THE
BIOLOGICAL BASES OF ADHD –
• Normal development
• Normal development of circuits involved with
cognitive control
• ADHD a problem of control
• Hypotheses and Research
• References : Casey, Durston, and Fosella
(2001). Evidence for a mechanistic model of cognitive control. Clinical
Neuroscience Research 1, 267-282.
** I was unable to insert the tables from the PowerPoint
into this word document; however, the descriptions of the tables are in this
document. I will try to get tables
asap.
Information about the developing human brain is relatively sketchy despite the
significant gains in the fields of pediatric neuroimaging and developmental
neurobiology.
This is due to low mortality rates
across the age range in addition to the rare occurrence of autopsies on this
population.
A significant amount of brain development occurs in utero, but changes continue
postnatally.
By 2 years, the brain has reached
close to 80% of its adult weight.
This is also a period of rapid synapse
formation that begins well before birth in nonhuman primates.
Based on limited human post-mortem
data, it has been suggested that synaptogenesis may not occur concurrently but
synaptic density may instead peak earlier in the auditory cortex, at 3 months,
and alter in the middle frontal gyrus, at 15 months.
In both human and nonhuman primate studies the early synaptic density peaks are
followed by a plateau phase that decreases during childhood and into adulthood.
PET studies of glucose metabolism
suggest that maturation of local metabolic rates parallel the time course of
overproduction and subsequent pruning of synapses.
The most consistently reported findings from these studies are: 1) a lack of
any significant change in cerebral volume after 5 years of age; 2) a significant
decrease in cortical gray matter by 12 years in parietal and prefrontal cortex;
and 3) an increase in cerebral white matter throughout childhood and young
adulthood. Some subcortical gray regions such as the basal ganglia have been
reported to decrease during childhood, particularly in males. This decrease in
basal ganglia volume (caudate nuclei and globus pallidum) has been shown to
occur between roughly 6 and 12 years of age.
Cortical gray matter in the frontal
and parietal cortices appears to decrease during childhood until roughly
puberty.
Connectively within these circuits, particularly between prefrontal cortex and
basal ganglia is an important aspect of brain development to assess. Refinement
of these projections may correspond to increase cognitive control over actions.
Klingber et al. [127] showed anisotropy was lower in frontal white matter in
children 8-12 years old compared with healthy adults.
They showed delayed myelination of the
frontal lobes consistent with previous reports.
The available data on human brain development suggest protracted development of
the prefrontal cortex and basal ganglia.
Development of cognitive control
appears to parallel this brain development.
Each of the basal ganglia thalamocortical circuits controls or supports a
different set of behaviors that range from skeletal and eye movements to
cognitive and emotionally driven actions as illustrated in Fig. 1.
The sensorimotor circuits (motor and
oculomotor) subserve voluntary skeletal and eye movement control.
The circuits involving association
cortex (dorsolateral and lateral orbital frontal cortex) are involved
presumably in guided or planned actions.
The limbic circuit is thought to be
involved in the approach or avoidance of emotionally relevant events.
The basal ganglia then act broadly to inhibit competing movements that would
otherwise interfere with the desired action.
Figure 1 Basic circuitry of the basal ganglia thalamocortical
circuit. On the left, the frontal cortex projects to the basal ganglia, then
thalamus and the loop is closed with a projection back to the frontal cortex.
On the right, this circuitry is better delineated. The frontal cortex projects
to different areas of the striatum (i.e.., putamen or caudate nuclei) and then
projects to either the direct or the indirect pathway. The direct pathway
involves an inhibitory projection to the internal capsule of the globus
pallidus (GPi) and substantia nigra (SNr) resulting in the dampening of an
inhibitory projection to the thalamus which results in disinhibition of
the thalamus. The indirect pathway
consists of an inhibitory projection to the external capsule of the globus
pallidus (GPe) which dampens the inhibitory projection to the subthalamic
nuclei (STN) resulting in excitation of the internal capsule of the globus
pallidus and substantia nigra. This in turn leads to an inhibition of the
thalamus.
