Article

Cerebellar Development and Clinical Outcome in Attention Deficit Hyperactivity Disorder

Columbia University, New York, New York, United States
American Journal of Psychiatry (Impact Factor: 12.3). 04/2007; 164(4):647-55. DOI: 10.1176/appi.ajp.164.4.647
Source: PubMed

ABSTRACT

Anatomic magnetic resonance imaging (MRI) studies have detected smaller cerebellar volumes in children with attention deficit hyperactivity disorder (ADHD) than in comparison subjects. However, the regional specificity and longitudinal progression of these differences remain to be determined. The authors compared the volumes of each lobe of the cerebellar hemispheres and vermis in children with ADHD and comparison subjects and used a new regional cerebellar volume measurement to characterize the developmental trajectory of these differences.
In a longitudinal case-control study, 36 children with ADHD were divided into a group of 18 with better outcomes and a group of 18 with worse outcomes and were compared with 36 matched healthy comparison subjects. The volumes of six cerebellar hemispheric lobes, the central white matter, and three vermal subdivisions were determined from MR images acquired at baseline and two or more follow-up scans conducted at 2-year intervals. A measure of global clinical outcome and DSM-IV criteria were used to define clinical outcome.
In the ADHD groups, a nonprogressive loss of volume was observed in the superior cerebellar vermis; the volume loss persisted regardless of clinical outcome. ADHD subjects with a worse clinical outcome exhibited a downward trajectory in volumes of the right and left inferior-posterior cerebellar lobes, which became progressively smaller during adolescence relative to both comparison subjects and ADHD subjects with a better outcome.
Decreased volume of the superior cerebellar vermis appears to represent an important substrate of the fixed, nonprogressive anatomical changes that underlie ADHD. The cerebellar hemispheres constitute a more plastic, state-specific marker that may prove to be a target for clinical intervention.

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Available from: Jay N Giedd
Am J Psychiatry 164:4, April 2007 647
Article
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This article is discussed in an editorial by Dr. Kates on p. 547.
Cerebellar Development and Clinical Outcome in
Attention Deficit Hyperactivity Disorder
Susan Mackie, B.S.
Philip Shaw, M.D., Ph.D.
Rhoshel Lenroot, M.D.
Ron Pierson, M.D.
Deanna K. Greenstein, Ph.D.
Tom F. Nugent III, B.S.
Wendy S. Sharp, M.S.W.
Jay N. Giedd, M.D.
Judith L. Rapoport, M.D.
Objective: Anatomic magnetic reso-
nance imaging (MRI) studies have de-
tected smaller cerebellar volumes in chil-
dren with attention deficit hyperactivity
disorder (ADHD) than in comparison sub-
jects. However, the regional specificity
and longitudinal progression of these dif-
ferences remain to be determined. The
authors compared the volumes of each
lobe of the cerebellar hemispheres and
vermis in children with ADHD and com-
parison subjects and used a new regional
cerebellar volume measurement to char-
acterize the developmental trajectory of
these differences.
Method: In a longitudinal case-control
study, 36 children with ADHD were divided
into a group of 18 with better outcomes and
a group of 18 with worse outcomes and
were compared with 36 matched healthy
comparison subjects. The volumes of six cer-
ebellar hemispheric lobes, the central white
matter, and three vermal subdivisions were
determined from MR images acquired at
baseline and two or more follow-up scans
conducted at 2-year intervals. A measure of
global clinical outcome and DSM-IV criteria
were used to define clinical outcome.
Results: In the ADHD groups, a nonpro-
gressive loss of volume was observed in
the superior cerebellar vermis; the volume
loss persisted regardless of clinical out-
come. ADHD subjects with a worse clinical
outcome exhibited a downward trajectory
in volumes of the right and left inferior-
posterior cerebellar lobes, which became
progressively smaller during adolescence
relative to both comparison subjects and
ADHD subjects with a better outcome.
Conclusions: Decreased volume of the
superior cerebellar vermis appears to rep-
resent an important substrate of the
fixed, nonprogressive anatomical changes
that underlie ADHD. The cerebellar hemi-
spheres constitute a more plastic, state-
specific marker that may prove to be a
target for clinical intervention.
