Re: A Few Simple Truths About ADHD
From: Steve Harris sbharris_at_ROMAN9.netcom.com (sbharris_at_ix.netcom.com)
Date: 07/30/04
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Date: 30 Jul 2004 16:52:58 -0700
"Toby" <imtoebee@yahoo.com> wrote in message news:<10giab6hi0gq3d8@corp.supernews.com>...
> > >>There is much evidence that shows that the brains of people with
> > ADHD are different that the brains of people without ADHD.<<
> >
> > COMMENT:
> > Actually there is much evidence, but most of it is conflicting. I can
> > name half a dozen things, from size differences to receptor densities,
> > which have shown up in studies of kids diagnosed with ADHD vs.
> > controls. But there is not one which every investigator has found who
> > looked for it. If there was, we could diagnose this problem with a
> > brain scan or imaging modality. We can't.
>
> Please cite. I can make stupid generalizations too, and word them as
> "studies have shown", but without citing my source, I would just be an
> ignorant ass like yourself.
COMMENT:
I have already posted my own review of the deplorable state of
available imaging for ADHD in April of 2001. I'll repost it below.
It's 3 years out of date, but since you've called me an "ignorant ass"
I'll expect a detailed critique on what I've done from you, plus
citation of more recent studies refuting me. Enjoy. Please be sure
I'll do the same for what you post.
[April 2001]
COMMENT:
Well, here we go. There is nothing to do at this point but a review.
You
wanted the cites, so have at it.
The question is not whether somebody or other has reported some
difference
or other between their small group of ADHD brains and normals, but
whether
or not any such differences are seen repeatedly in other studies and
by
other groups, and are robust enough to be seen by most groups. In
short, are
real. The answer, so far as I can tell, is that there are no such
differences known yet.
Here is the abstract from the 1994 paper you quote from the NIMH group
(Rapoport is last author, not first):
This study finds that the normally larger R > L caudate nucleus volume
seen
in normal boys is not present in ADHD boys.
Caudate volume decreases with age in normals, but not in the ADHD.
Brain
volume is also 5% smaller in ADHD boys.
Am J Psychiatry 1994 Dec;151(12):1791-6
Quantitative morphology of the caudate nucleus in attention deficit
hyperactivity disorder.
Castellanos FX, Giedd JN, Eckburg P, Marsh WL, Vaituzis AC, Kaysen D,
Hamburger SD, Rapoport JL
Child Psychiatry Branch, NIMH, Bethesda, MD 20892.
OBJECTIVE: Because the caudate nuclei receive inputs from cortical
regions
implicated in executive functioning and attentional tasks, caudate and
total
brain volumes were examined in boys with attention deficit
hyperactivity
disorder (ADHD) and normal comparison subjects. To gain developmental
perspective, a wide age range was sampled for both groups. METHOD: The
brains of
50 male ADHD patients (aged 6-19) and 48 matched comparison subjects
were
scanned by magnetic resonance imaging (MRI). Volumetric measures of
the head
and body of the caudate nucleus were obtained from T1-weighted coronal
images. Interrater reliabilities (intraclass correlations) were 0.89
or
greater.
RESULTS: The normal pattern of slight but significantly greater right
caudate volume across all ages was not seen in ADHD. Mean right
caudate
volume was slightly but significantly smaller in the ADHD patients
than in
the comparison subjects, while there was no significant difference for
the
left. Together these
facts accounted for the highly significant lack of normal asymmetry in
caudate volume in the ADHD boys. Total brain volume was 5% smaller in
the
ADHD boys, and this was not accounted for by age, height, weight, or
IQ.
Smaller brain volume in ADHD did not account for the caudate volume or
symmetry differences. For the normal boys, caudate volume decreased
substantially (13%) and significantly with age, while in ADHD there
was no
age-related change. CONCLUSIONS: Along with previous MRI findings of
low
volumes in corpus callosum regions, these results support
developmental
abnormalities of frontal-striatal circuits in ADHD.
PMID: 7977887
COMMENT:
Now, a previous study by the same group: again similar findings but
also a
smaller RIGHT globus pallidus (note this, since the opposite will be
found
at Johns Hopkins).
Arch Gen Psychiatry 1996 Jul;53(7):607-16
Quantitative brain magnetic resonance imaging in attention-deficit
hyperactivity disorder.
Castellanos FX, Giedd JN, Marsh WL, Hamburger SD, Vaituzis AC,
Dickstein DP,
Sarfatti SE, Vauss YC, Snell JW, Lange N, Kaysen D, Krain AL, Ritchie
GF,
Rajapakse JC, Rapoport JL
Child Psychiatry Branch, National Institute of Mental Health,
Bethesda, Md,
USA.
