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Etiological Factors in ADHD
Article: Maternal Lifestyle Factors in Pregnancy Risk of ADHD
James H. Johnson, Ph.D.
University of Florida
Etiological Factors
• In recent years increased information has
accumulated regarding the etiological factors in
ADHD.
• Unfortunately, findings are often inconsistent and
not all of the findings fit neatly together.
• And, many of the studies are correlational in nature
thus making it difficult to infer causality.
• Nevertheless, research has has provided some basis
for drawing inferences regarding the causal factors
in ADHD.
• Taken together these findings strongly suggest the
role of biological factors as primary contributors.
Pregnancy and Birth Factors
• In reviewing factors that my contribute to the
development of ADHD, it seems appropriate to start
by again noting that ADHD has been found to be
related to a variety of pregnancy and birth
complications.
• Examples include various types of complications that
could result in oxygen deprivation.
– Cord wrapped around neck
– Meconium Aspiration
– Forceps Delivery
• ADHD has also been linked to certain physical health
problems in the mother. Examples include
– Toxemia
– Eclampsia
Low Birth Weight
• Low birth weight is another factor that has been
linked with elevated rates of ADHD.
• Here research has suggested that rates of ADHD in
low birth weight children are significantly higher
than in children of normal birth weight
• For example, in one study of extremely low birth
weight (<901 grams) infants , Stjernquist and
Svenningsen (1995) reported 25% of the premature
sample to have ADHD at age 4, while none in the
normative sample met the criteria for this disorder .
• Similar findings have been obtained with children
displaying birth weights of <1,500 grams.
Low Birth Weight
• Of note is another study by Astbury et al. (1987)
who examined low birth weight children focusing on
differences between those who did and did not
develop ADHD.
• They found that children who later developed
ADHD were ones who showed more extensive signs
of hypoxia and ischemia.
• In reviewing this literature, Lou (1996) hypothesizes
that ADHD arises from these early hypoxic and
ischemic episodes due to the high susceptibility of
the neurons of the striatum to hypoxic injury.
• He theorizes that this damage to the striatum leads
to a disruption in the self regulation of behavior.
Prenatal Smoking
• Maternal smoking during pregnancy has been
hypothesized as an environmental factor that
leads to the development of both behavioral and
cognitive impairments.
• This is believed to be due to the fact that
nicotine causes fetal brain damage secondary to
prolonged hypoxia as well as through nicotine's
hypothesized role in modulating the dopanergic
activity of the brain .
Prenatal Smoking
• Over the past several years a number of studies have
confirmed the association between maternal
smoking and ADHD.
• As an example, in one such study, Milberger et al.
(1996) found that 22% of ADHD children (vs. 8% of
normal children) had mother's who reported
smoking a pack of cigarettes per day for at least 3
months during pregnancy.
• This study was limited in generalizability, however,
as all children in the ADHD group were boys.
• In subsequent studies with both males and females
these investigators found maternal smoking to be
significantly higher in ADHD children of both sexes
than in normals.
Maternal Alcohol Use
• Findings related to ADHD and maternal
alcohol are mixed.
• Studies clearly indicate that alcohol use
during pregnancy can contribute to physical
and mental impairments in heavy drinkers,
as in FAS, as well as less severe impairments.
• Multiple studies have also suggested a link
between prenatal alcohol use and the
development of ADHD - although this
relationship has not been found in all studies.
Maternal Alcohol Use
• For Example, a recent study of prenatal exposure to
alcohol by Mick et al (2002) , which also studied
smoking, found that twice as many children with
ADHD had mothers who either drank alcohol daily
or binged heavily during pregnancy than children
without ADHD.
• However, negative results were found by Hill et al
(2002), who used dichotomized exposure data
collected retrospectively.
• In this study, the univariate association between
alcohol exposure and ADHD disappeared after
adjusting for familial risk of alcoholism, intrauterine
exposure to smoking, and information regarding
alcohol and parental psychopathology.
Maternal Alcohol Use
• Conclusion: While there are a number of
studies that do suggest a link between prenatal
alcohol exposure and ADHD, there are also
contradictory findings.
• In some studies no relationship is found after
controlling for other relevant variables.
• More good research is needed !
• Question: Does the apparent link between
alcohol exposure and ADHD result from some
factor (or factors) that contributes, both to
maternal drinking and to childhood ADHD?
