Developmental Trajectories of Brain Volume Abnormalities in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder - Commentary by Fred A. Baughman Jr., MD (10/10/02)

 Fred A.
Baughman Jr. comments on (10/10/02):
Developmental
Trajectories of Brain Volume Abnormalities in Children and Adolescents With
Attention-
 Deficit/Hyperactivity
Disorder

  F. Xavier Castellanos, MD
 

[Fred A. Baughman Jr., MD:long a member of
the national professional advisory board of CHADD, created by Ciba/Novartis for
Ciba/Novartis, which has professed throughout it's existence, that ADHD is a
"neurobiological disorder," a disease; that children with it are brain-abnormal,
brain-diseased]

; Patti P. Lee, MD; Wendy Sharp, MSW; Neal O. Jeffries,
PhD; Deanna K. Greenstein, PhD; Liv S. Clasen, PhD; Jonathan D. Blumenthal, MA;
Regina S. James, MD; Christen L. Ebens, BA; James M. Walter, MA; Alex Zijdenbos,
PhD; Alan C. Evans, PhD; Jay N. Giedd, MD; Judith L. Rapoport, MD

Context Various anatomic brain
abnormalities have been reported for attention-deficit/hyperactivity disorder
(ADHD), with varying methods, small samples, cross-sectional designs, and
without accounting for stimulant drug exposure.

Objective To compare regional
brain volumes at initial scan and their change over time in medicated and
previously unmedicated male and female patients with ADHD and healthy controls.

[Fred A. Baughman Jr., MD:Their objective, quite simply, should be to determine whether or
not ADHD is a bona fide, diagnosable, disease having, as it must, a confirming
macroscopic (gross), microscopic or chemical abnormality, demonstrable in life
or at death (autopsy)]

Design,
Setting, and Participants Case-control study
conducted from 1991-2001

[Fred A. Baughman Jr., MD:Swanson and Castellanos made no mention
that such a study was underway in their November 16-18, 1998 presentation at the
NIH Consensus Conference on ADHD in which they presented "a meta-analysis of
studies from several independent laboratories that have reported ADHD/HKD
abnormalities in two specific but still coarsely defined brain regions of the
frontal lobes and basal ganglia" failing, as they did so to acknowledge that the
ADHD subjects in all of these studies had been on long-term stimulant
treatment-the only known physical variable.  When questioned by myself, from the
audience, Swanson presenting for he and Castellanos, acknowledged the need for
brain scan studies of non-drug-exposed ADHD subjects, and also the fact that no
such study had been undertaken to that date.  Nor  did he mention that any had been
planned.  And yet here we have a
"Case-control study conducted from 1991-2001.]

…..at the National
Institute of Mental Health, Bethesda, Md, of 152 children and adolescents with
ADHD (age range, 5-18 years) and 139 age- and sex-matched controls (age range,
4.5-19 years) recruited from the local community, who contributed 544 anatomic
magnetic resonance images.

Main
Outcome Measures Using completely
automated methods, initial volumes and prospective age-related changes of total
cerebrum, cerebellum, gray and white matter for the 4 major lobes, and caudate
nucleus of the brain were compared in patients and controls.

[Fred A. Baughman Jr., MD:true
scientists seeking to determine the presence or absence of abnormality, would be
prepared to find any abnormality. 
These "scientists" seemed convinced that their would be volume changes
"of total cerebrum, cerebellum, gray and white matter for the 4 major lobes, and
caudate nucleus of the brain."]

Results On initial scan,
patients with ADHD had significantly smaller brain volumes in all regions, even
after adjustment for significant covariates. This global difference was
reflected in smaller total cerebral volumes (-3.2%, adjusted F_1,280 =
8.30,
P = .004) and in
significantly smaller cerebellar volumes (-3.5%, adjusted F_1,280 =
12.29,
P = .001). Compared
with controls, previously unmedicated children with ADHD demonstrated
significantly smaller total cerebral volumes (overall F_2,288 = 6.65;
all pairwise comparisons Bonferroni corrected, -5.8%;
P = .002) and
cerebellar volumes (-6.2%, F_2,288 = 8.97,
P<.001). Unmedicated
children with ADHD also exhibited strikingly smaller total white matter volumes
(F_2,288 = 11.65) compared with controls (-10.7%,
P<.001) and with
medicated children with ADHD (-8.9%, P<.001). Volumetric
abnormalities persisted with age in total and regional cerebral measures
(P = .002) and in the cerebellum (P = .003). Caudate nucleus
volumes were initially abnormal for patients with ADHD (P = .05), but
diagnostic differences disappeared as caudate volumes decreased for patients and
controls during adolescence. Results were comparable for male and female
patients on all measures. Frontal and temporal gray matter, caudate, and
cerebellar volumes correlated significantly with parent- and clinician-rated
severity measures within the ADHD sample (Pearson coefficients between -0.16 and
-0.26; all P values were
<.05).

Conclusions Developmental
trajectories for all structures, except caudate, remain roughly parallel for
patients and controls during childhood and adolescence, suggesting that genetic
and/or early environmental influences on brain development in ADHD are fixed,
nonprogressive, and unrelated to stimulant treatment.