BACKGROUND: Anatomic magnetic resonance imaging (MRI) studies of
attention-deficit hyperactivity disorder (ADHD) have been limited by
small
samples or measurement of single brain regions. Since the
neuropsychological
deficits in ADHD implicate a network linking basal ganglia and frontal
regions, 12 subcortical and cortical regions and their symmetries were
measured to
determine if these structures best distinguished ADHD. METHODS:
Anatomic
brain MRIs for 57 boys with ADHD and 55 healthy matched controls, aged
5 to
18 years, were obtained using a 1.5-T scanner with contiguous 2-mm
sections.
Volumetric measures of the cerebrum, caudate nucleus, putamen, globus
pallidus, amygdala,
hippocampus, temporal lobe, cerebellum; a measure of prefrontal
cortex; and
related right-left asymmetries were examined along with midsagittal
area
measures of the cerebellum and corpus callosum. Interrater
reliabilities
were .82 or greater for all MRI measures. RESULTS: Subjects with ADHD
had a
4.7%
smaller total cerebral volume (P = .02). Analysis of covariance for
total
cerebral volume demonstrated a significant loss of normal right > left
asymmetry in the caudate (P = .006), smaller right globus pallidus (P
=
.005), smaller right anterior frontal region (P = .02), smaller
cerebellum
(P = .05), and reversal of normal lateral ventricular asymmetry (P =
.03) in
the ADHD group.
The normal age-related decrease in caudate volume was not seen, and
increases in lateral ventricular volumes were significantly diminished
in
ADHD. CONCLUSION: This first comprehensive morphometric analysis is
consistent with hypothesized
dysfunction of right-sided prefrontal-striatal systems in ADHD.
PMID: 8660127
COMMENT:
Now we ask: are these findings repeatable by other groups? Is the
difference
"real"?
The Spanish also find reversed caudal asymmetry, which is due to an
abnormally enlarged RIGHT caudate in AHDH boys. So far so good. (There
is
also a Spanish version of this article in Rev Neurol 2000 May
16-31;30(10):920-5, using data from the same 11 patients).
Arch Neurol 1997 Aug;54(8):963-8
Magnetic resonance imaging measurement of the caudate nucleus in
adolescents
with attention-deficit hyperactivity disorder and its relationship
with
neuropsychological and behavioral measures.
Mataro M, Garcia-Sanchez C, Junque C, Estevez-Gonzalez A, Pujol J
Department of Psychiatry and Clinical Psychobiology, University of
Barcelona, Spain.
OBJECTIVE: To investigate structural basal ganglia abnormalities in
attention-deficit hyperactivity disorder (ADHD) and their relationship
with
the neuropsychological deficits and behavioral problems found in ADHD.
DESIGN: Case-control study. SETTING: Adolescents were recruited from a
local
polytechnic
institute of secondary education. SUBJECTS: Eleven adolescents with
ADHD and
19 healthy control subjects. Subjects with ADHD were diagnosed by the
school
psychologist from a total population of 450 students according to the
Diagnostic and Statistical Manual of Mental Disorders, Third Edition,
Revised. Diagnosis
was confirmed by the Conners Teachers Rating Scale and a structured
family
interview. MAIN OUTCOME MEASURES: Magnetic resonance imaging
single-slice
transversal measurements of the head of the caudate nucleus and a
comprehensive neuropsychological evaluation, which was specially
designed to
assess frontal-striatal functioning. RESULTS: The ADHD group had a
larger
right caudate nucleus area than the control group. In control
adolescents,
larger caudate nucleus areas were associated with poorer performance
on
tests of attention and
higher ratings on the Conners Teachers Rating Scale. CONCLUSIONS:
These
findings provide further evidence of the involvement of the caudate
nucleus
in the neuropsychological deficits and behavioral problems found in
ADHD.
The larger caudate nucleus found in the ADHD group could be related to
a
failure of the maturational processes that normally result in volume
reduction.
PMID: 9267970
COMMENT:
The Greeks, alas, see LEFT > RIGHT pattern in normals, the reverse of
what
the above groups see (very confusing -- what IS normal?), and think
that
AHDH kids have a smaller LEFT caudate than is normal, not a larger
RIGHT
one. Hmmm.
BTW, L > R size for motor nuclei is what one would expect to happen a
little
more often in R handedness, which is (of course) what one should see
most
often. But these studies do not control for handedness. One suspects
that we
are seeing noise:
J Child Neurol 1993 Oct;8(4):339-47
Attention deficit-hyperactivity disorder and asymmetry of the caudate
nucleus.