Fig. 1. Simplified diagram of five parallel basal ganglia thalamocortical
circuits including (1) the motor circuit with projection zones in the premotor
cortex (PMC), supplementary motor areas (SMA), and primary motor cortex; (2)
the oculomotor circuit with primary projection zones in the supplementary eye
fields (SEF) and frontal eye fields (FEF); (3) dorsolateral prefrontal (DLPFC)
circuit; (4) lateral orbital frontal (LOFC) circuit; (5) the limbic circuit
with primary projection zones in the anterior cingulate (AC) and medial
orbitofrontal cortex.
Assuming that the direct pathway is involved in facilitating cortically
mediated behaviors, then its disruption may result in constantly interrupted
behaviors such as those observed in ADHD or constantly interrupted thoughts
such as those observed in schizophrenia.
If
the indirect pathway is involved in inhibiting cortically mediated behavior,
then its disruption may result in
irrepressible
repetitive behaviors and thoughts similar to those observed in obsessive
compulsive disorder and Tourette’s syndrome or in ruminations of hopelessness
in depression.
Over-activity
of the direct pathway may lead to irrepressible repetitive behaviors and over
activity of the indirect pathway may lead to constantly interrupted behaviors.
The basal ganglia are involved in inhibition of behaviors [55] while the
frontal cortex is involved in guiding these actions by supporting
representations of relevant information from interference due to competing
information.
The
basal ganglia, which consist primarily of inhibitory projections (GABA), are
involved in the inhibition of inappropriate behaviors and disruption in the
development of this brain region results in deficits in inhibitory control.
One
can hypothesize that the frontal cortex, which consists primarily of excitatory
projections (glutamate) is involved in maintenance of relevant information for
action and disruption of this brain region results in deficits in the ability
to carry out the relevant actions.
Hypofrontality as observed in ADHD would result in constantly interrupted
behaviors or actions.
Hyperfrontality
as observed in obsessive compulsive disorder [44] would result in irrepressible
behaviors.
These
regions are strongly innervated by dopamine, a neurotransmitter thought to be
critically involved in regulation of attention and behavior.
An important neuromodulator in the basal ganglia thalamocortical
circuitry
is dopamine, particularly at the level of the prefrontal cortex and striatum.
Sustained
attention tasks in rats are enhanced by administration of the DI dopamine
receptor agonist.
Pharmacological
studies have shown that amphetamine and methylphenidate, drugs that increase
the amount of free dopamine at the synapse, lead to enhanced attention.
The effects of dopamine have been examined in several computational models and
are predicted to be essential for the protection of stable representations [3]
as well as in the prediction of reward.
Development of the dopaminergic system parallels the development of performance
on tasks involving suppression of
attentional
or behavior responses.
Performance
on tasks of cognitive control show significant improvement with age during the
first 12 years of life. One factor thought to contribute to this age-dependent
increase in performance is the development of the dopaminergic system.
In humans, the development of this system is coincident with a period of rapid
synaptogensis in dendritic spines followed bya slower plateau phase of growth
until adolescence.
In a second study of 26 children with and 26 children without ADHD, Casey et
al, tested children on all three attention tasks. They showed significant correlations between
performance on these tasks and asymmetry and size of the basal ganglia (caudate
nucleus and globus pallidus) and prefrontal cortex.
In
contrast, behavioral data from the ADHD children typically was in the opposite
direction or did not correlate.
These
results imply that deficits in cognitive control observed in ADHD may be due to
abnormalities of the prefrontal cortex and basal ganglia and that variations in
these structures in healthy individuals relates to performance on cognitive
control tasks.
The following slides are based on a review by Baumeister and Hawkins (2001) in
Clinical Neuropharmacology Vol 24, No 1, pp, 2-10
From its inception, ADHD has been
thought to have a biologic etiology.