JAMA.
2002;288:1740-1748

[Fred A. Baughman Jr., MD: On to the study
itself]

Attention-deficit/hyperactivity
disorder (ADHD), the most common childhood psychiatric disorder

[Fred A. Baughman Jr., MD:important,
because not a single psychiatry entry in any volume of the DSM has been proved
to be an organic disease having, as it must, an objective physical abnormality
by which to confirm it's presence in one or more patients]

, is thought
to reflect subtle abnormalities in central nervous system
functioning.

¹

[Fred A. Baughman Jr., MD:thought
by psychiatry, but no other branch of medicine.  Carey, a pediatrician, and an authority
on temperament testified at the Consensus Conference: What is now most often
described as ADHD in  the United
States appears to be a set of normal behavioral variations that sometimes lead
to dysfunction through dissonant environmental interactions.  This discrepancy leaves the validity of
the construct in doubt."  Carey,
suspecting it is not a disease at all would not begin the application of
biomedical technologies]

.For this reason, ADHD is being studied
increasingly with a variety of brain imaging techniques throughout the life
span. Magnetic resonance imaging (MRI) is particularly suitable for the study of
pediatric patients, providing high-resolution images without ionizing radiation.
Previous MRI neuroimaging studies, most with small samples

[Fred A. Baughman Jr., MD:and all
using  subjects, virtually all of
whom have been on Schedule II amphetamines and amphetamine-like medications-the
only known physical variable]

, have reported smaller anatomic areas
and/or volumes in patients with ADHD in regions of the corpus
callosum,

^2-6 smaller volumes
and/or hypoactivation of prefrontal brain,^7-11 basal
ganglia,^8,
9,
12-16 and
cerebellum.^16-18 However, a recent
study noted inconsistencies in the ADHD neuroimaging literature and concluded
that specific abnormalities have not yet been convincingly
demonstrated.¹⁹                   

[Fred A. Baughman Jr., MD:The
totality of the CT and MRI brain scanning literature reviewed by Swanson and
Castellanos at the 1998 CC, encompassing the 12 years, 1986-1998 was performed
on MBD/ADD/ADHD subjects, virtually all of whom were on stimulants-the only
known physical variable-and found atrophy or shrinkage of the brain and parts of
the brain.  Swanson and Castellanos
did not mention the presence of drugs in their presentation at the CC until I
called Swanson on the point.  This
12 years of literature stands as proof-replicated time after time, that the
long-term use/prescription of these medications causes brain atrophy.  There has never yet been validation of
ADHD as a disease.  Such was clearly
the status of ADHD as of the CC, November, 1998 by which time the ADHD epidemic
was approximately 4 million in the US. 
Furthermore, as each of these studies was published they were invariably
represented to be confirmation of ADHD, the "disease", with mention of the
drug-exposure status of the subjects, buried in the small print of "methods"
within the original article, and otherwise, forever
lost.]

"urn:schemas-microsoft-com:office:office" /?>

Although we
previously conducted anatomic studies in male (n = 112)²⁰ and female (n =
100)¹⁶ patients with ADHD
and controls, we were unable to rigorously contrast or combine the 2 sets of
findings because the original measurement techniques used were no longer
available. Moreover, we have continued to recruit new patients, including a
sizable number of patients who had never been previously exposed to psychotropic
medications.

The present
study was designed to examine brain anatomy using the same automated measures
from cross-sectional scans of a large sample of male and female patients with
ADHD, determine the effect of prior stimulant drug exposure on anatomic
abnormalities in ADHD, and examine brain regional longitudinal growth
trajectories in patients and controls.

We
hypothesized that patients with ADHD would have smaller brain regional volumes,
particularly in caudate nucleus,^8,
13
cerebellum,^16-18 and frontal
lobe^8,
9; previously
unmedicated children and adolescents with ADHD would demonstrate similar brain
abnormalities as medicated patients¹⁶; and caudate anatomic
abnormalities would diminish with age. Examination of age-related changes in
other brain regions was exploratory.

[Fred A. Baughman Jr., MD:It
seemed to me viewing the brain scanning literature, 1986 through the present,
that they knew the subjects (most on Schedule II stimulants) would have brain
atrophy and that they anticipated representing this, not as drug-induced, but as
"proof" that ADHD is a disease, that the atrophy is it's confirming, objective
abnormality.  In their current study
this is what they pretend to refute while "proving" once again that ADHD is a
disease with the brain atrophy its confirming abnormality.  As you shall see they do not wash away
the 12 years of proof after proof that the stimulant drugs cause brain atrophy
and they do not prove, in it's place that brain atrophy is the demonstrable,
diagnostic abnormality making ADHD an unquestioned disease]

METHODS
 Patients

A total of 89 male
(mean initial age, 10.5 years; range, 5.1-18.4) and 63 female (mean initial age,
9.4; range, 5.3-16.0) children and adolescents with Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition
(DSM-IV²¹)-defined
ADHD were recruited from the surrounding community.