(Am J Psychiatry 2007; 164:647–655)
Attention deficit hyperactivity disorder (ADHD) is a
developmental disorder affecting 5%–10% of school-age
children and 4.4% of adults (1). Clinical features include
inattentiveness, motor hyperactivity, and impulsivity. Al-
though considerable progress has been made in defining
the neural substrate for the disorder, a paucity of longitu-
dinal studies has hindered the development of a unified
hypothesis to explain the clinical features of the disorder.
There has been increasing interest in the role of the cer-
ebellum in the pathogenesis of ADHD. Structural anoma-
lies of the cerebellum are among the most consistently re-
ported features of ADHD, notably reductions in overall
volume (2), particularly in the cerebellar vermis (3–7). Dif-
fusion tensor imaging of cerebellar white matter has re-
vealed that attentional impairment is associated with de-
creased fractional anisotropy in this region (8). Although
the cerebellum has traditionally been considered a site of
motor control, lesion studies and functional imaging stud-
ies in healthy subjects have demonstrated a wide range of
cognitive and affective functions in cerebellar structures,
including temporal information processing, shifting at-
tention, verbal working memory, implicit learning, execu-
tive function, and emotional regulation (9–12). Dysfunc-
tion in each of these cognitive domains has in turn been
implicated in the etiology of ADHD (13, 14).
Measurement of the cerebellum is technically difficult,
complicated by differences in nomenclature, poorly de-
fined gray-white boundaries, and a reliance on two-di-
mensional measurement (15). Previous studies have been
largely cross-sectional and thus have been unable to test
the hypothesis that differences in the trajectory of growth
rather than differences in absolute volume at single time
point may be the most useful neuroanatomic endopheno-
type for ADHD. Our previous longitudinal study (2) sug-
gested a fixed, nonprogressive reduction in total cerebellar
volume but did not examine the possibility that the defi-
cits in ADHD are highly regional.
We reexamined longitudinal data from a sample of 36
children with ADHD and 36 children without ADHD, all of
whom underwent neuroanatomic magnetic resonance im-
aging (MRI) scans on at least three separate occasions. The
current study included 157 scans from the children for
whom we previously reported changes in total cerebellar
volume (2) and an additional 72 scans acquired since that
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time, for a total of 229 scans. We measured the three hemi-
spheric lobes and the corpus medullare on each side as well
as three lobes of the midline vermis. We hypothesized that
we would replicate the finding of smaller overall cerebellar
volumes reported in previous structural imaging studies,
and we expected to refine previous findings of a smaller
midsagittal area in the inferior vermis (3–7) through a novel
method of volumetric analysis. Given evidence regarding re-
gional cerebellar activation during attention tasks in func-
tional studies (16), we also anticipated prominent findings
in the posterior hemispheres. By adopting a longitudinal de-
sign, we further aimed to characterize the developmental
trajectories of individual hemispheric and vermal lobar vol-
umes in relation to the diagnosis of ADHD and in relation to
long-term clinical outcome. In light of recent findings relat-
ing clinical outcome to abnormalities in the prefrontal cor-
tex (17), we hypothesized that volume normalizes in some
regions of the cerebellum as disease symptoms diminish,
thus distinguishing groups with better and worse outcomes.
Method
Participants
Thirty-six children and adolescents who met DSM-IV criteria
for ADHD and for whom at least three usable MRI scans were
available were selected from a larger sample of participants re-
cruited for imaging studies at the National Institute of Mental
Health (NIMH). Recruitment details have been described else-
where (2). Diagnoses were made on the basis of the Diagnostic In-
terview for Children and Adolescents (18) and a rating on the hy-
peractivity subscale of the Connerss Teacher Rating Scale greater
than two standard deviations above age- and sex-specific mean
ratings (19). Exclusion criteria were a full-scale IQ score below 80
and evidence of medical or neurological disorders. Comorbid
psychiatric diagnoses among participants were relatively mild
and were not the focus of treatment in any case. Thirty-five par-
ticipants had combined-type ADHD (97%), and one (3%) had the
hyperactive subtype. Fourteen participants (39%) underwent
four scans, and one (3%) underwent five scans.
