementation. As a result, a therapeutic algorithm adapted to our clinical environment was developed and presented as part of this dissertation. Besides, in 77 patients, we saw an improvement in pain, muscular shortening, and motor coordination and a tendency to decrease the frequency of falls. The third objective, was to evaluate gait in children with ITW through instrumental gait 12 analysis. For that, 28 patients with ITW were compared with a control group of 33 healthy children. Spatiotemporal and kinematic parameters were assessed. The distribution of every parameter was represented and differences between groups were calculated by Cohen's d and its 95% confidence interval was measured. The major findings were the great variability in the values of individual parameters and the absence of clear patterns in the hierarchical clustering analysis. Children with ITW walk with a longer stance phase, higher hip flexion, anterior pelvic tilt, and lower ankle dorsiflexion in the swing phase. A method based on the combination of distance-time warping of kinematic curves and multidimensional scaling shows that the kinematic abnormalities in ITW correspond to a continuous phenotypic spectrum instead of several patterns that be distinguished within the same entity. The fourth objective was to evaluate the changes in spatiotemporal and kinematic parameters in 28 children with ITW after a single session of BTx administration in triceps surae muscles. Mixed-effect models adjusted by Bayesian techniques detected improvements in the percentage of stance phase and a modest increase in ankle dorsiflexion at initial contact and a correction of other parameters reflecting gait compensations. Changes were also noticed in parameters that are not altered in patients with ITW, such as those related to knee flexion during stance time which could reflect the effect of BTx on gastrocnemii activity. In conclusion, these results support the importance of improved access to evaluation and management tools of ITW in our current clinical setting. Protocols, diagnostic aids such as TWT, prognosis markers and therapies, will allow efficient management of pain, impaired range of movement, gait and balance problems. Long-term effects of these therapies or response variability are still uncertain. On the other hand, instrument gait analysis has shown to be useful in ITW research, and will hopefully provide quality information which will lead to simplified technologies and improved access to patients who suffer this illness
... However, the etiology of ADHD remains enigmatic. While it is believed that ADHD is highly heritable [22], environmental factors that act as a trigger also play a vital role in the disorder [23]. Experts have recognized that intrauterine factors, parentchild interactions, cognitive stimulation and family socioeconomic status are all crucial to neurodevelopment [14]. ...
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Background: Air pollution nowadays has seriously threatened the health of the Chinese population, especially in the vulnerable groups of fetuses, infants and toddlers. In particular, the effects of air pollution on children's neurobehavioral development have attracted widespread attention. Moreover, the early detection of a sensitive period is very important for the precise intervention of the disease. However, such studies focusing on hyperactive behaviors and susceptible window identification are currently lacking in China. Objectives: The study aims to explore the correlation between air pollution exposure and hyperactive behaviors during the early life stage and attempt to identify whether a susceptible exposure window exists that is crucial for further precise intervention. Methods: Based on the Longhua Child Cohort Study, we collected the basic information and hyperactivity index of 26,052 children using a questionnaire conducted from 2015 to 2017, and the Conners' Parent Rating Scale-revised (CPRS-48) was used to assess hyperactive behaviors. Moreover, the data of air pollution concentration (PM10, PM2.5, NO2, CO, O3 and SO2) were collected from the monitoring station between 2011 to 2017, and a land-use random forest model was used to evaluate the exposure level of each subject. Furthermore, Distributed lag non-linear models (DLNMs) were applied for statistic analysis. Results: The risk of child hyperactivity was found to be positively associated with early life exposure to PM10, PM2.5 and NO2. In particular, for an increase of per 10 µg/m3 in PM10, PM2.5 and NO2 exposure concentration during early life, the risk of child hyperactivity increased significantly during the seventh month of pregnancy to the fourth month after birth, with the strongest association in the ninth month of pregnancy (PM10: OR = 1.043, 95% CI: 1.016-1.071; PM2.5: OR = 1.062, 95% CI: 1.024-1.102; NO2: OR = 1.043, 95% CI: 1.016-1.071). However, no significant associations among early life exposure to CO, O3 and SO2 and child hyperactive behaviors were observed. Conclusions: Early life exposure to PM10, PM2.5 and NO2 is associated with an increased risk of child ADHD-like behaviors at the age around 3 years, and the late-prenatal and early postnatal periods might be the susceptible exposure windows.