Structural Imaging Studies Follows:
|
Location
|
ADHD probands
|
Contrast subjects
|
Findings
|
Comments
|
|
Basal ganglia Aylwrd et al. 1996
[12]
|
10 boys
|
11 normal controls; 16 boys with
ADHD + TS
|
Globus pallidus volume smaller in
ADHD (significant on left)
|
Caudate and putamen also smaller in
ADHD, also smaller in ADHD,
|
|
Castellanos et al 1996 [15]
|
55 healthy controls
|
55 healthy controls
|
Normal symmetry in prefrontal
brain, caudate, and globus pallidus significantly decreased in ADHD;
cerebellum volume also smaller
|
Data support hypothesis that
prefrontal-striatal- cortical circuitry mediates ADHD, particularly on right
side
|
|
Filipek et al. 1997 [13]
|
15 males (same subjects as
Semrud-Clikeman et a. 1994)[77]
|
15 normal controls
|
Caudate smaller (only) significant
left) in ADHD; right anterior superior white matter also significantly
diminished; posterior white matter volumes decreased only in stimulant non-responder
|
First
study to quantify gray and white matter separately; authors suggest using
medication response to subtype patient groups
|
|
Mataro et al. 1997 [78]
|
11 adolescents with ADHD
|
19 healthy control subjects (three
grils in each group\
|
Right caudate larger in ADHD;
larger caudate nucleus areas associated with poorer performance on tests of
attention and higher ratings on Conner Teachers Rating Scale
|
Single
slice axial MRI-not volumetric measure; only study to find larger size in
ADHD
|
|
Cerebellum Berquin et al. 1998 [18]
|
46 right-handed boys (subset of
Castellanos 1996) [15]
|
47 right-handed boys
|
Posterior inferior cerebellar
vermis volume and area significantly smaller
|
Contrast survived covariance for
total cerebral volume differences
|
|
Mostofsky et al. 1998 [19]
|
12 males
|
23 males
|
Posterior inferior cerebellar
vermis area significantly smaller
|
Contrast survived covariance for
total cerebral volume differences
|
|
Castellanos et al. 2001 [16]
|
50 girls
|
50 girls
|
Posterior inferior cerebellar
vermis volume significantly smaller (-12%, same as boys)
|
Contrast survived covariance for
total cerebral volume; most robust and replicated finding in ADHD
|
Brain
Size: Three magnetic resonance imaging (MRI)
studies have reported that total cerebral volume was significantly lower (by
approximately 5%) in children with ADHD compared with control subjects (24-26).
Moreover, in each study the ADHD group
had a significantly lower mean intelligence quotient (IQ) than control
subjects.
IQ was statistically controlled, no
significant difference in cerebral volume was found (24,26).
In addition, two independently
conducted MRI studies found no difference in brain volume using ADHD and
control subjects that did not differ in IQ (27,28).
Thus, no difference between persons
with ADHD and control subjects.
Frontal Lobe: Filipek et al. (27) reported that total
frontal lobe volume and right-side (but not left-side) frontal lobe volume were
significantly decreased in children with ADHD.
In addition, the right side (R)
greater than left side (R>L) asymmetry in frontal lobe volume that was
observed in control subjects was significantly reduced in children with ADHD.
Another group of investigators (26)
reported essentially the same pattern of results except that there was no
significant difference between control subjects and children with ADHD in total
anterior frontal volume.
In that study (26), the smaller volume
of the right frontal region in ADHD was still observed after controlling
statistically for IQ differences.
Consistent with these observations, another study (30) found that children with
ADHD had a smaller right (but not left) frontal lobe width than control
subjects and that children with ADHD had reduced R>L frontal width
asymmetry.
Considering the consistency of these
findings, it is somewhat surprising that an MRI study of children who developed
ADHD secondarily to closed brain injury of frontal lobe lesions actually
predicted the nonoccurrence of ADHD.