[Fred A. Baughman Jr., MD:If brain scanning of
this patient population began in 1991, and DSM IV was not published
until 1994, the 1991-1993 subjects could not have been defined according to DSM
IV criteria. DSM III? DSM IIIR? In a 1995 review of the
neuro-imaging literature on ADHD, Ernst [28] commented: “The definition of ADHD
has changed over time.This change
has contributed to the selection of research samples with differing clinical
characteristics, making comparisons among studies difficult…samples of children
with ADHD who were diagnosed according to DSM-III-R (1987) criteria include
children who do not meet DSM-III (1980) criteria.”
What Ernst pointed out is that the ADD of DSM-III
(1980), the ADHD of DSM-III-R (1987), and the ADHD of DSM-IV (1994) are 3
separate, incomparable entities.
The 1980, DSM III, ADD was never confirmed as an organic disease before
it was jettisoned in favor of the 1987, DSM IIIR version of ADHD, and that, in
turn was never confirmed as a disease before it was jettisoned in favor of the
DSM IV version of ADHD…all of this in- committee at the American Psychiatric
Association, long ago bought and paid for by Big Pharma.
Is this science?
Are these scientists?
Do we owe it to them to consider what
they write here as science?
Should non-compromised
scientists be allowed “in” to inspect?
]

Inclusion criteria
were: hyperactive, inattentive, and impulsive behaviors that were impairing in
at least 2 settings and a Conners’ Teacher Hyperactivity rating greater than 2
SD above age- and sex-specific means.^22,
23 The
DSM-IV diagnosis of ADHD was
based on the Parent Diagnostic Interview for Children and
Adolescents,²⁴ Conners’ Teacher
Rating Scales,^22,
23 and the Teacher
Report Form.²⁵ A clinical
psychologist administered the Wechsler Intelligence Scale for
Children-Revised²⁶ to 110 patients with
ADHD and the Wechsler Intelligence Scale for Children-III²⁷ to 41 patients (1 was
too young to be tested). Exclusion criteria were a full-scale IQ of less than
80, evidence of medical or neurological disorders on examination or by clinical
history, Tourette disorder, or any other axis I psychiatric disorder requiring
treatment with medication at study entry.

[Fred A. Baughman Jr., MD:No matter the
multiplicity of measures, not one is an objective, physical measure; no one or
several positive results on such wholly subjective tests or scales equates to,
suggests, or implies, organic disease of the brain.  Recall that "biological" psychiatry has
yet to offer us their first biological proof.]

A total of 56
unrelated healthy female (mean initial age, 10.0 years; range, 5.2-16.1) and 83
male (mean initial age, 10.9; range, 4.5-19.0) controls were recruited from the
community via the National Institutes of Health Normal Volunteer Office and
outreach to local schools. Screening included an initial telephone interview,
parent and teacher rating scales,²⁵ in-person assessment
including physical and neurological examinations including
handedness,²⁸ and clinical history
obtained by a child and adolescent psychiatrist (J.N.G.)

[Fred A. Baughman Jr., MD arent and
teacher rating scales they would have us believe are tools with which to
validate the presence of organic disease of the brain.  Neurological examinations were done and
apparently ruled out all objective neurological abnormalities; things such as
abnormal gait, paralysis of one side or the other, visual field defects, facial
palsy, objective physical abnormalities, as compared to the so-called invisible
disabilities of special education and of psychiatry, generally]

.
Vocabulary and block design subtests from the Wechsler Intelligence Scale for
Children-Revised (n = 80), Wechsler Intelligence Scale for Children-III (n =
23), Wechsler Abbreviated Scale of Intelligence

²⁹ (n = 20), Wechsler
Preschool and Primary Scale of Intelligence³⁰ (n = 10), and
Wechsler Adult Intelligence Scale-Revised³¹ (n = 1) were
obtained. Five controls were not tested but were within the healthy range by
reported academic history. Approximately 4 candidates were screened for every 1
accepted,³² with the most common
exclusions being positive family psychiatric history and possible psychiatric
diagnosis based on teacher report.

This study
was conducted at the Child Psychiatry Branch of the National Institute of Mental
Health in Bethesda, Md, between 1991 and 2001. The institutional review board
approved the research protocol, and written informed consent and assent to
participate in a study of brain development were obtained from parents and
children, respectively, at study entry and at each subsequent MRI examination.

[Fred A. Baughman Jr., MD:It would be informative to obtain and review their informed consent
documents]

Healthy volunteers and patients not currently
participating in treatment studies were paid to participate.

Behavioral
Measures

Primary symptom
severity measures were those that remained constant across the study decade
using the Attention Problems Factors from the Child Behavior Checklist and
Teacher Report Form²⁵ and the Clinical
Global Impressions scale for Severity of Illness.³³ Medication status was
obtained from parental history.

[Fred A. Baughman Jr., MD:Nothing less than a life-history of
medication usage can suffice in a study such as this]

MRI
Acquisition

All patients and
controls were studied on the same 1.5-T General Electric Signa scanner
(Milwaukee, Wis). T1-weighted images with contiguous 1.5-mm slices in the axial
plane and 2.0-mm slices in the coronal plane were obtained using 3-dimensional
spoiled gradient recalled echo in the steady state. Imaging parameters were echo
time of 5 ms, repetition time of 24 ms, flip angle of 45°, acquisition matrix of
256 <<…OLE_Obj…>> 192, number of excitations equals 1,
and 24 cm field of view. Head placement was standardized as previously
described.¹⁶