Thirty-six unrelated comparison subjects who had no personal
or family history of psychiatric or neurological disorders were re-
cruited from the community as part of the ongoing recruitment of
the Child Psychiatry Branch at NIMH. Matched selection was
used to minimize group differences in IQ, socioeconomic status,
gender, and handedness. All subjects had undergone at least
three scans; 18 (50%) had four scans, four (11%) had five scans,
and one (3%) had seven scans.
The NIMH institutional review board approved the research pro-
tocol, and written informed consent and assent to participate in the
study were obtained from the parents and children, respectively.
Clinical Outcome Measures
The last available score on the Childrens Global Assessment
Scale (CGAS) (20) was used to characterize clinical outcome. Pa-
tients with ADHD were divided into groups with better (N=18)
and worse (N=18) outcomes on the basis of the mean final follow-
up CGAS score, which was 62.4 (SD=14.6); a better outcome was
defined as a CGAS score 62 and a worse outcome as a CGAS
score <62. CGAS scores, symptom scores, and diagnostic data
were available for all ADHD patients at baseline and at the last fol-
low-up. Clinical assessments were performed independently of
neuroimaging analyses. The mean ages of the groups at each
wave of the assessment and MRI scanning did not differ signifi-
cantly. At the last follow-up, patients were further categorized ac-
cording to DSM-IV criteria as having inattentive subtype only (N=
11), hyperactive/impulsive subtype only (N=2), or combined type
(N=12) or as having attained full remission (N=10).
Neuroanatomic Analyses
T1-weighted images with contiguous 1.5-mm sections in the
axial plane and 2.0-mm sections in the coronal plane were ob-
tained using three-dimensional spoiled gradient recalled echo in
the steady state on a Signa 1.5-T scanner (General Electric Medi-
cal Systems, Milwaukee, Wisc.) (echo time=5 msec; repetition
time=24 msec; flip angle=45°; acquisition matrix=256×192; num-
ber of signals acquired=1; field of view=24 cm). The original MR
images were registered into standardized stereotaxic space using
a linear transformation and corrected for nonuniformity artifacts
(21). An advanced neural net classifier was used to segment the
registered and corrected volumes into white matter, gray matter,
CSF, and background (22).
Gray and white matter volumes of the total cerebrum were
quantified using an automated technique developed at the Mon-
treal Neurological Institute that combines voxel-intensity based
tissue classification into gray matter, white matter, and CSF with
a probabilistic atlas (23, 24). The cerebellum could not be classi-
fied owing to the complexity of its gray-white border.
The cerebellar parcellation method developed by Pierson and
colleagues at the University of Iowa (15) was used in conjunction
with the BRAINS2 software package (25) to generate outlines of
each lobe of the cerebellar cortex and corpus medullare. Briefly,
31 landmarks were manually defined and used as the basis for the
application of a neural net to generate surface masks of each of
the cerebellar subregions. These were then reviewed and edited
manually. Volumes of each subregion were measured and
summed to provide the total cerebellar volume.
Masks of vermal subregions were manually traced. A midline
guide trace in the sagittal plane marked the superior, inferior, an-
terior, and posterior limits of the vermis, and the axial plane was
used to generate guide traces approximating the lateral borders.
The vermis was defined in each coronal slice by manual tracing
with reference to these guide traces. Regional subdivision was ac-
complished through placement of limiting boundaries in the sag-
ittal plane, where the primary and prepyramidal fissures were
readily apparent throughout the vermis.
The left and right cerebellar cortices were each divided into an-
terior, superior-posterior, and inferior-posterior lobes using the
nomenclature of Larsell and Jansen (26). The anterior lobe was
composed of lobules I–V and delineated by the primary fissure.
The superior-posterior lobe was defined to include lobules VI and
VIIA-folium in the vermis region and lobule VI and crus I of VIIA
in the hemispheres. It was separated from the inferior-posterior
lobe by the horizontal fissure. The inferior-posterior lobe con-
sisted of the lobules VIIA-tuber through X. The three hemispheric
lobes consist predominantly of gray matter, although white mat-
ter branching off into the folia was included in the lobes. The left
and right corpora medullare were also defined, including all of
the central region, which appears as white matter. The MRI acqui-
sition method used for this study was not able to visualize or sep-
arate out the deep nuclei within the corpus medullare. The vermis
was divided into anterior, superior, and inferior regions. The pri-
mary fissure determined the posterior extent of the anterior lobe,
and the prepyramidal fissure separated the superior from the in-
ferior lobe. These regions are illustrated in Figure 1.