Basal Ganglia: One study found that total volume of the
caudate nucleus was reduced in children with ADHD compared with controls,
whereas two studies found no effect.
Two studies (27,31) found that the
left but not the right caudate was decreased in subjects with ADHD compared
with control subjects, whereas two other studies [using overlapping samples
[25,26]) found the opposite pattern of results.
Filipek et al. (27) reported that
control subjects had a smaller right than left caudate nucleus volume, whereas
in subjects with ADHD these volumes were equal (i.e., children with ADHD showed
an absence of R<L asymmetry).
Hynd et al. (31), like Filipek et al. (27), found that the right caudate (using
area measures in a single axial section) was smaller than the left in control
subjects.
Aylward et al. (29) found no asymmetry
in caudate volume in either children with ADHD or control children.
Corpus Callosum:
Two studies found that children with
ADHD have reduced size of posterior regions of the corpus callosum only
(28,34), two found that the abnormality is confined to the anterior corpus callosum
(35,36), one found abnormalities in both anterior and posterior regions (37),
and one found no morphologic abnormalities in the corpus callosum of subjects
with ADHD compared with normal subjects who had siblings with ADHD (38).
Cerebellum: One study (26) found that cerebellar volume
(after controlling for total cerebral volume) was significantly decreased in
children with ADHD compared with control subjects, but there were no
differences between groups with respect to total midsagittal area of the
vermian lobules.
Conversely, a follow-up study by the
same group of investigators (24), which employed most of the same subjects with
ADHD but used an improved image quantification technique, found the opposite
pattern of effect.
Another study using computed
tomography scans found evidence suggestive of mild cerebellar atrophy in adults
with a history of hyperactivity (22).
However, in this study, group
differences did not reach statistical significance and many of the subjects had
histories of antisocial behavior and alcohol abuse.
Lateral Ventricles:
One MRI study (26) found that the
left-side but not the right-side lateral ventricle was decreased in volume in
children with ADHD. Another study (28) reported that posterior but not the
anterior lateral ventricle volume was increased in children with ADHD.
Functional Imaging Studies:
Frontal Lobes:
Although most of these studies
reported evidence for decreased activity of this brain area in subjects with
ADHD, the evidence is not entirely consistent.
Of the studies that reported
significant effects in frontal lobe activity (41-45); five found decreased
activity exclusively, although activity was increased in some frontal loci
946-50); three reported no differences between subjects with ADHD and control
subjects (51-53); and one reported that subjects with ADHD had increased
frontal lobe activity (54).
Table 3 summarizes the functional abnormalities that have been reported in
particular regions of the frontal lobes of subjects with ADHD.
Frontal area Result Reference
Anterior Frontal L 50
Anterior Frontal L 47
Anterior Frontal * 47
Anteriormedial Frontal * 47
Dorsal Frontal 46
Global Frontal 42
Global Frontal 54
Global Frontal R 41
Global Frontal L * 41
Global Frontal L 43
Inferior Prefrontal R 48
Inferior Frontal Gyrus R
49
Frontal area Result Reference
Inferior Posterior Front 50
Mesial Prefrontal R 48
Middle Frontal Gyrus R 49
Posterior Frontal L 47
Posterior Frontal * 47
Precentral L 49
Prefrontal 46
Prefrontal R 44
Premotor 45
Premotor 49
Premotor R 48
Superior Posterior Front 50
Superior Prefrontal 45
Basal
Ganglia:
Three studies (52, 53, 54) reported
that striatal activity was significantly decreased in children with ADHD. However, studies that examined specifically
the caudate nucleus or the putamen provided little corroborating support. Of
the six (42, 45, 47, 48, 50, 51) on caudate nucleus only one (48) found a
significant difference. In the same
studies looking at the putamen, only one found differences (47). Decrease in
females.
Occipital Lobes:
Few studies have been done looking at
the Occipital lobes. The results are
inconsistent here also. One (47) found
decreased activity in ADHD girls but not boys, one study found increased
activity in ADHD boys but not girls (50). One found no difference between ADHD
and controls (46).