Image
Analysis

T2-weighted images
were obtained for evaluation by a clinical neuroradiologist. All raters were
blind to demographic characteristics. Quantification of MRI images was performed
via a 3-part fully automated image analysis process that determines the volumes
of gray and white matter compartments in frontal, temporal, parietal, and
occipital lobes as well as basal ganglia and cerebellum with excellent
test-retest reliability as described elsewhere in detail.^34-36

Visual
inspection of each scan revealed that 544 of 594 total scans (92%) were
processed successfully; 50 were excluded because of classification and
segmentation errors due to motion. Failure rate was significantly higher (
<<…OLE_Obj…>> ²₁ with Yates correction
= 4.08,
P = .04) in 34 of 317
patients (11%) than in 16 of 277 controls (6%). All remaining scans from
patients with ADHD (283 scans) were used. The comparison group was selected from
a pool of healthy controls after excluding siblings in order not to violate the
statistical assumption of independence. The remaining 139 potential controls
(ie, no more than 1 per family within the age range of our patients) were
selected by the data manager (L.S.C.) to best match each target patient for sex,
age, and longitudinal intervals, prior to morphometric analyses.

[Fred A. Baughman Jr., MD:By
"morphomentric" they mean anatomic configuration]

Whenever precise
matching on all parameters was not possible, patients and controls were matched
on average-age across their own scans. Because we were unable to match all
patients and controls 1-to-1, we made every effort to maintain proportional
scan-densities across the entire age-range of the 152 patients.

Statistical
Analyses

Demographic and
clinical measures were compared by 2-way analyses of variance (testing main
effects of diagnoses and sex and their interaction) or 2-sample
t tests for continuous
measures, and with <<…OLE_Obj…>> ² or Fisher
exact test for nominal measures. Analyses of variance of the 10 regional brain
measures and 3 summary measures obtained at initial scan (n = 291 independent
participants) were initially performed with diagnoses and sex as
between-participant factors. Because we did not obtain full-scale IQ scores from
controls, Wechsler vocabulary standard score was used, as it is the single best
predictor of full-scale IQ.²⁷ To account for
between-group differences in vocabulary, height, weight, handedness, and
medication status, analyses of covariance were performed with these potential
covariates. Nonsignificant covariates were deleted from the final models.
Pearson correlations were computed for symptom severity measures and brain
volumes in the patient sample.

To examine
the influence of medications more closely we compared patients with ADHD who
were never previously treated with psychotropic medications (unmedicated ADHD),
medicated patients (medicated ADHD), and controls.

[Fred A. Baughman Jr., MD:3 groups: (1)
ADHD-never on any medication; (2) ADHD-medicated ( they do not say, but should,
exact doses and for how long), and (3) normal controls]

The unmedicated
ADHD patients were significantly younger than the medicated ADHD and controls;
thus, we confirmed findings in age-matched subgroups (n = 128). All pairwise
comparisons were conducted with Bonferroni corrections.

[Fred A. Baughman Jr., MD:   The fact that the unmedicated
patients (32% of all ADHD patients) were "significantly younger" means they were
also smaller and possessed of smaller brain.  This we are told was handled with a
particular statistical treatment]

�

[Fred A. Baughman Jr., MD:There were
152 with ADHD, 103 (68%) of whom were medicated and 49 (32%) not medicated.   Had the goal of their research
been to demonstrate that ADHD is a disease, perhaps one characterized by brain
atrophy, they would have made this the one and only aim of their research and
would have constituted the largest possible group of (1) never-medicated ADHD
patients, comparing them with a like number of (2) normal controls.  This would have eliminated the drugs as
a physical variable.  Swanson, at
the CC lamented that they had difficulty recruiting never-drugged ADHD subjects
because all or most are so quickly medicated.  This excuse does not fly; thousands of
new diagnoses are made in the US daily, of this their can be no doubt.  Such a study could quickly be
constituted and would be the pure study, absent the drugging confounder, that is
needed.  To determine  whether the drugs are causing the brain
atrophy or not would require a pure study comparing (1) ADHD patients never
drugged to (2) ADHD patients-drugged.   It has seemed to me that the NIMH
and research biological psychiatry has, instead, avoided doing these studies,
continuing instead to produce and publicize studies of drugged ADHD subjects
showing brain atrophy, in turn, representing such brain atrophy  as due to ADHD; proof it exists, saying
little or nothing to the  public of
the almost certain cause, the encepalopathic drugs they are
on.]

Finally,
longitudinal analytic methods^37,
38 were used to examine
growth patterns of caudate, cerebellum, total cerebrum, and the white and gray
components of the 4 major lobes. The initial full longitudinal growth model was
expressed as a cubic:

Size =
Intercept + <<…OLE_Obj…>> ₁
<<…OLE_Obj…>> (Age – Mean Age) +
<<…OLE_Obj…>> ₂ <<…OLE_Obj…>>
(Age – Mean Age)² + <<…OLE_Obj…>>
₃ <<…OLE_Obj…>> (Age – Mean
Age)³ + <<…OLE_Obj…>>

The model
parameters (intercept and <<…OLE_Obj…>> coefficients)
were initially allowed to reflect interactions between sex and diagnostic group.
To account for within-person correlations, intercepts were treated as normally
distributed random effects that varied by individual, while
<<…OLE_Obj…>> coefficients for age, age-squared, and
age-cubed terms were modeled as fixed effects. The full cubic model was compared
with simpler quadratic, linear, and constant models with interactions. Once the
order of the model was established, testing was performed to determine whether
an additive model could replace the interactions between sex and diagnostic
group for the height and shape parameters of the curves. With respect to shape
of the curves, there were neither significant sex differences nor sex by
diagnosis interactions for any structure. Consequently, final models allowed for
sex and diagnosis effects in the height parameters (intercept) of the curves and
included only diagnostic differences in shape
parameters.