Intraclass correlations (ICCs) for all hemispheric regions and
the corpus medullare were >0.80 for both intrarater and interrater
reliability. In the vermis, intrarater reliability ICCs were all >0.80,
and interrater ICCs were all >0.68.
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Statistical Analysis
Differences between groups were assessed by t tests and analy-
sis of variance (ANOVA) for continuous measures and chi-square
tests and Fisher’s exact test for categorical measures. Mixed-
model polynomial regression was used to examine cerebellar de-
velopment. This method was chosen over traditional methods,
such as repeated-measures ANOVA, because it permits the inclu-
sion of multiple measurements per person, missing data, and ir-
regular intervals between measurements, thereby increasing sta-
tistical power. For the polynomial comparisons between ADHD
and comparison groups, the ith individual’s jth cerebellar volume
was modeled as follows:
Volume
ij
= intercept + β
1
(diagnosis=ADHD) + β
2
(age –
mean age) + β
3
(age – mean age)
2
+ β
4
(diagnosis=ADHD ×
[age – mean age]) + β
5
(diagnosis=ADHD × [age – mean age]
2
)
+ d
i
+ e
ij
where the intercept and β terms are fixed effects, d
i
is a normally
distributed random effect that models within-person depen-
dence, and e
ij
represents the usual normally distributed residual
error. F values determined whether polynomial terms signifi-
cantly contributed to the explanatory power of a model. After the
order of the model was determined (linear or quadratic), F or t
tests were used to determine whether the diagnostic curves dif-
fered in shape (that is, whether the coefficient[s] for age terms dif-
fered between groups) and height (group difference in expected
volume at the average age). Parameter estimates of the fixed ef-
fects were used to generate fitted values in the graphs. Similar
analyses were conducted for the three group comparisons. Fitted
lines spanned the middle 80% of the data.
In view of the multiple statistical tests conducted, we adopted
an alpha threshold of 0.01. Cohens d was used to calculate effect
sizes (27).
Results
Demographic and Clinical Characteristics
The ADHD and comparison groups were statistically
comparable on all characteristics except handedness (Ta-
bles 1 and 2). Outcome groups, defined either by the final
CGAS score or by DSM-IV diagnosis at follow-up, were sta-
tistically comparable on all clinical characteristics except
frequency of baseline diagnoses of oppositional defiant
disorder and anxiety disorders.
Neuroanatomic Results
ADHD Group Versus Comparison Group. In the time
1 comparisons, relative to the comparison group, the
ADHD group had significantly smaller volumes of the su-
perior vermis (p=0.0007; d=0.85) and whole vermis (p=
0.006; d=0.68) (Table 3). In the comparisons across the tra-
jectory of development, all cerebellar regions were mod-
eled using quadratic terms except the three vermal subdi-
visions, the whole vermis, and the corpora medullare,
where a constant growth model was appropriate.
Consistent with the time 1 comparisons, diagnostic dif-
ferences at the sample average age (13.57 years) were sig-
nificant for the superior vermis (F=13.95, df=1, 155, p=
0.0003) and the whole vermis (F=4.55, df=1, 155, p=0.01).
The ADHD and comparison groups differed significantly
with respect to development of the left anterior hemi-
sphere, with the trajectory of the ADHD group converging
to that of the comparison group by late adolescence (dif-
ference in shape, F=7.13, df=2, 153, p=0.001) (Figure 2). De-
velopmental trajectories for all other cerebellar regions
were statistically parallel, including the superior and whole
vermis measures, with the ADHD groups mean volume re-
maining smaller over the course of the age span.
Better Versus Worse Clinical Outcome ADHD Groups.
In the time 1 comparisons of the better and worse out-
come groups, differences were observed in the superior
vermis (F=7.0, df=2, 69, p=0.002), with a Tukey post hoc
FIGURE 1. Regional Anatomic Measures for the Cerebellum
a
a
Reprinted from Pierson et al. (15), with permission from Elsevier.