Hynd GW, Hern KL, Novey ES, Eliopulos D, Marshall R, Gonzalez JJ,
Voeller KK
Department of Special Education, University of Georgia, Athens 30602.
The neurologic basis of attention deficit-hyperactivity disorder
(ADHD) is
poorly understood. Based on previous studies that have implicated
metabolic
deficiencies in the caudate-striatal region in ADHD, we employed
magnetic
resonance imaging to investigate patterns of morphology of the head of
the
caudate nucleus in normal and ADHD children. In normal children, 72.7%
evidenced
a left-larger-than-right (L > R) pattern of asymmetry, whereas 63.6%
of the
ADHD children had the reverse (L < R) pattern of asymmetry of the head
of
the caudate nucleus. This reversal of normal asymmetry in ADHD
children was
due to a
significantly smaller left caudate nucleus. The reversal in asymmetry
of the
head of the caudate was most notable in ADHD males. These results
suggest
that normal (L > R) morphologic asymmetry in the region of the caudate
nucleus may be
related to asymmetries observed in neurotransmitter systems implicated
in
ADHD. The behavioral symptoms of ADHD may reflect disinhibition from
normal
levels of dominant hemispheric control, possibly correlated with
deviations
in asymmetric caudate-striatal morphology and deficiencies in
associated
neurotransmitter systems.PMID: 8228029
COMMENT:
Okay, very well, what do we see when we DO control for handedness?
Here is a
study from Johns Hopkins. They find small LEFT globus pallidus volume
in
AHDH, in contrast to the NIMH study above which finds smaller RIGHT
globus
palidus volumes in AHDH. Wups. Also, at Johns Hopkins they see NO
difference
in the caudates in these boys, contradicting everybody else. Wups
again.
J Child Neurol 1996 Mar;11(2):112-5
Basal ganglia volumes in children with attention-deficit hyperactivity
disorder.
Aylward EH, Reiss AL, Reader MJ, Singer HS, Brown JE, Denckla MB
Department of Psychiatry and Behavioral Sciences, Johns Hopkins
University,
Baltimore, MD 21205, USA.
Previous research has demonstrated volume reduction of the left globus
pallidus in children with the codiagnoses of Tourette syndrome and
attention-deficit hyperactivity disorder (ADHD), in comparison with
children
who have Tourette syndrome alone and with normal controls. The purpose
of
this study was to
determine whether children with ADHD alone also had volume reduction
of the
globus pallidus or other basal ganglia structures. Subjects were 10
boys
with ADHD, 16 boys with Tourette syndrome and ADHD, and 11 normal
control
boys.
Groups were matched for age. Boys with ADHD were individually matched
for
age, handedness, and IQ to 10 of the 16 boys with Tourette syndrome
and
ADHD. Volumes of caudate, putamen, and globus pallidus were measured
and
corrected for brain
volume. The boys with ADHD had significantly smaller left globus
pallidus
volume and total globus pallidus volume (corrected for brain volume)
than
the normal controls. The Tourette syndrome plus ADHD group did not
differ
from the ADHD
group on any of the measures. We conclude that small globus pallidus
volume,
particularly on the left side, is associated with ADHD.PMID: 8881987
COMMENT:
But wait. It's not the basal ganglia which are different in ADHD.
It's the cerebellum. The cerebellar posterior/inferior vermis is
smaller in
ADHD boys. Johns Hopkins again:
J Child Neurol 1998 Sep;13(9):434-9
Evaluation of cerebellar size in attention-deficit hyperactivity
disorder.
Mostofsky SH, Reiss AL, Lockhart P, Denckla MB
Kennedy Krieger Institute, Department of Neurology, Johns Hopkins
University
School of Medicine, Baltimore, MD 21205, USA.
Evidence from animal and human research suggests that the cerebellum
may
play a role in cognition. This includes domains of executive function
that
are normally attributed to the prefrontal cortex and are typically
deficient
in individuals with attention-deficit hyperactivity disorder (ADHD).