[Fred A. Baughman Jr., MD:numberable statistical
treatments]

Hypothesis
tests and model selection were based on F statistics. We included data from
individuals who had only a single scan (about 40% of both groups), because
single scans provide additional information about between-participant variation
and overall curve shape. These methods have been useful for combining
cross-sectional and longitudinal anatomic MRI data.^39-41 Statistical power
exceeded 80% at P = .05 for all brain
measures. Minimally detectable adjusted differences ranged from 2.7% (caudate
and cerebellum) to 5% for occipital gray matter, and averaged 3% for cortical
volumes. Statistical analyses were performed using SPSS version 10.0 (SPSS Inc,
Chicago, Ill), except for the mixed-model random regression analyses, which were
performed with SAS version 8.02 (SAS Institute Inc, Cary, NC), and the power
analyses, which were conducted with PASS 2000 (NCSS Statistical Software,
Kaysville, Utah). Two-tailed significance levels were defined as
P
<<…OLE_Obj…>> .05.

RESULTS
<<…OLE_Obj…>>

Participants

Final study
participants consisting of 152 children and adolescents with ADHD and 139
controls were each successfully scanned up to 4 times over a decade.

[Fred A. Baughman Jr., MD:In the studies I suggest above, several years of follow-up and one
set of scans of all is all that would be
required.]

As

Table 1
<../fig_tab/joc20194_t1.html> shows, there were
several group differences between male and female patients (females were
younger, shorter, and weighed less), and between patients and controls. Patients
were shorter and weighed less, had lower vocabulary standard scores, and a lower
percentage of individuals were strongly right-handed (scoring 10 or more of 12
items). Sex and diagnosis did not interact significantly for any demographic
measure. Female and male patients with ADHD were comparable on vocabulary,
handedness, parent and teacher attention problem scores, and prevalence of
learning disorders.⁴²

[Fred A. Baughman Jr., MD:None
of the following are physical variables: vocabulary , parent and teacher
attention problem scores, and prevalence of learning
disorders]

.Physician’s Clinical Global Impressions ratings
reflected significantly greater severity in females, who also had a higher
percentage of combined-type ADHD, mood disorder (history of major depression
and/or dysthymia) and lower prevalence of conduct disorder and tic disorder not
otherwise specified.

[Fred A. Baughman Jr., MD:Of these, only tic disorder is a physical
variable; if present prior to any medication it would be called Tourette's
syndrome, if present only after stimulant treatment it would be called
"stimulant-induced tic syndrome/disease]

At the time of the first
scan, 103 patients (68%) were being treated with psychostimulants.

The 49

[Fred A. Baughman Jr., MD:32% of all ADHD subjects]

patients with ADHD (22 females, 27
males) who were successfully scanned before ever being treated with psychotropic
medications (unmedicated ADHD) were significantly younger than the medicated
patients (medicated ADHD) and controls (

Table 2
<../fig_tab/joc20194_t2.html>).

[Fred A. Baughman Jr., MD:Which,
without wholly valid statistical adjustment would mean that the ADHD-unmedicated
group, as a whole is younger than ADHD-medicated and controls, making the
ADHD-unmedicated group smaller (in height and weight) and possessed, as well, of
smaller brains.  They will argue,
and posit, within their study that they have statistically treated for
this]

.  
Unmedicated patients with ADHD were rated as comparable in severity by
parents, but as significantly less severely affected by physicians and teachers.

[Fred A. Baughman Jr., MD:As if ADHD severity as judged by physicians, teachers or parents
equated to "brain disease" severity]

They also tended to score
higher on the vocabulary IQ subtest, but not significantly (P =
.06).

Sixty-one
patients (40%) were scanned once, 61 (40%) twice, 20 (13%) 3 times, and 10 (7%)
4 times. Fifty-two controls (37%) were scanned once, 55 (40%) twice, 29 (21%) 3
times, and 3 (2%) 4 times. Mean ages at each scan did not differ significantly
between diagnostic groups (at first scan, F_1,289 =
2.28,
P = .13; at second
scan, F_1,176 = 0.08, P = .78; at third scan,
F_1,60 = 0.02, P = .89; at fourth
scan, F_1,11 = 1.06, P = .32). Female
participants (mean, 9.7 years [SD, 2.6]) were significantly younger than male
participants (mean, 10.7 years [SD, 3.3];
P = .006), regardless
of diagnosis. Mean intervals between scans did not differ significantly between
diagnostic groups (mean for patients with ADHD, 2.6 years [1.1]; mean for
controls, 2.4 years [1.0]; T₂₂₉ = 1.60;
P = .11). 