Minor Physical Anomalies
• As has been noted earlier, there seems to be
evidence that ADHD may be associated with
early defects in embryological development.
• These early problems in embryological
development are often reflected in minor
physical anomalies displayed by children.
• They are reflected in morphological features
such as unusually small or large head
circumference, slightly misshapen ears, high
palate, as well as other features.
Minor Physical Anomalies
• Waldrop and her associates have suggested
that the presence of multiple minor physical
anomalies is associated with ADHD in boys.
• Here the number of anomalies has been
found to be associated with early age of onset
and severity of symptoms.
• These associations suggest that problems
with early embryological development may
be related to both minor physical anomalies
and the development of ADHD, at least in
males.
Other Pregnancy and Birth
Factors
• Month of birth has also been suggested to be related to
ADHD.
• Births in September are overrepresented among children
with ADHD.
• Of what relevance is month of birth – The best answer is
we don’t really know.
• It has been suggested that season of birth may serve to
influence the timing of seasonally mediated viral
infections to which mothers and fetuses may have been
exposed.
• It has been suggested that this may account for nno
more than 10% of ADHD cases.
The Role of Specific Toxins
• Another environmental factor found in some studies
to be related to ADHD is exposure to lead.
• While the relationship is not strong, elevated lead
burden bears a statistically significant relationship
to symptoms of ADHD.
• Although, only about 30+% of children with high
lead burdens are judged to be hyperactive . . .
• And, although most children with excessive lead
burdens do not develop ADHD . . .
• Evidence does suggest that lead can be a contributor
to ADHD.
• It does not,however, seem to be a major contributor
in most children . [Note Oliver David’s Research]
Role of Neurological Insult
• Multiple factors that can result in brain damage
are associated with ADHD.
• For example, as we have seen, anoxia is
associated with increased frequencies of
hyperactivity and attention problems.
• ADHD occurs more often in children with seizure
disorders, who are presumed to have neurological
involvement
• As noted earlier, diseases such as encephalitis
can result in symptoms of ADHD as can various
types of infections.
• We also know that frontal lobe injury can cause
symptoms of ADHD.
• There is also some suggestion that right parietal
lobe lesions may contribute to ADHD.
Neurological Factors
• These findings suggest that neurological
insult can result in an increased
probability of developing ADHD.
• However, most children with ADHD do not
have a significant history of brain injury.
• Indeed, such injuries are unlikely to
account for the development of ADHD in
most children.
• In fact probably 95% of hyperactive
children show no evidence of documented
neurological impairment.
• This does not mean, however, that
biological factors are not involved.
Relationship to Thyroid Disorder
• Earlier we noted that physical conditions such as
thyroid disorder can result in or mimic this
disorder.
• Some children have a genetically based
hypersensitivity to thyroid hormones.
• This is referred to as RTH for Resistance to
Thyroid Hormone
• One study has found that 70% of individuals with
RTH met diagnostic criteria for ADHD.
• Other research has suggested that 64% of patients
with RTH display hyperactivity or learning
disabilities.
Relationship to Thyroid Disorder
• Despite these findings and others which have
documented a link between RTH and at least mild
to moderate symptoms of ADHD, only 1 in 2,500
children with ADHD show RTH.
• This suggests that thyroid dysfunction is unlikely to
be a major cause of ADHD.
• RTH children with ADHD may show a more
positive behavioral response to liothyronine, than
do ADHD children who do not have RTH.
• While not a major cause of ADHD, the effects of
RTH is a good example of how biological factors,
other than clear neurological impairment, can
result in ADHD symptomatology.
Genetics: Family Aggregation
Studies
• Studies dating as far back as the 1970's indicated
that children with hyperactivity tend to frequently
have parents with ADHD and other psychiatric
disorders.
• Adoption studies also suggested that, for
hyperactive children, there were higher rates of
hyperactivity in biological than adoptive parents.
• In the 1990's there were numerous other studies
that provided more convincing information
regarding the possible genetic contribution to
ADHD.
Genetics: Family Aggregation Studies
• For example, Biederman et al found between 10 and
35% of the immediate family members of children
with ADHD to display this disorder.
• Risk for siblings of children with ADHD was
approximately 32%.
• Other studies by Biederman have suggested that, if a
parent has ADHD, the risk to the offspring is 57%.