To
investigate cerebellar
structure in ADHD, magnetic resonance imaging morphometry was used to
measure the area of the cerebellar vermis in 12 males with ADHD and 23
male
controls matched for age and Wechsler Full-Scale IQ. Analyses were
conducted
to evaluate
group differences, as well as differences between matched pairs of
subjects
with ADHD and those without ADHD. All measurements were corrected for
overall brain size. Both analyses revealed that the size of the
posterior
vermis was significantly decreased in males with ADHD (P < .05 in both
analyses), and that
within the posterior vermis, the inferior posterior lobe (lobules
VIII-X)
was involved in this reduction (P < .05 for group analysis, P < .005
for
matched pair analysis), while the superior posterior lobe (lobules
VI/VII)
was not involved in the reduction. The finding of abnormal inferior
posterior vermal
size suggests that dysfunction within this region of the cerebellum
may
underlie clinical deficits seen in individuals with ADHD.PMID: 9733289
COMMENT:
And now, for the French opinion: they agree with the Hopkins people.
It's
the cerebellum posterior/inferior vermis. This is Rapoport again,
however,
so it's not a totally independent report from the NIMH study.
Neurology 1998 Apr;50(4):1087-93
Cerebellum in attention-deficit hyperactivity disorder: a morphometric
MRI
study.
Berquin PC, Giedd JN, Jacobsen LK, Hamburger SD, Krain AL, Rapoport
JL,
Castellanos FX
Service de Pediatrie 1, CHU Hopital Nord, Amiens, France.
Clinical, neuroanatomic, neurobehavioral, and functional brain-imaging
studies suggest a role for the cerebellum in cognitive functions,
including
attention. However, the cerebellum has not been systematically studied
in
attention-deficit hyperactivity disorder (ADHD). We quantified the
cerebellar and vermal volumes,
and the midsagittal areas of three vermal regions, from MRIs of 46
right-handed boys with ADHD and 47 matched healthy controls. Vermal
volume
was significantly less in the boys with ADHD. This reduction involved
mainly
the posterior inferior lobe (lobules VIII to X) but not the posterior
superior lobe (lobules
VI to VII). These results remained significant even after adjustment
for
brain volume and IQ. A cerebello-thalamo-prefrontal circuit
dysfunction may
subserve the motor control, inhibition, and executive function
deficits
encountered in
ADHD.PMID: 9566399
COMMENT:
No, wait. It's actually the posterior corpus callosum which is
different. So
say the folks in Seattle:
J Am Acad Child Adolesc Psychiatry 1994 Jul-Aug;33(6):875-81
Attention-deficit hyperactivity disorder: magnetic resonance imaging
morphometric analysis of the corpus callosum.
Semrud-Clikeman M, Filipek PA, Biederman J, Steingard R, Kennedy D,
Renshaw
P, Bekken K
University of Washington, Seattle 98195.
OBJECTIVE: The following study seeks to document possible differences
in
corpus callosal area and shape between children with attention-deficit
hyperactivity disorder (ADHD) and controls. METHODS: Fifteen carefully
diagnosed right-handed
male subjects with ADHD with overactivity symptomatology were compared
to 15
right-handed male control subjects. The corpus callosum was divided
into
seven areas on the midsagittal slice of a magnetic resonance image
with
shape analysis also conducted. RESULTS: An exploratory shape analysis
showed
no significant
differences in shape between the groups. No group differences were
found in
the area, length, or anterior regions of the corpus callosum. The ADHD
subjects were found to have significantly smaller posterior corpus
callosum
regions than the control group, with the splenium accounting for most
of the
variance between the
groups. CONCLUSIONS: The splenial area of the corpus callosum is
smaller in
children with ADHD than in a sample of normally developing children.
These
smaller areas may relate to commonly seen sustained attention deficits
which
in turn negatively impact on the development of more advanced levels
of
attention
such as self-regulation. Further study of the regions surrounding the
splenial area is suggested to determine whether they are correlated in
size
to the smaller corpus callosum.
PMID: 8083145
COMMENT:
And finally, just to confuse the issue a bit, the NIMH people find
that
girls with ADHD have the same cerebellar volume reduction as boys with
the
same (supposed) disease and also slightly smaller brains (p = .05).
BUT
their caudal nuclei are perfectly normal. And are not asymmetric, even
in
controls.
Arch Gen Psychiatry 2001 Mar;58(3):289-95
Quantitative brain magnetic resonance imaging in girls with
attention-deficit/hyperactivity disorder.
Castellanos FX, Giedd JN, Berquin PC, Walter JM, Sharp W, Tran T,
Vaituzis
AC, Blumenthal JD, Nelson J, Bastain TM, Zijdenbos A, Evans AC,
Rapoport JL
Child Psychiatry Branch, National Institute of Mental Health, Bldg 10,
Room
3N-202, 10 Center Dr-MSC 1600, Bethesda, MD 20892-1600, USA.