[Fred A. Baughman Jr., MD:Again,
had the goal of their research been to demonstrate whether or not, yes or no,
ADHD is a disease characterized by brain atrophy, they would have made this the
one and only aim of their research and would have constituted the largest
possible group of (1) never-medicated ADHD patients, comparing them with a like
number of (2) normal controls.  This
would have eliminated the drugs as a physical variable.  Swanson, at the CC lamented that they
had difficulty recruiting never-drugged ADHD subjects because all or most are so
quickly medicated.  This excuse does
not fly; thousands of new diagnoses are made in the US daily, of this their can
be no doubt.  Such a study could
quickly be constituted and would be the pure study, absent the drugging
confounder, that is needed.  To
determine  whether the drugs are
causing the brain atrophy or not would require a pure study comparing (1) ADHD
patients never drugged to (2) ADHD patients-drugged.   It has seemed to me that the NIMH
and research biological psychiatry has, instead, avoided doing these studies,
continuing instead to produce and publicize studies of drugged ADHD subjects
showing brain atrophy, in turn, representing such brain atrophy  as due to ADHD; proof it exists, saying
little or nothing to the  public of
the almost certain cause, the encepalopathic drugs they are on.  Both of the studies I suggest above
would run for 5 years with all subjects matched for sex, and age, have a single,
technically adequate scan at the start of the study and again at the end.  Growth  of the brain continues, at a much slower
rate than before, until 12-15 years, when the average adult weight of 1230 to
1275 g is females and 1350 to 1410 g in males is attained.  Here we see that brain size is very much
a function of age, and that the brain of females is smaller, generally than
males.]

Analyses
of Initial Scans

Table 3
<../fig_tab/joc20194_t3.html> contains the
unadjusted means (SDs) of the 291 initial cross-sectional scans by diagnosis as
well as the means (SEs) adjusted for all significant covariates. Three summary
measures were obtained for the cerebrum, defined by excluding cerebellum,
brainstem, and cerebrospinal fluid.

As
expected,^43,
44 all measures were
significantly smaller in female participants

[Fred A. Baughman Jr., MD:see above, female brain
smaller than male, with this difference implying nothing about functional
capacity]

(F_{1, 287} ranged from 10.65 for parietal gray
matter to 98.61 for cerebellum;

P<.001), but sex did
not interact significantly with diagnosis for any brain anatomy measure.
Accordingly, mean values for sex and corresponding statistics are not presented
here (they can be found at <http://intramural.nimh.nih.gov/research/chp/index2.html>). A significant main
effect of diagnosis was found between patients with ADHD and controls for all
measures with small-to-medium effect sizes ranging from 0.30 to 0.46, which
remained significant or were somewhat enhanced (eg, adjusted effect size for
temporal white matter = 0.64) when adjusted for the significant covariates of
vocabulary, height, or medication status. When we adjusted for the significant
group differences in total cerebral volume, the only brain region that remained
significantly smaller in ADHD was the cerebellum (d = .27; 95% confidence
interval [CI], 0.03-0.50; F_1,287 = 4.97;
P = .03).

Effects of
Prior Drug Treatment

Table 4
<../fig_tab/joc20194_t4.html> displays the
contrasts between 3 nonoverlapping groups consisting of 49

[Fred A. Baughman Jr., MD:32%]

unmedicated patients with ADHD, 103 medicated patients

[Fred A. Baughman Jr., MD:68%]

with
ADHD, and 139 healthy controls. Unmedicated patients with ADHD did not differ
significantly from medicated patients with ADHD on any gray matter measures, or
in caudate or cerebellum. By contrast, unmedicated patients with ADHD had
strikingly smaller white matter volumes (F_2,288 = 11.65) compared
with controls (-10.7%,

P<.001) and with
medicated children with ADHD (-8.9%; P<.001; all pairwise
comparisons Bonferroni corrected). Unmedicated patients with ADHD had smaller
cerebellar volumes (-6.2%, P<.001), smaller
temporal gray (-4.6%, P = .02), and smaller
total cerebral volumes (-5.8%, P = .002) compared with
controls.

[Fred A. Baughman Jr., MD:No
conclusions regarding the functional significance of these findings can be
drawn.  The authors, however, draw
the conclusion that these and similar findings explain their ADHD behaviors;
behaviors, Carey asserts, are normal behaviors, having no pathological
significance]

Differences between unmedicated patients with ADHD and
controls in frontal (-3.8%) and parietal gray matter (-4.1%) would also have
been significant if not corrected for multiple comparisons. Medicated
patients with ADHD did not differ significantly from controls on any white
matter measure.

[Fred A. Baughman Jr., MD:An observation the authors take to mean that
stimulant medications do no damage to the brain]

Robust differences
from controls remained for all gray matter measures (ranging from -3.4% to
-6.6%), caudate (-4.3%), cerebellum (-3.6%), and the summary measures of total
cerebral volume (-3.3%) and total gray volume (-3.9%).

Because the
unmedicated patients with ADHD were significantly younger than the other 2
subgroups, and white matter increases with increasing age throughout the age
range,⁴⁵ we performed
secondary analyses restricted to an age-matched subset of 128 participants
(consisting of 24 unmedicated patients with ADHD, 50 medicated patients with
ADHD, and 54 controls [61 females]). All measures remained essentially
unchanged.

[Fred A. Baughman Jr., MD:Again the need for statistical "corrections" of the fact that
the ADHD-unmedicated  group-32% of
the total ADHD group were "significantly younger."]

