Pathophysiology

The pathophysiology of ADHD is unclear and there are a number of competing

theories.[85] Research on children with ADHD has shown a general reduction of
brain volume, but with a proportionally greater reduction in the volume of the left-
sided prefrontal cortex. These findings suggest that the core ADHD features of
inattention, hyperactivity, and impulsivity may reflect frontal lobe dysfunction, but
other brain regions particularly the cerebellum have also been implicated.[86]
Neuroimaging studies in ADHD have not always given consistent results and as of
2008 are only used for research not diagnostic purposes.[87] A 2005 review of
published studies involving neuroimaging, neuropsychological genetics, and
neurochemistry found converging lines of evidence to suggest that four connected
frontostriatal regions play a role in the pathophysiology of ADHD: The lateral
prefrontal cortex, dorsal anterior cingulate cortex, caudate, and putamen.[88]

In one study a delay in development of certain brain structures by an average of

three years occurred in ADHD elementary school aged patients. The delay was most
prominent in the frontal cortex and temporal lobe, which are believed to be
responsible for the ability to control and focus thinking. In contrast, the motor
cortex in the ADHD patients was seen to mature faster than normal, suggesting that
both slower development of behavioral control and advanced motor development
might be required for the fidgetiness that characterizes ADHD.[89] It should be
noted that stimulant medication itself may affect growth factors of the central
nervous system.[90]

The same laboratory had previously found involvement of the "7-repeat" variant of
the dopamine D4 receptor gene, which accounts for about 30 percent of the genetic
risk for ADHD, in unusual thinness of the cortex of the right side of the brain;
however, in contrast to other variants of the gene found in ADHD patients, the
region normalized in thickness during the teen years in these children, coinciding
with clinical improvement.[91]

Additionally, SPECT scans found people with ADHD to have reduced blood
circulation (indicating low neural activity),[92] and a significantly higher
concentration of dopamine transporters in the striatum which is in charge of
planning ahead.[93][94] A study by the U.S. Department of Energy’s Brookhaven
National Laboratory in collaboration with Mount Sinai School of Medicine in New
York suggest that it is not the dopamine transporter levels that indicate ADHD, but
the brain's ability to produce neurotransmitters like dopamine itself. The study was
done by injecting 20 ADHD subjects and 25 control subjects with a radiotracer that
attaches itself to dopamine transporters. The study found that it was not the
transporter levels that indicated ADHD, but the dopamine itself. ADHD subjects
showed lower levels of dopamine (hypodopaminergia) across the board. They
speculated that since ADHD subjects had lower levels of dopamine to begin with,
the number of transporters in the brain was not the telling factor. In support of this
notion, plasma homovanillic acid, an index of dopamine levels, was found to be
inversely related not only to childhood ADHD symptoms in adult psychiatric
patients, but to "childhood learning problems" in healthy subjects as well.[95] One
interpretation of dopamine pathway tracers is that the biochemical "reward"
mechanism works for those with ADHD only when the task performed is inherently
motivating; low levels of dopamine raise the threshold at which someone can
maintain focus on a task which is otherwise boring.[96] Neuroimaging studies also
found that neurotransmitters level (e.g. dopamine and serotonin) in the synaptic
cleft goes down during depression.[97][98]

A 1990 PET scan study by Alan J. Zametkin et al. found that global cerebral glucose
metabolism was 8 percent lower in medication-naive adults who had been
hyperactive since childhood.[99] Further studies found that chronic stimulant
treatment had little effect on global glucose metabolism,[100] a 1993 study in girls
failed to find a decreased global glucose metabolism, but found significant
differences in glucose metabolism in 6 specific regions of the brains of ADHD girls
as compared to control subjects. The study also found that differences in one
specific region of the frontal lobe were statistically correlated with symptom
severity.[101] A further study in 1997 also failed to find global differences in
glucose metabolism, but similarly found differences in glucose normalization in
specific regions of the brain. The 1997 study also noted that their findings were
somewhat different than those in the 1993 study, and concluded that sexual
maturation may have played a role in this discrepancy.[102] The significance of the
research by Zametkin has not been determined and neither his group nor any other
has been able to replicate the 1990 results.[103][104][105]