• Thus, family aggregation studies find that ADHD
clusters among biological relatives of children or
adults with this disorder.
• This strongly implies a hereditary bases for this
condition.
Genetics: Twin Studies
• Large scale twin studies in the 90's have been quite
consistent in finding high heritability for ADHD.
• For example, Gilger et al (1992) found that, if one
twin was diagnosed with ADHD, the concordance
for the disorder was 81% in monozygotic twins and
29% in dizygotic twins.
• In summarizing results of ADHD twin studies,
Stevenson (1994) concluded that the average
heritability is .80 for symptoms of this disorder.
• Other studies are consistent in suggesting that 70 90% of the trait of hypearactivity-impulsivity is due
to genetic factors (averaging around 80%).
ADHD: Molecular Genetics
• Molecular genetics has begun to identify
specific genes related to ADHD.
• A “dopamine type 2 gene” has been found
to be related to ADHD as well as Tourette’s
and alcoholism.
• More recently a "dopamine transporter
gene" and a “dopamine repeater gene”have
been identified.
• This latter gene, found to be related to
ADHD in multiple studies, seems to be
related to post-synaptic sensitivity in the
frontal and prefrontal cortical regions, and
to be associated with executive functions.
ADHD: Molecular Genetics
• With developments in molecular genetics
occurring at an increasingly rapid rate (due
to the Human Genome Project), in the near
future, we may have genetic tests that can
provide early screening for ADHD and
possibly associated comorbidities.
• Would these be useful? Why/Why Not?
• Genetic factors are clearly strongly
implicated in the development of this
disorder.
• Indeed, hereditary is probably the most well
supported etiological factors in the
development of ADHD
Psychophysiological Studies
• Studies using psychophysiological measures
of nervous system electrical activity,
measured in different ways (EEG, GSR),
have been somewhat inconsistent in findings
group differences between ADHD and
normal control children.
• However, when differences from normals are
found, they are consistently in the direction
of diminished arousal or arousability in
children with ADHD.
Psychophysiological Responsivity
• In addition to regular EEG and GSR studies, there
are also a number of Evoked Potentials studies
where EP's have been obtained while children with
ADHD are performing vigilance tasks.
• While results vary, the most consistent pattern has
been lower amplitude responses in certain portions
of their ERP's which are thought to be related to
functioning of the prefrontal regions of the brain.
• These types of responses suggest an under
responsiveness of ADHD children to stimulation.
• It is interesting to note that this under
responsiveness is corrected with stimulant
medication
Neuropsychological Findings
• Results from research involving
neuropsychological testing has often
suggested that children with ADHD have
problems;
–
–
–
–
–
–
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in inhibiting behavioral responses,
with working memory,
with planning and organization,
with verbal fluency,
with perserveration,
In motor sequencing,
with other “frontal lobe” functions.
Neuropsychological Findings
• Research suggests that, not only do children with
ADHD show these types of executive functioning
deficits, but siblings of children with ADHD, who do
not have ADHD themselves, have milder but
significant impairments in these same executive
functions.
• These findings suggest possible genetic risk for
executive function deficits in families that have
ADHD children , even if symptoms of ADHD are not
fully manifest in family members.
• Taken together, findings in this area provide support
for the view that dysfunction of the prefrontal lobes
likely play a significant role in the development of
ADHD.
Studies of Cerebral Blood Flow
• Studies of cerebral blood flow in ADHD
and normal children have consistently
shown decreased blood flow to the
prefrontal regions and pathways
connecting these regions to the limbic
system via the striatum and specifically
its anterior region (the Caudate Nucleus)
• Studies using PET scans to assess cerebral
glucose metabolism in the frontal regions
have found diminished metabolism in,
adults and adolescent with ADHD.
Studies of Cerebral Blood Flow
• Significant correlation's between
diminished metabolic activity in the left
anterior frontal region and severity of
symptoms in adolescents with ADHD have
also been demonstrated
• This demonstration of a relationship
between decreased metabolic activity in
specific brain regions and severity of ADHD
symptoms is crucial to documenting the
importance of the link between brain
activation and ADHD related behaviors
• Other studies have also suggested
decreased blood flow to the striatum,
which is increased with stimulant drugs.
PET SCAN
• This is a P.E.T. scan (positron
emission tomography) of the
human brain.
• The brain on the left is the
brain of person without ADD
and the brain on the right is
that of a person with ADD.