Relationship to
Clinical Measures

We examined
correlations between the 10 regional measures and behavioral ratings. Within the
patient group, smaller volumes were significantly correlated in the expected
direction with greater symptom severity. Frontal and temporal gray matter,
caudate, and cerebellar volumes were significantly and negatively correlated
with physician’s Clinical Global Impressions rating (n = 139, Pearson
coefficients ranged between -0.16 for frontal gray and -0.26 for cerebellum,
all
P<.05). The same 4
regions were also significantly and negatively correlated with parent-rated
child behavior checklist attention problems with Pearson coefficients between
-0.16 and -0.22 (all P<.05). Correlations
were largely unaffected when adjusted for age.

Wechsler
vocabulary standard score was significantly and positively correlated with all
anatomic volumes in patients with ADHD (n = 151;
r ranged from
0.19-0.35; all P<.02), and in
frontal and occipital gray and white matter and cerebellar volumes in controls
(n = 134; r ranged from
0.18-0.24; all P<.02). Although the
magnitude of the correlations was greater in patients than in controls, none of
the coefficients differed significantly from each other, and all regional
volumes correlated significantly with the vocabulary score when the 2 groups
were combined (n = 285; eg, for total cerebral volume,
r =
0.31;
P<.001).

Analyses
of Initial and Follow-up Scans

Sixty percent of all
participants had at least 2 scans (n = 178), including 62 (21%), who had at
least 3 scans and 13 (4%), who had 4 scans obtained at 2- to 3-year intervals.
Data from all 544 resulting scans were used to derive longitudinal growth curves
for patients and controls of both sexes. The age range for male participants
extended between 4.6 and 19.0 years, while female participants ranged between
5.2 and 16.3 years, reflecting our initial focus on males with
ADHD.²⁰

Predicted
longitudinal growth curve parameters did not differ significantly between male
and female participants except for the height of each curve (intercept) at the
corresponding age midpoint, which were significantly higher for males for all
measures, regardless of diagnosis (empirical
P<.001, derived from
F statistics confirmed with permutation tests with 1000 iterations). There were
no significant interactions between sex and diagnosis for any developmental
growth patterns (intercepts or curve parameters <<…OLE_Obj…>>
_1-3). Figure 1
<../fig_tab/joc20194_f1.html> shows the predicted
developmental growth curves along with 95% CIs for each group’s average total
cerebral volume. Developmental curves were significantly higher in controls than
in patients with ADHD for total cerebral volume and for all other brain
measures. Diagnostic differences in curve height remained significant after
adjusting for vocabulary standard score (total cerebral volume,
P = .002). There were
no significant differences in curve shape between patients and controls, except
for caudate. After adjustment for diagnostic differences in total cerebral
volume, only caudate (P = .02) and cerebellum (P = .003) remained
significantly smaller in patients with ADHD.

Figure 2
<../fig_tab/joc20194_f2.html> depicts unadjusted
predicted growth curves for caudate nucleus and cerebellum. Caudate was the only
region in which the developmental trajectories did not remain statistically
parallel for patients and controls (adjusted,
P = .05). These
differences in shape represent a normalization of caudate volume for patients by
midadolescence. By contrast, diagnostic differences in cerebellar curves
continue throughout our age range (unadjusted,
P<.001;
adjusted, P = .003), with a
nonsignificant tendency toward a greater difference in late adolescence
(unadjusted, P = .10). The general
absence of diagnostic differences in curve shapes indicates that developmental
curves for patients with ADHD, although significantly lower, were essentially
parallel to curves for healthy controls, with the exception of the caudate
nucleus.

[Fred A. Baughman Jr., MD:To speak of diagnostic differences is misleading.  The brain/part of brain volume
differences described herein are group differences.  There is no kind of brain scan that is
of diagnostic value or that can ever diagnose a single case of ADHD or, for that
matter any psychiatric condition. 
The reason there is no objective, physical test in all of "biological
psychiatry" is that not a single psychiatric condition, in 35 years of disease
claims, has a proven, demonstrated, demonstrable physical abnormality...not a
gene, not a chemical imbalance, nothing. 
Nor does the present study ruin their pristine
record]

COMMENT
<<…OLE_Obj…>>

Fully automated
measures of brain cortical and subcortical volumes from the initial scans of 291
male and female patients show that the cerebrum as a whole and the cerebellum
are smaller in children and adolescents with predominantly combined-type
ADHD

[Fred A. Baughman Jr., MD:They have proved no such thing]

. Rather than reflecting a
selective frontal-striatal effect, volumes were decreased to a comparable extent
in all 4 lobes and were statistically more prominent only in the cerebellum. Our
findings were not ascribable to differences in cognitive level, height, age,
weight, or handedness and were not related to comorbid diagnoses (data not
shown).

This is the
first neuroimaging study to our knowledge to include a substantial number (n =
49) of previously unmedicated children and adolescents with ADHD.

[Fred A. Baughman Jr., MD:Why, with Nasrallah et al having suggested that stimulant medication
was causing brain atrophy in 1986, has it taken research psychiatry all this
time to address this question, and, at that not yet authoring or performing the
appropriate study necessary to answer the two, separate, fundamental questions
(1) Is ADHD an abnormality/disease-yes or no? and (2) does Ritalin/amphetamine
treatment cause brain atrophy?]