... A complete understanding of the causes of ADHD is not currently available [1]. It is known that some cases of ADHD can be inherited, and having blood relatives, such as a parent or sibling, with ADHD or another mental health disorder is a risk factor. ...
... Since genetic factors along with environmental factors are among the main causes of ADHD (14), it is therefore essential to conduct genetic studies on the genes encoding the products involved in the production of dopamine and the study of polymorphisms involved in the incidence of ADHD. ...
Article
Full-text available
Objectives Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children that lead to numerous complications. This study examined the changes in rs2283265 polymorphisms in the dopamine receptor D2 (DRD2) and rs27072 in the dopamine transporter gene (SLC6A3) in ADHD patients.
... In particular, non-shared environmental risk factors that act through interactions with genes and DNA variants that regulate gene expression -such as those in promoters, untranslated regions of genes or loci that encode microRNAs -seem to play an important role in ADHD (Faraone et al., 2015). Indeed, environmental factors that include psychosocial adversity, dietary factors or environmental toxins (Thapar et al., 2012) are thought to account for 10-40% of the variance in obtaining a diagnosis of ADHD (Sciberras et al., 2017). As a disorder with onset in early childhood, the investigation of environmental risks for ADHD has focused on pre-and early postnatal insults. ...
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As genes associated with common disorders are increasingly identified, we need to progress from observing associations to identifying risk pathways. The high-activity COMT genotype, in the presence of attention-deficit/hyperactivity disorder (ADHD), has previously been shown to be associated with extreme antisocial behavior. The same genotype has also been implicated in affecting cognitive function in healthy individuals. Impaired cognitive function might therefore lie on the risk pathway from genotype to clinical outcome. To replicate the association between COMT genotype and antisocial behavior in ADHD and to then test whether (1) impaired executive control or (2) impaired social understanding act as intermediate phenotypes for this association and lie on the risk pathway between COMT genotype and antisocial behavior. Prospective epidemiological cohort sample. The Avon Longitudinal Study of Parents and Children. Four thousand three hundred sixty-five children with data on COMT Val¹⁵⁸Met genotype, ADHD symptoms and diagnoses, and measures of social cognition/understanding and executive control. Antisocial behavior at age 7.5 years assessed using DSM-IV conduct disorder symptoms. We replicated the association of the high-activity COMT genotype, in the presence of ADHD, with extreme antisocial behavior (odds ratio, 2.82; 95% confidence interval, 2.02-3.94; P < .001 for the most severe antisocial behavior). The high-activity COMT genotype was associated with both executive control and impaired social understanding. The strength of the association between genotype and antisocial behavior was unchanged by including executive control in the model but dropped when impaired social understanding was included (odds ratio, 1.87; 95% confidence interval, 1.26-2.76; P = .002). The high-activity COMT genotype in ADHD is associated with antisocial behavior in part via impaired social understanding. Impaired executive control was also associated with the high-activity COMT genotype but may not lie on the risk pathway to antisocial behavior. The findings demonstrate the importance of testing links between genotype, intermediate phenotype, and clinical outcome in the same sample to identify potential risk pathways.
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Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia. We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5-17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autism or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35,243 Icelandic controls. Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0·156 vs 0·075; p=8·9×10(-5)). This increased rate of CNVs was particularly high in those with intellectual disability (0·424; p=2·0×10(-6)), although there was also a significant excess in cases with no such disability (0·125, p=0·0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0·0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0·031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0·0095) and schizophrenia (p=0·010). Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct. Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.