Inferior
Anterior
Superior
Superior
posterior
lobe
III
IV
V
VI
Crus I,
VIIA
Crus II,
VIIA
VIIB
VIII
IX
Anterior
lobe
Corpus
medullare
Inferior
posterior
lobe
Hemispheric Lobes Vermal Lobes
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test indicating significantly smaller volumes for the worse
outcome ADHD group relative to the comparison group
(Tukey’s honestly significant difference=5.04, df=2, 69, p=
0.002) and nonsignificant differences for the remaining
two comparisons (Table 4).
In the comparisons across the trajectory of develop-
ment, similar to the time 1 comparisons, the better and
worse outcome groups had significantly smaller superior
vermis volumes than the comparison group at the sample
average age (13.57 years) (F=4.62, df=1, 154, p=0.01 and F=
11.97, df=1, 154, p=0.0007, respectively).
The outcome groups differed in the trajectory of growth
for the entire cerebellum (p=0.01). While the better out-
come group exhibited a trajectory parallel to that of the
comparison group, the worse outcome group exhibited a
progressive relative decrease in total volume, falling further
away from the normal trajectory during adolescence (Fig-
ure 3). This pattern was largely attributable to bilateral
changes in the inferior-posterior hemispheres of the worse
outcome group (comparison with better outcome group,
F=5.96, df=2, 151, p=0.003 and F=4.91, df=2, 151, p=0.01 for
left and right, respectively; compared with the comparison
TABLE 1. Demographic Characteristics of 36 Children and Adolescents With ADHD and 36 Healthy Comparison Subjects
Characteristic
Group
All ADHD Patients
(N=36; 115 scans)
ADHD Patients With
Worse Outcome
(N=18; 54 scans)
ADHD Patients With
Better Outcome
(N=18; 61 scans)
Healthy Comparison
Subjects
(N=36; 114 scans)
N % N % N % N %
Female 14 38.9 7 38.9 7 38.9 14 38.9
Race
White 2980.61372.21688.93391.7
Black 4 11.1 3 16.7 1 5.6 2 5.6
Hispanic 12.815.600.012.8
Other 2 5.6 1 5.6 1 5.6 0 0.0
Handedness
a
Right 32 88.9 17 94.4 15 83.3 36 100.0
Left 12.800.015.600.0
Mixed 3 8.3 1 5.6 2 11.1 0 0.0
Mean SD Mean SD Mean SD Mean SD
Age at first scan 10.5 3.1 10.0 3.1 11.1 3.1 10.3 3.2
Age over all scans 13.6 4.0 12.8 3.9 14.3 4.0 13.6 4.2
Gray matter plus white matter
volume for all scans (ml) 1,118.26 126.91 1,128.56 140.58 1,109.15 113.86 1,144.16 114.85
Height over all scans (inches) 61.16 7.60 61.10 8.43 61.20 6.87 62.38 8.12
Time between scans (years) 2.7 1.2 2.8 1.3 2.7 1.2 3.0 1.3
IQ 109.1 16.9 106.1 16.8 112.1 17.0 114.9 12.1
Socioeconomic status
b
44.7 20.9 43.3 23.6 46.1 18.3 36.7 19.5
a
Significant difference between groups (Fisher’s exact test=6.57, p=0.05).
b
Hollingshead Index of Social Position; lower score indicates higher socioeconomic status.
TABLE 2. Clinical Characteristics of ADHD Patients, by Outcome Group
Characteristic
Group
ADHD Patients With Worse
Outcome (N=18)
ADHD Patients With Better
Outcome (N=18)
N % N %
Medications
Stimulant exposure at first scan 12 67 13 72
Stimulant exposure at last scan 17 94 17 94
Antiadrenergic medication 2 11 0 0
Antianxiety medication 1 6 0 0
Antidepressant medication 3 17 2 11
Comorbid diagnoses at baseline
Tics 211 211
Conduct disorder 5 28 3 17
Oppositional defiant disorder
a
13 73 7 39
Learning disability 0 0 2 11
Anxiety disorders
b
11 61 3 17
Mood disorders 8 44 6 33
Mean SD Mean SD
Children’s Global Assessment Scale score at baseline 47.5 9.7 47.0 6.3
Children’s Global Assessment Scale score at last follow-up
c
49.7 6.5 75.0 7.6
Conners’s Teacher Rating Scale hyperactivity subscale score at baseline 1.8 0.7 1.6 0.7
Time between first stimulant exposure and first scan (years) 3.22 3.17 2.79 2.80
a
Significant difference between groups (χ
2
=4.05, df=1, p<0.05).
b
Significant difference between groups (Fisher’s exact text, p0.01).
c
Significant difference between groups (t=10.73, df=34, p<0.001).