We attempted to recruit children
with equivalent severity of ADHD symptoms by using identical diagnostic and
symptom severity criteria. Unmedicated patients with ADHD did not differ from
medicated children with ADHD on parent-rated attention problems, but they had
significantly lower teacher and physician ratings, and higher vocabulary
standard scores.

[Fred A. Baughman Jr., MD:as if objective measures]

These differences
should have minimized anatomic brain differences between unmedicated patients
with ADHD and controls. In fact, findings were generally as striking for the
unmedicated patients with ADHD as for those who were being treated with
medications, and were more pronounced for white matter volumes.

[Fred A. Baughman Jr., MD:Here, in a single reach, they would have us believe they have
validated, ADHD as a disease, and, at the same time exonerated
Ritalin/amphetamine treatment of all harm to the brain, that so strongly
suggested, time and again by the scanning research of 1986-1998 and the
present]

Thus, our
analyses show that decreased brain volumes in ADHD in both white and gray matter
compartments are not due to drug treatment. Conversely, we have no evidence that
stimulant drugs cause abnormal brain development.⁴⁶

[Fred A. Baughman Jr., MD:Yes there
is something to treat-ADHD! No! there is nothing to fear from the stimulant
drugs; leave no child untreated, take them from the home of negligent parents
refuse to treat them as is already being done by the hundreds of thousands in
the US today. 
]

Patients with
ADHD had developmental trajectories for nearly all brain regions that paralleled
growth curves for controls but on a lower track. The one exception, foreshadowed
by an earlier cross-sectional study,¹³ was the caudate
nucleus, for which differences between patients and controls became negligible
by midadolescence. As the caudate nucleus reaches its maximum volume around 10
years, the potential relationship between normalization of caudate volume in
ADHD and decreased ratings of hyperactivity/impulsivity in children with
ADHD,⁴⁷ as well as in
quantitative measures of movement in normative samples,⁴⁸ should be addressed
in future studies.

Longitudinal
follow-up of functional outcome is continuing; hence, we cannot report
definitively on the relationship between continuing anatomic deviance or
normalization vs outcome. Preliminarily, global functional outcome in 64
patients with ADHD (20 females) evaluated 4 years after initial scan does not
suggest any significant relationships between continuing anatomic deviance and
clinical follow-up status.

We did not
find evidence of a primarily frontal abnormality in ADHD. Instead, we found the
smallest diagnostic effect sizes in frontal lobes. However, these results cannot
be interpreted as definitive evidence against the frontal-striatal hypothesis of
ADHD pathogenesis, because our units of analysis, while highly reliable, were
too large. These methods have been useful in detecting age-, sex-, and
diagnosis-specific differences in growth curves,^39-41,
49 and their application
to ADHD was warranted. Alternate approaches, such as unbiased pixel-based
analyses,⁵⁰ may be needed to
detect more localized anatomic abnormalities in regions such as cingulate,
orbitalfrontal, or dorsolateral prefrontal cortex in patients with
ADHD.⁵¹ However, these
methods may also require even larger or more closely matched contrast groups
(eg, twin or sibling controls) given the mostly modest effect sizes and
substantial between-subject variations in brain anatomy.⁵²

Limitations
of this study include the use of referred samples for patients and highly
screened controls that may not be optimally representative. We recruited female
patients with ADHD who were comparable in severity with our previous samples of
males,⁵³ but in so doing may
have selected females who are atypical of most community and clinical samples.
We lost significantly more scans from children with ADHD because of excessive
motion, but again, this bias should have removed the most symptomatic
patients.

In
conclusion, ADHD is associated with about a 3% (adjusted; 4% unadjusted)
decrease in volume throughout the brain. Intriguingly, this decrease is most
marked in white matter of unmedicated patients. Furthermore, with the exception
of caudate nucleus, longitudinal growth curves are roughly parallel, suggesting
that the fundamental developmental processes active during late childhood and
adolescence are essentially healthy in ADHD, and that neuropsychiatric symptoms
appear to reflect fixed earlier neurobiological insults or abnormalities. Future
studies should focus on younger patients being enrolled into controlled
treatment studies while in preschool and on the development of improved
quantitative measures of brain anatomy and of the component endophenotypes of
ADHD.⁵⁴ Finally, despite the
importance of these findings, anatomic MRI studies remain appropriate only for
research, as they cannot yet contribute to the diagnostic assessment of
ADHD.

[Fred A. Baughman Jr., MD:Here, in the final sentence is the  confession that MRI for all the millions
of dollars of tax and Pharma money spent on MRI/ADHD research is good for
nothing more than deceiving all who read about it an all who read the press
releases and abstracts (always cleansed of all mention that the brain atrophy,
shrinkage, shriveling that  might
just be due to those long-known encephalotoxins: Ritalin and the amphetamines
given us as "treatment" for the never-proved disease; ADHD.  Has Castellanos, et al, proven that ADHD
is not a fraud?  They have not.
]

�

Fred A. Baughman Jr., MD:  I invite my readers to read on.  In the appended material I expand upon
many of the studies Castellanos, et al refer to, i.e., that appear in their
bibliography.