BACKGROUND: Anatomic studies of boys with
attention-deficit/hyperactivity
disorder (ADHD) have detected decreased volumes in total and frontal
brain,
basal ganglia, and cerebellar vermis. We tested these findings in a
sample
of girls with ADHD. METHODS: Anatomic brain magnetic resonance images
from
50 girls
with ADHD, of severity comparable with that in previously studied
boys, and
50 healthy female control subjects, aged 5 to 15 years, were obtained
with a
1.5-T scanner with contiguous 2-mm coronal slices and 1.5-mm axial
slices.
We measured volumes of total cerebrum, frontal lobes, caudate nucleus,
globus pallidus,
cerebellum, and cerebellar vermis. Behavioral measures included
structured
psychiatric interviews, parent and teacher ratings, and the Wechsler
vocabulary and block design subtests. RESULTS: Total brain volume was
smaller in girls with ADHD than in control subjects (effect size,
0.40; P
=.05). As in our previous
study in boys with ADHD, girls with ADHD had significantly smaller
volumes
in the posterior-inferior cerebellar vermis (lobules VIII-X; effect
size,
0.54; P =.04), even when adjusted for total cerebral volume and
vocabulary
score. Patients and controls did not differ in asymmetry in any
region.
Morphometric differences correlated significantly with several ratings
of
ADHD severity and were not predicted by past or present stimulant drug
exposure. CONCLUSIONS: These results confirm previous findings for
boys in
the posterior-inferior lobules of the cerebellar vermis. The influence
of
the cerebellar vermis on prefrontal and striatal circuitry should be
explored.PMID: 11231836
========================================
So which parts are real and which are artifacts of small samples
and measurements of small differences?
THE NUCLEAR IMAGING STUDIES:
Here is the OTHER study you quote, another NIHM study:
N Engl J Med 1990 Nov 15;323(20):1361-6
Cerebral glucose metabolism in adults with hyperactivity of childhood
onset.
Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Rumsey J,
Hamburger S,
Cohen RM
Section on Clinical Brain Imaging, National Institute of Mental
Health, NIH,
Bethesda, MD 20892.
BACKGROUND AND METHODS. The cause of childhood hyperactivity
(attention
deficit-hyperactivity disorder) is unknown. We investigated the
hypothesis
that cerebral glucose metabolism might differ between normal adults
(controls) and adults with histories of hyperactivity in childhood who
continued to have
symptoms. Each patient was also the biologic parent of a hyperactive
child.
None of the adults had ever been treated with stimulant medication. To
measure cerebral glucose metabolism, we administered 148 to 185 MBq (4
to 5
mCi) of [18F]fluoro-2-deoxy-D-glucose intravenously to 50 normal
adults and
25 hyperactive adults while they performed an auditory-attention task.
Images were obtained for 30 minutes with a Scanditronix
positron-emission
tomograph with a resolution of 5 to 6 mm. Whole-brain and regional
rates of
glucose metabolism were measured with computer assistance by two
trained
research assistants,
working independently, who were blinded to the subjects' status
(control or
hyperactive). RESULTS. Global cerebral glucose metabolism was 8.1
percent
lower in the adults with hyperactivity than in the normal controls
(mean +/-
SD, 9.05 +/- 1.20 mg per minute per 100 g vs. 9.85 +/- 1.68 mg per
minute
per 100 g; P =
0.034). In the adults with hyperactivity, glucose metabolism was
significantly reduced, as compared with the values for the controls,
in 30
of 60 specific regions of the brain (P less than 0.05). Among the
regions of
the brain with the greatest reductions in glucose metabolism were the
premotor cortex and the
superior prefrontal cortex. When the seven women with hyperactivity or
the
six patients with learning disabilities were omitted from the
analysis, the
results were similar. CONCLUSIONS. Glucose metabolism, both global and
regional, was reduced in adults who had been hyperactive since
childhood.
The largest
reductions were in the premotor cortex and the superior prefrontal
cortex-areas earlier shown to be involved in the control of attention
and
motor activity.
Comment in:
N Engl J Med. 1990 Nov 15;323(20):1413-5
N Engl J Med. 1991 Apr 25;324(17):1216-7
PMID: 2233902
MY COMMENT:
The areas where the largest deficits in uptake occurred were the
prefrontal
and premotor cortices.
Alas, what you don't add to your reference is that the same group
(with two
of the same authors) writing 8 years later cannot find any real
metabolic
differences between ADHD and normals. Naturally, they downplay this.
If
you've been published in the NEJM, what are you going to do-- say you
can't
see the effect anymore?