• This study was conducted
to determine brain activity
by measuring glucose
metabolism.
• This was the first study to
show differences in brain
activity between ADD and
non-ADD brains.
PET SCAN
• The red areas within (not
surrounding) the brain represent
metabolic activity.
• The non-ADD brain has more
metabolic or electrical activity (red)
than the ADD brain.
• This metabolic activity is partly
responsible for an individuals'
ability to focus and concentrate
and is the result of the
neurotransmitters or brain
chemicals (i.e. dopamine,
serotonin, etc.).
• Higher levels (or a greater uptake
or utilization) of neurotransmitters
increase the metabolic activity.
PET SCAN
• The ADD brain is generally
metabolically less active (or
understimulated), than the nonADD brain.
• It relies on external factors in
order to become stimulated
enough to focus and concentrate.
• Therefore, the verbal and/or
physical impulsivity or activity that
is part of the ADD individual is
necessary to stimulate the brain.
• Medication increases the metabolic
activity of the brain and reduces
the need for external stimulation.
MRI Studies
• Early MRI studies found differences in
the area of the Corpus Callosum, with
this structure being smaller in children
with ADHD. – Not always replicated.
• Other MRI studies have found children
with ADHD to have a smaller left
caudate nucleus than did normal
children.
•
These
findings are interesting in light of the
results of earlier blood flow studies
suggesting lower levels of activation in
this specific area in children with ADHD.
MRI Studies
• Several more recent MRI studies, with
larger samples, have replicated these early
results by finding that ADHD children had
significantly smaller anterior right frontal
regions, a smaller caudate nucleus, and
smaller golbus pallidus regions that
normals.
• Research has also found decreased
cerebellar volume in children with ADHD.
• Work in this area suggests that
abnormalities in the development of the
frontal-striatal regions, and other brain
structures, may underlie the development
of ADHD.
Neurotransmitter Deficiencies
• The possibility of a neurotransmitter
dysfunction in children with ADHD has
been suggested for many years.
• This notion seemed to result from
observations of the response of children
with ADHD to stimulant drugs.
• The fact that stimulant drugs have an
impact on ADHD and that they increase
dopamine has contributed to the
neurotransmitter dysfunction
hypothesis.
Neurotransmitter Deficiencies
• There is more direct evidence of
neurotransmitter deficiencies from
studies of cerebral spinal fluid in ADHD
and normal children which suggests
decreased dopamine levels in ADHD
children
• There is also some evidence of a
deficiency in the availability of
norepinephrine in children with ADHD.
• This is of interest given that a very new
non-stimulant ADHD medication,
Straterra, is thought to act on
norepinephrine levels.
PSYCHOSOCIAL FACTORS
IN ADHD
• There is little evidence for the role
of psychosocial factors in the
development of ADHD, although
factors such as parent-child conflict
may exacerbate problems in a child
with ADHD.
• Psychosocial factors may also
contribute to the development of
certain comorbid disorders that may
complicate the clinical picture.
Etiology: Overview
• In reviewing the literature on the etiology
of ADHD, Barkley suggests …
• “It should be evident from the
research…that neurological and genetic
factors make a substantial contribution to
symptoms of ADHD and the occurrence of
this disorder.
• A variety of genetic and neurological
etiologies (e.g., pregnancy and birth
complications, acquired brain damage,
toxins, infections, and genetic effects) can
give rise to the disorder through some
disturbance in a final common pathway in
the nervous system
Etiology: Overview
• That final common pathway
appears to be the integrity of
the prefrontal cortical-striatal
network
• It now appears that
hereditary factors play the
largest role in the occurrence
of ADHD symptoms in
children.
• It may be that what is
transmitted genetically is a
tendency toward a smaller
and less active prefrontalstriatal network.
Etiology: Overview
• The condition can also be caused or
exacerbated by pregnancy
complications, exposure to toxins,
or neurological disease
• Social factors alone cannot be
supported as causal in this disorder,
but such factors may exacerbate the
condition, contribute to its
persistence, and more likely,
contribute to the forms of comorbid
disorders associated with ADHD.
Etiology: Overview
• Cases of ADHD can arise without
genetic predisposition if the child
is exposed to a significant
disruption or neurological injury
to this final common neurological
pathway, but this would seem to
account for only a small minority
of ADHD children.