Temporal lobes:
Again results were inconsistent. In a study (45) with adults there was
decrease activity in the left but not the right anterior and posterior, but not
the middle, temporal lobes. In a second study (50) (adolescent), there was a
decrease in the right but not the left temporal regions of boys but not girls.
In a third study there was an increase in the middle temporal lobe on the right
side only. One study (46) found no effect.
Parietal lobes:
One study found decrease in both left
and right (45). In a second study there
was decrease on the left side only in boys (50). In a third study (47), there was significant increase on the
right side only. One study (46) found no effect.
Discussion:
There seems to be a consensus among
experts today that ADHD is associated with structural and/or functional
abnormalities in the brain.
Neuroimaging literature provides no
convincing evidence for the existence of abnormality in the brains of persons
with ADHD.
Few trends in the findings are
apparent.
Structural imaging studies of the
corpus callosum have consistently reported that areas of this structure are
decreased in subjects with ADHD. However, studies are inconsistent with respect
to the particular areas affected.
A
possible explanation of the data is that lesions anywhere in the corpus
callosum is associated with ADHD, but different parts of the corpus callosum
are connected to different cortical areas so the effect should be variable.
ADHD
is characterized by a slightly smaller (4%) total brain volume (both white and
gray matter), less-consistent abnormalities of the basal ganglia and a striking
(15%) decrease in posterior inferior cerebellar vermal volume. These changes do
not progress with age. In contrast, patients with COS have smaller brain volume
due to a 10% decrease in cortical gray volume.
In normal child development, there are robust and complex changes in white and
gray matter.
White matter volume increases linearly during this age range,
reflecting increasing myelination [4,9], while gray matter volume increases
until early to mid-adolescence before decreasing during late adolescence [8],
presumably from synaptic pruning and reduction of neuropil.
Abnormalities appear to be a fixed, rather than an ongoing, process. Longitudinal
changes during childhood and adolescence did not differ between 73 ADHD
subjects. These anatomic abnormalities are not due to stimulant drug effects
since the 17 medication-naïve patients showed the same brain pattern at least
before age 4. Impulsivity per se is not likely to cause the late progressive
abnormalities seen for the schizophrenic group. Candidate processes for the
abnormalities in ADHD focus on prenatal or early postnatal events.
Decreased total brain volume and increased lateral ventricular volume as seen
in adult onset schizophrenia.
The decreased brain volume here is due
exclusively to the robust 10% decrease in cortical gray matter, as the total
white matter volume does not differ significantly between the COS and healthy
groups.
Clinically these changes parallel a decline in full-scale IQ [29] and lack of
normal maturation of neurological status [30] for these patients.
Clinically these changes parallel a decline in full-scale IQ [29] and lack of
normal maturation of neurological status [30] for these patients.
The stress and abnormal thought and behavior experienced by psychotic patients
might be responsible for the progressive loss of gray matter and
cytoarchitectonic deficiencies found in these individuals.
Could schizophrenic behavior be a
cause rather than an effect of the decreased and decreasing frontal gray brain
volume?
Could sever inattention and
impulsivity produce small gray matter volume?
Is at least consistent with the idea
that changes in synaptic efficacy could play a critical role in the onset of
schizophrenia [39,40]
Even the abnormality in environmental input to the brain of a schizophrenic
patient is considerably less severe than the conditions involved with most of
the experiments exploring plasticity
Schizophrenic behaviors result from
these abnormalities rather than the reverse
The total and regional growth curves for this group run parallel to normal
brain curves [21].
Thus, the events leading to the
anatomic differences in ADHD probably occur early in neurodevelopment.
Even a subtle injury during this
vulnerable process of neurodevelopment and organization in utero (second or
third trimester) can affect the brain development and size globally, thus
explaining the changes seen in ADHD [50].
Incidence of pregnancy-related complications, prematurity are slightly higher
in ADHD [51].