J Neuropsychiatry Clin Neurosci 1998 Spring;10(2):168-77
Age-related changes in brain glucose metabolism in adults with
attention-deficit/hyperactivity disorder and control subjects.
Ernst M, Zametkin AJ, Phillips RL, Cohen RM
Laboratory of Cerebral Metabolism, National Institute of Mental
Health,
Rockville, Maryland, USA.
Using positron emission tomography and
[18F]-2-fluoro-2-deoxy-D-glucose, the
authors determined cerebral metabolic rates for glucose (CMRglc) in 39
adults (18-51 years old) with attention-deficit/hyperactivity disorder
(ADHD) and 56 healthy control adults (19-56 years old) during the
performance of a continuous
attention task. Increased age was associated with reduced global
CMRglc in
ADHD women, but not in ADHD men, control men, or control women. Better
performance on the attention task was significantly associated with
increased age only in the
ADHD female group. Determining the role of behavioral, hormonal, and
genetic
factors is a challenge for future research.
PMID: 9608405
COMMENT:
Golly, it's "challenging" when you can't find your own jazzy effect,
all
right....
Below we find Zemetkin trying again, with teenaged girls. His results
are
not significant, but he reports the % decreases anyway. That takes
guts, but
we're not fooled.
Arch Gen Psychiatry 1993 May;50(5):333-40
Brain metabolism in teenagers with attention-deficit hyperactivity
disorder.
Zametkin AJ, Liebenauer LL, Fitzgerald GA, King AC, Minkunas DV,
Herscovitch
P, Yamada EM, Cohen RM
Section on Clinical Brain Imaging, National Institute of Mental
Health,
Bethesda, Md.
OBJECTIVES: We sought to obtain and compare values of cerebral glucose
metabolism in normal minors and minors with Attention Deficit
Hyperactivity
Disorder (ADHD). We also sought to confirm our earlier findings of
reduced
brain metabolism in adults with ADHD, and to examine whether these
results
might be diagnostically useful. DESIGN: Case-control study. SETTING:
Adolescents were recruited to National Institutes of Health Clinical
Center/Research Facility through advertisement at local high schools
and
ADHD organizations. PATIENTS: Subjects were 10 normal adolescents and
10
adolescents with ADHD diagnosed with
structured interviews using DSM-III-R criteria. MAIN OUTCOME MEASURES:
Positron emission tomography and fludeoxyglucose F18 were used to
study
cerebral glucose metabolism in minors while they performed an
auditory-attention task. RESULTS: Global or absolute measures of
metabolism
did not statistically differ between groups, although hyperactive
girls had
a 17.6% lower absolute brain metabolism than normal girls. As compared
with
the values for the controls, normalized glucose metabolism was
significantly
reduced in six of 60 specific regions of
the brain, including an area of the left anterior frontal lobe (P <
.05).
Lower metabolism in that specific region of the left anterior frontal
lobe
was significantly inversely correlated with measures of symptom
severity (P
< .001-.009, r = -.56 to -.67). CONCLUSIONS: Global or absolute
measures of
metabolism using positron emission tomography and fludeoxyglucose F18
did
not
statistically differentiate between normal adolescents with ADHD.
Positron
emission tomography scans can be performed and are well tolerated by
normal
teenagers and teenagers with ADHD. The feasibility of normal minors
participating in research involving radiation was established.
Comment in:
Arch Gen Psychiatry. 1996 Nov;53(11):1059-61
PMID: 8489322
COMMENT:
Here is another earlier one failing to find any glucose metabolism
differences in ADHD girls. Subregional differences are seen on
multiple
after-the-fact comparisons, but if you do enough fishing expedition
comparisons, you're of course bound to see some differences somewhere
in
something, just by the luck of the draw. (There's a rock song about
that:
"I've got a girl named Boniferroni...")
J Am Acad Child Adolesc Psychiatry 1997 Oct;36(10):1399-406
Cerebral glucose metabolism in adolescent girls with
attention-deficit/hyperactivity disorder.
Ernst M, Cohen RM, Liebenauer LL, Jons PH, Zametkin AJ
Laboratory of Cerebral Metabolism, National Institute of Mental
Health,
Bethesda, MD, USA.