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group, F=5.03, df=2, 151, p=0.008 and F=5.3, df=2, 151, p=
0.01, for left and right, respectively) (Figure 4).
Differences in developmental trajectories were also noted
in the left anterior hemisphere, which, as in the diagnostic
comparison, demonstrated a pattern of normalization with
age. This normalization was prominent in the better outcome
group (F=7.42, df=2, 151, p=0.001) but did not reach statistical
significance in the worse outcome group (Figure 5).
To determine whether grouping the ADHD participants
according to follow-up DSM-IV diagnosis would yield sim-
ilar developmental patterns for the hemispheric volumes,
we conducted post hoc mixed-effect regression analyses.
Consistent with the above results, for the right inferior-
posterior volumes, participants with persistent com-
bined-type ADHD significantly diverged from the com-
parison group in a manner similar to that of the worse out-
come group (F=4.32, df=2, 154, p=0.015). No other
comparisons were statistically significant at 0.01 (see the
figure in the data supplement that accompanies the on-
line version of this article).
Discussion
This is the first structural imaging study of ADHD to delin-
eate the development of each lobe of the cerebellar hemi-
spheres using longitudinal data and a volumetric regional
measure of the cerebellar vermis. Using both a new semiauto-
mated method for analyzing hemispheric lobes and a new
manual method for accurately quantifying vermal subdivi-
sions, we detected a highly specific abnormality—a smaller
superior vermis—that has not previously been detected using
whole cerebellar volumes or midsagittal vermal areas. Fur-
thermore, the longitudinal design and clinical outcome strat-
ification allowed us to demonstrate hemispheric differences
between better and worse outcome groups, with the worse
outcome group deviating progressively with age. These find-
ings emphasize the mixture of fixed and progressive neuroan-
atomic deficits in ADHD (2, 17). The former may reflect a fun-
damental disease phenotype, and the latter may represent
plastic anatomic changes that are related to symptom status.
TABLE 3. Regional Cerebellar Volumes (ml) for ADHD Patients and Healthy Comparison Subjects
Region
Group
ADHD Patients (N=36)
Healthy Comparison
Subjects (N=36) Analysis
a
Mean SD Mean SD t (df=70) Cohen’s d
Hemispheres
Left anterior
b
7.51 1.18 8.05 1.60 1.62 0.39
Left corpus medullare 7.15 0.78 7.76 1.29 2.43 0.58
Left inferior-posterior 30.11 3.41 30.59 3.28 0.61 0.15
Left superior-posterior 23.30 3.19 23.75 3.34 0.58 0.14
Right anterior 7.73 1.46 7.68 1.84 –0.10 –0.02
Right corpus medullare 7.10 0.89 7.75 1.32 2.46 0.59
Right inferior-posterior 30.36 3.91 30.76 3.62 0.45 0.11
Right superior-posterior 23.74 3.18 24.10 3.70 0.44 0.11
Vermis
Anterior 3.48 0.58 3.71 0.69 1.57 0.38
Superior
c
2.18 0.44 2.56 0.45 3.57* 0.85
Inferior 3.06 0.42 3.34 0.60 2.31 0.55
Whole
d
8.72 1.17 9.62 1.48 2.85* 0.68
Total 137.0 12.7 140.5 15.0 1.06 0.25
a
In the longitudinal analysis (data not shown), all models incorporated quadratic terms except the anterior, inferior, superior, and whole ver-
mis and the left and right corpora medullare. In F tests of the height difference of curves at the sample average age, df=1, 155 for linear mod-
els and df=1, 153 for quadratic models; in F tests of group differences in the shape of the trajectory, df=1, 155 for linear models and df=2,
153 for quadratic models.
b
Difference between groups in the shape of the trajectory was significant in the longitudinal analysis (F=7.17, df=2, 153, p=0.001).
c
Difference between groups in height of curves at the sample average age (13.57 years) was significant in the longitudinal analysis (F=18.95,
df=1, 155, p=0.0003).
d
Difference between groups in height of curves at the sample average age (13.57 years) was significant in the longitudinal analysis (F=6.55,
df=1, 155, p=0.01).