Prematurity, leaves us without a
specific hypothesis of what might mediate this subtle global reduction to brain
volume
This region of cerebellar vermis is
highly dopaminergic [52] and appears, like most brain volumetric measures to be
highly heritable, [Giedd J, Castellanos X: unpublished data].
The posterior inferior verimis, thus,
may be an important part of cerebello-striato-frontal circuitry and hence in
the aetiopathogenesis of ADHD.
Thus any defect in dopaminergic circuitry could alter these growth modulators
and ultimately the brain size and development.
These alleles have been examined in
ADHD populations and show no significant association with any of these brain
volumetric measures [55].
Subtle abnormalities in BDNF, NT--3
and others may cause localized abnormality of dopamine circuitry.
The caudate nucleus volume is decreased in boys with ADHD [56,57].
This is interesting as healthy girls
have a larger caudate nucleus, probably owing to higher concentration of
estrogen receptors in the region. This might explain the smaller caudate volume
in ADHD boys and lower incidence of ADHD in girls. This would not account for
the fact that brain MRI findings for ADHD boys and girls are very similar.
(A reduced number of neurons generated
during early neurodevelopment) (An excessive degree of synapse reduction of an
initially fairly normal number of synapses and neurons).
Post-mortem studies to determine if there is a reduced cell number in the
brains of people with schizophrenia have not produced consistent results in
many parts of the brain [34,60].
Found increased densities of neurons
in the prefrontal cortex and temporal lobe [62,64].
Decreased loss of expression of
synaptic markers in schizophrenia [65] and most recently decreased expression
of several functional genes important in presynaptic function and development [66].
Reduced neuropil hypothesis.
As development progresses the extra connects are eliminated or pruned.
The possible mechanisms behind
pathologic elimination of the synapses are too numerous and complex to
thoroughly review here.
Neuromuscular junction (NMJ)
At birth in the rodent, all muscle
fibers are innervated by at least two axons, and by 3 weeks postnatally all but
one axon has been eliminated from all of the muscle cells [68].
Requires activation of the system
because it fails to take place in paralyzed preparations.
To involve a number of protein kinases, enzymes which regulate protein function
by altering their state of phosphorylation. Neurotransmitter receptors are
known to be targets for kinase action leading to synapse elimination Activation
of appropriate kinases, phosphorylation of neurotransmitter receptors and
subsequent, selective destabilization of the synapses involving those receptors
[69]. Loss of synaptic acetylcholine receptors has been shown to be an early
step in the loss of synapses at the NMJ [70]. Differential activation of localized
kinases, which have different effects on receptor stability.
(protein kinase C or PKC) in synapse elimination in the central nervous system
has been obtained in experiments on the CF/PC system mentioned above.
Mutation of one isoform of PKC which inactivates the kinase has been shown to
block synapse elimination in the mouse cerebellum [71]. The activity of this
particular molecule, PKC, is essential for normal elimination of redundant
synapses.
Trophic factors have been shown to have powerful effects on neuronal survival
and synaptic structure and function during development [50, 72-74]. Competition
for a limited supply of trophic material has been postulated to account for at
least a portion of the synapse loss that occurs during development. Trophin
BDNF has been shown to prevent the normally occurring pruning that is essential
for development of the normal architecture of the visual cortex [75] and an
inadequate supply could result in inadequate development or survival of
cortical synapses.
Has been shown that a neuropeptide, vasoactive intestinal peptide (VIP)
controls the duration of the mitotic cycle in the neuroblasts in the
ventricular germinal zone and that this affects the total number of neurons
that get born during development. Result in markedly microcephalic animals
[74]. Such interference with the process of neuron generation could be involved
in the early deficit in brain size seen in ADHD.
Following on the initial speculation
of Feinberg [76], McGlashan and Hoffman [35] and others have used computer
modeling of neural networks to test the plausibility of the ‘over-pruning’
hypothesis of schizophrenia