OBJECTIVE: Low cerebral metabolic rates for glucose (CMRglc) have been
reported in a small sample of girls with
attention-deficit/hyperactivity
disorder (ADHD). This study was an effort to replicate this finding in
a
larger independent sample. METHOD: Using positron emission tomography
and
[18F]fluorodeoxyglucose,
CMRglc were compared between 10 girls with ADHD (14.10 +/- 1.91 years)
and
11 normal girls (14.3 +/- 1.70 years). RESULTS: Global CMRglc was
similar
between ADHD and control girls. Lateralization of normalized CMRglc
differed
significantly between ADHD and control girls in parietal and
subcortical
regions, with rCMRglc lower on the left than on the right side in
girls with
ADHD, and conversely in control girls. The sylvian area of the
parietal
region and the anterior putamen of the subcortical region were the
main
contributors to this effect. Normalized rCMRglc of the hippocampus was
higher in ADHD than in
control girls. Sexual maturation was the only clinical characteristic
that
differed between present and previous samples, and it correlated with
global
CMRglc. CONCLUSIONS: Although failing to confirm abnormally low CMRglc
in
girls
with ADHD, this study suggested that (1) functional interactions
between sex
and brain development may contribute to ADHD pathophysiology, and (2)
sexual
maturation should be controlled in future CMRglc studies of adolescent
girls.
PMID: 9334553
COMMENT:
In the above study, they found that what they thought was an ADHD
effect in
girls was just the female brain turning off at puberty <allow myself a
grin
here; feminists deserve it for their comments about the same process
in
boys>. Anyway, the NIMH people above were trying to replicate the
study
below, in which they thought they had found glucose uptake differences
between ADHD and normal girls, but did NOT see it in boys. And as
we've
seen, the latter study could not confirm the girl data, either, so
basically, they are back to square-one by the above 1997 study. I
don't
think the New England Journal of Medicine made them retract the 1990
article, however. This is, after all, the National Institute of Mental
Health.
J Am Acad Child Adolesc Psychiatry 1994 Jul-Aug;33(6):858-68
Reduced brain metabolism in hyperactive girls.
Ernst M, Liebenauer LL, King AC, Fitzgerald GA, Cohen RM, Zametkin AJ
Section on Clinical Brain Imaging, National Institute of Mental
Health, NIH,
Bethesda, MD 20892.
OBJECTIVE: This study assesses the effect of attention-deficit
hyperactivity
disorder (ADHD) and gender on cerebral glucose metabolism (CMRglu),
using
positron emission tomography and 18F-fluorodeoxyglucose. METHOD:
Nineteen
normal (6 females; 14.3 +/- 1.3 years old) and 20 ADHD adolescents (5
females; 14.7 +/-
1.6 years old) participated in the study. An auditory continuous
performance
task was used during the 30-minute uptake of 18F-fluorodeoxyglucose.
RESULTS: There were no statistically significant differences in global
or
regional CMRglu
between ADHD (N = 20) and normal (N = 19) adolescents. However, the
global
CMRglu in ADHD girls (N = 5) was 15.0% lower than in normal girls (N =
6) (p
= .04), while global CMRglu in ADHD boys was not different than in
normal
boys. Furthermore, global CMRglu in ADHD girls was 19.6% lower than in
ADHD
boys (p =
.02) and was not different between normal girls and normal boys.
Clinical
rating scales did not differentiate ADHD girls from ADHD boys, nor
normal
girls from normal boys. CONCLUSIONS: The greater brain metabolism
abnormalities in females than males strongly stress that more
attention be
given to the study of girls
with ADHD.PMID: 8083143
COMMENT:
Ah, but not to be outdone. If glucose doesn't work, there's always
dopamine
metabolism! And after the 1997 final glucose fiasco, that's what we
see NIMH
focus on.
Am J Psychiatry 1999 Aug;156(8):1209-15
High midbrain [18F]DOPA accumulation in children with attention
deficit
hyperactivity disorder.
Ernst M, Zametkin AJ, Matochik JA, Pascualvaca D, Jons PH, Cohen RM
Laboratory of Cerebral Metabolism, NIMH, Bethesda, Md., USA.
mernst@intra.nida.nih.gov
OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly
prevalent childhood psychiatric disorder characterized by impaired
attention, excessive motor activity, and impulsivity. Despite
extensive
investigation of the neuropathophysiology of ADHD by a wide array of
methodologies, the neurobiochemical substrate of this disorder is
still
unknown. Converging
evidence, however, suggests a primary role of the dopaminergic system.
METHOD: This study examined the integrity of presynaptic dopaminergic
function in children with ADHD through use of positron emission
tomography
and the tracer [18F]fluorodopa ([18F]DOPA). Accumulation of [18F]DOPA
in
synaptic terminals, a
measure of dopa decarboxylase activity, was quantified in regions rich
in
dopaminergic innervation, including caudate nucleus, putamen, frontal
cortex, and midbrain (i.e., substantia nigra and ventral tegmentum).