*p<0.01.
FIGURE 2. Developmental Trajectory of Left Anterior Hemi-
sphere in ADHD Patients and Healthy Comparison Subjects
a
Significant difference between ADHD group (115 scans) and healthy
comparison group (114 scans) (F=7.17, df=2, 153, p=0.001).
8.5
8.0
7.5
7.0
6.5
8 9 10 11 12 13 14 15 16 17 18 19
Volume (ml)
Age (years)
ADHD patients (N=36)
Healthy comparison
subjects (N=36)
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In addition to its role in motor control, the cerebellum
contributes to a wide range of cognitive and affective pro-
cessing. Lesion studies demonstrate critical roles for the
cerebellum in motor and perceptual tasks in which events
span milliseconds, thus requiring exquisite temporal con-
trol (28), in the orientation of spatial attention (29, 30), in
verbal working memory (31), in language processing, and
in affective regulation (10, 32). Functional imaging studies
with healthy subjects similarly demonstrate cerebellar ac-
tivation in wide range of cognitive tasks (12, 33, 34). Pre-
cise localization of function within the cerebellum has
proved challenging given the limits of functional imaging
in the posterior fossa, the heterogeneity of cerebellar dam-
age among patients with lesions, and the possibility that
cognitive functions, such as verbal working memory, re-
quire the coordinated action of multiple cerebellar regions
(31). While this complicates interpretation of our more re-
gional findings, some considerations are relevant.
The nonprogressive deficit localized in the superior vermis
in ADHD patients in our study may represent a neuroana-
tomic basis of fundamental deficits in cognitive and affective
processing that are resistant to plastic developmental
changes in ADHD. Lesion studies have found additionally
that the degree of hypoplasia in the cerebellar superior ver-
mis is selectively associated with the severity of deficits in at-
tention-orientation (30). Similarly, in studies of superficial
siderosis (10, 35)—an acquired neurological disorder of he-
mosiderin deposition particularly affecting the superior cer-
ebellar vermis—deficits were identified in speech produc-
tion, visual recall, executive impairments, and social
comprehension; Schmahmann (10) emphasized the latter in
his clinical description of socioemotional dysregulation
among patients with vermal damage. Functional imaging
studies also implicate the vermis in complex cognitive activ-
ities, including time estimation (36), perceptual processing
of stimuli at short intervals (37, 38), and the alerting and ex-
ecutive control aspects of attention (39). Deficits in time in-
formation are consistently found in ADHD, including prob-
lems with motor timing, time discrimination, and time
reproduction (40–44). These deficits may lead to failures in
appreciating the temporal structure of the environment,
which could underpin many symptoms of ADHD (14). For
TABLE 4. Regional Cerebellar Volumes (ml) for ADHD Patients With Better and Worse Outcomes and Healthy Comparison Subjects
a
Region
Group
ADHD Patients With Worse
Outcome (N=18)
ADHD Patients With Better
Outcome (N=18)
Healthy Comparison
Subjects (N=36)
Mean SD Mean SD Mean SD
Hemispheres
Left anterior 7.56 1.20 7.47 1.18 8.05 1.60
Left corpus medullare 7.21 0.89 7.09 0.67 7.76 1.29
Left inferior-posterior 29.59 3.27 30.62 3.56 30.59 3.28
Left superior-posterior 23.78 3.82 22.83 2.42 23.75 3.34
Right anterior 7.67 1.22 7.78 1.70 7.68 1.84
Right corpus medullare 7.31 1.03 6.89 0.70 7.75 1.32
Right inferior-posterior 29.78 3.18 30.93 4.55 30.76 3.62
Right superior-posterior 24.28 3.83 23.21 2.35 24.10 3.70
Vermis
Anterior 3.43 0.57 3.52 0.61 3.71 0.69
Superior
b
2.10 0.50 2.27 0.37 2.56 0.45
Inferior 3.06 0.46 3.06 0.40 3.34 0.60
Whole 8.60 1.35 8.85 0.97 9.62 1.48
Total 137.2 13.5 136.8 12.2 140.5 15.0
a
In the longitudinal analysis (data not shown), all models incorporated quadratic terms except the anterior, inferior, superior, and whole ver-
mis and the left and right corpora medullare. Results indicated significant differences (at p0.01) in the F test of height differences of curves
at the sample average age (df=1, 154 for linear models and df=1, 151 for quadratic models) between the better outcome and comparison
groups and between the worse outcome and comparison groups for the superior vermis (p=0.01 and p=0.0007, respectively). In the F test of
group differences in the shape of the trajectory (df=1, 154 for linear models and df=2, 151 for quadratic models) between the better out-
come versus worse outcome groups and the worse outcome and comparison groups for the left inferior-posterior hemisphere, right inferior-
posterior hemisphere, and total vermis (p=0.003, 0.01, and 0.01 and p=0.008, 0.01, and 0.01, respectively).