Critics, such as Jonathan Leo and David Cohen, who reject the characterization of
ADHD as a disorder, contend that the controls for stimulant medication usage were
inadequate in some lobar volumetric studies which makes it impossible to
determine whether ADHD itself or psychotropic medication used to treat ADHD is
responsible for the decreased thickness observed[106] in certain brain regions.
While the main study in question used age-matched controls, it did not provide
information on height and weight of the subjects. These variables it has been
argued could account for the regional brain size differences rather than ADHD itself.
[107][108] They believe many neuroimaging studies are oversimplified in both
popular and scientific discourse and given undue weight despite deficiencies in
experimental methodology
eMedicine Specialties > Pediatrics: Developmental and
Behavioral > Medical Topics

Attention Deficit Hyperactivity Disorder

Author: Susan Louisa Montauk, MD, Medical Director, The Affinity Center, Cincinnati;
Professor, Departments of Family Medicine and Public Health Science, University of Cincinnati
College of Medicine
Coauthor(s): Christine A Mayhall, PhD, Clinical Psychologist, The Affinity Center
Contributor Information and Disclosures

Updated: Oct 6, 2010

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Introduction
Background

The term attention deficit is misleading. In general, the current predominating theories suggest
that persons with attention deficit hyperactivity disorder (ADHD), attention deficit disorder
(ADD), actually have difficulty regulating their attention; inhibiting their attention to nonrelevant
stimuli, and/or focusing too intensely on specific stimuli to the exclusion of what is relevant. In
one sense, rather than too little attention, many persons with ADHD (ADD) pay too much
attention to too many things, leading them to have little focus.

Three basic forms of ADHD (ADD) are described in the Diagnostic and Statistical Manual IV
(DSM-IV) of the American Psychiatric Association (APA).1 They are (1) attentional; (2)
hyperactive/impulsive; and (3) combined, which is most frequently a combination of attentional
and hyperactive forms.

The major neurologic functions disturbed by the neurotransmitter imbalance of ADHD (ADD)
fall into the category of executive function. The 6 major tasks of executive function that are most
commonly distorted with ADHD (ADD) include (1) shifting from one mindset or strategy to
another (ie, flexibility), (2) organization (eg, anticipating both needs and problems), (3) planning
(eg, goal setting), (4) working memory (ie, receiving, storing, then retrieving information within
short-term memory), (5) separating affect from cognition (ie, detaching one's emotions from
one's reason), and (6) inhibiting and regulating verbal and motoric action (eg, jumping to
conclusions too quickly, difficulty waiting in line in an appropriate fashion).

Contrary to some media accounts, ADHD (ADD) is not new. In the early 1900s, diagnosis
emphasized the hyperactivity component. Today, hyperactivity, impulsivity, and inattention are
the areas of focus. However, reports have alluded to disorders involving hyperactivity,
impulsivity, and inattention in conjunction with distractibility and inappropriate arousal patterns
throughout medical history. What is new is the enhanced awareness of ADHD (ADD) secondary
to rapidly accumulating research findings and its addition to the DSM in 1980.

Pathophysiology

Findings from neuropsychological studies suggest that the frontal cortex and the circuits linking
them to the basal ganglia are critical for executive function and, therefore, to attention and
exercising inhibition. Many findings support this view, including those described below.

Executive functions are major tasks of the frontal lobes. MRI of the right mesial prefrontal cortex
in persons with ADHD (ADD) strongly supports decreased activation (low arousal) during tasks
that require inhibition of a planned motor response and timing of a motor response to a sensory
cue. MRI in persons with ADHD (ADD) also strongly supports weakened activity in the right
inferior prefrontal cortex and left caudate during a task that involves timing of a motor response
to a sensory cue.

The catecholamines are the main neurotransmitters with frontal-lobe function. Catecholamine
controlled dopaminergic and noradrenergic neurotransmission appear to be the main targets for
medications used to treat ADHD (ADD).

A 10-year study by National Institute of Mental Health (NIMH) demonstrated that the brains of
children and adolescents with ADHD (ADD) are 3-4% smaller than those of children without the
disorder, and that pharmacologic treatment is not the cause. The more severe patients' ADHD
(ADD) symptoms were, as rated by parents and clinicians, the smaller their frontal lobes,
temporal gray matter, caudate nucleus, and cerebellum were.
In addition to the role of the neurotransmitters most commonly associated with the frontal lobes
and the pathways mentioned above, some investigations have begun exploring a possible role for
5-hydroxytryptamine (5-HT). Although the brain’s motor regions are innervated by 5-HT
projections, no connection between 5-HT and ADHD (ADD) motor pathology has yet been
identified. However, connections have been made to attention-related processes. Altered 5-HT
activity does appear to be at least part of the cause for difficulties with perceptual sensitivity and
the appropriate recognition of the relative significance of stimulation.