RESULTS: Accumulation of [18F]DOPA in the right midbrain was higher by
48%
in 10 children with ADHD than in 10 normal children. Despite its
magnitude,
this difference
would not have reached statistical significance if corrected by the
Bonferroni test for multiple comparisons. However, [18F]DOPA in the
right
midbrain was correlated with symptom severity. No other dopamine-rich
regions significantly differed between groups. CONCLUSIONS: These
findings
are suggestive of
dopaminergic dysfunction at the level of the dopaminergic nuclei in
children
with ADHD. Abnormality in dopa decarboxylase activity may be primary
or
secondary to deficits in other functional units of the dopamine
pathway
(e.g., receptor, uptake transporter, vesicular transporter,
degradation
enzymes). Efforts toward defining the origin of this abnormality
should help
delineate
mechanisms of midbrain control of attention and motor behavior
important for
the understanding of the causes and treatment of ADHD. PMID: 10450262
COMMENT:
Again we're reporting non-statistically significant fishing expedition
data.
Same-old, same-old. The midbrain, eh? But no, earlier, it had
actually been
reprorted to be........the prefrontal cortex:
J Neurosci 1998 Aug 1;18(15):5901-7
DOPA decarboxylase activity in attention deficit hyperactivity
disorder
adults. A [fluorine-18]fluorodopa positron emission tomographic study.
Ernst M, Zametkin AJ, Matochik JA, Jons PH, Cohen RM
Laboratory of Cerebral Metabolism, National Institute of Mental
Health,
Bethesda, Maryland 20892, USA.
Converging evidence implicates the dopaminergic system and the
prefrontal
and nigrostriatal regions in the pathophysiology of attention deficit
hyperactivity disorder (ADHD). Using positron emission tomography
(PET) with
[fluorine-18]fluorodopa (F18-DOPA), we compared the integrity of the
presynaptic dopaminergic function between 17 ADHD adults and 23
healthy
controls. The ratio of the isotope concentration of specific regions
to that
of nonspecific regions reflects DOPA decarboxylase activity and
dopamine
storage processes. Of three composite regions (prefrontal cortex,
striatum,
and midbrain), only the
prefrontal cortex showed significantly different F18-DOPA ratios in
ADHD as
compared with control adults (p < 0.01). The medial and left
prefrontal
areas were the most altered (lower F18-DOPA ratios by 52 and 51% in
ADHD as
compared with controls). Similarly, the interaction [sex x diagnosis]
was
significant
only in the prefrontal cortex (p < 0.02): lower ratios in men than in
women
in ADHD and vice versa in controls. These findings suggest that a
prefrontal
dopaminergic dysfunction mediates ADHD symptoms in adults and that
gender
influences this abnormality. On the basis of previous neuroimaging
findings
in ADHD showing discrepant findings in adults and adolescents and on
evidence for
midbrain dopaminergic defect in adolescents, we hypothesize that the
prefrontal dopaminergic abnormality in ADHD adults is secondary and
results
from an interaction of the primary subcortical dopaminergic deficit
with
processes of
neural maturation and neural adaptation.PMID: 9671677
COMMENT:
You'll notice they don't dare publish this stuff in the same journal
the
next time they find some OTHER brain area lighting up. A little
gamesmanship, there.
======================================================
EXECUTIVE SUMMARY:
The MRI data for AHDH are completely screwed up, and nobody can agree
with
anybody else on what's different, if anything. Rapoport, working with
the
French, and also at the NIHM, seems to think that the cerebellar
vermis is
smaller, and at Hopkins they actually agree with this. Abstracting
from
everything I've read, I judge that this one difference has the largest
chance of being a real, objective, repeatable finding. However, the
available MRI data are overall in such a state that at this point the
jury
is still out. No candy bar for you.
The nuclear imaging (PET) data are (if anything) in even worse shape.
Some
early data reports lower glucose uptake, later data basically
contradicts
that thorougly. The hot areas in dopaminergic uptake (a better bet for
a
finding, probably) are found variously in various places, and none of
them
are at this time statistically significant if you Bonferroni-correct
for the
large number of inter-area comparisons done. So again, no candy bar.
The
NIHM in general seem to have made it their mission to find some kind
of
imaging difference between ADHD people and normals. Rapoport in
particular
travels around the world rustling up such differences. That's nice,
but
we'll need to see some more of that popping up in the same places in
the
brain, when Rapoport is not around. That's what's required in science.
Final conclusion: no cigar.
SBH
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