b
Comparison between groups, F=7.0, df=2, 69, p=0.002.
FIGURE 3. Developmental Trajectory of Whole Cerebellum
in ADHD Patients With Better and Worse Outcomes and
Healthy Comparison Subjects
a
a
Difference between better outcome group and worse outcome
group, p=0.01; between worse outcome group and healthy com-
parison group, p=0.01; between better outcome group and healthy
comparison group, n.s.
135
130
140
145
8 9 10 11 12 13 14 15 16 17 18 19
Volume (ml)
Age (years)
Healthy comparison
subjects (N=36)
ADHD patients with
better outcome (N=18)
ADHD patients with
worse outcome (N=18)
Page 6
Am J Psychiatry 164:4, April 2007 653
MACKIE, SHAW, LENROOT, ET AL.
ajp.psychiatryonline.org
example, impulsive behaviors in a child with ADHD may rep-
resent a failure to produce the precise timing required to par-
ticipate in social exchanges. Similarly, transient lapses in at-
tention and response variability (noted most clearly in
neuropsychological testing) may also reflect an impaired, in-
consistent style of temporal information processing (13).
In our study, participants with ADHD in the worse clini-
cal outcome group showed a progressively smaller total
cerebellar volume over time, attributable mainly to the de-
viant trajectory of the inferior-posterior hemispheres. Le-
sion and functional imaging studies converge to show the
importance of the lateral cerebellar hemispheres in execu-
tive function (10, 45), spatial cognition, linguistic process-
ing (32), and verbal working memory (31, 46, 47). Meta-
analysis has confirmed moderate deficits in executive
functions in ADHD (particularly of response inhibition,
set shifting, and working memory) (48), which are likely to
represent one of possibly multiple pathways to the cardi-
nal symptoms of the disorder (13). For example, working
memory deficits lead to lapses in the maintenance of task-
relevant information “online” and could underlie some
symptoms of inattention. Additionally, deficits in the cere-
bellar components of motor control and response inhibi-
tion may contribute to hyperactivity. Future work can
assess whether the progressively deviant structural trajec-
tory in those with worse clinical outcome in ADHD is ac-
companied by a pattern of progressive cognitive deficits
that contribute to the persistence of symptoms.
As the study participants with ADHD moved into ado-
lescence, the volume of the left anterior hemisphere con-
verged to that of the comparison group. This volumetric
normalization occurred in a region that some lesion stud-
ies have linked specifically with time perception and pre-
cise motor timing (9). Recent high-resolution functional
imaging studies with healthy subjects have demonstrated
marked activation of the anterior and superior hemi-
spheres (lobules V–VI) during the perception and motor
performance of temporal sequences (49) and implicated
the anterior and superior cerebellum in visual and mem-
ory search (50). In adults with persistent ADHD, an anom-
alous decrease in activation of the superior and anterior
hemispheres during working memory tasks directly impli-
cates this region in one of the deficits associated with
ADHD (51). It is possible that the structural normalization
we report in our better outcome group is associated with
improvements in these and related cognitive functions,
representing a possible plastic compensatory response.
No firm conclusions can be drawn about etiological
factors in this descriptive study. Structural features of the
cerebellum are highly heritable (with an additive genetic
value of 0.49)—although less so than those of other
lobes—and thus genetic factors are likely to be important
(52). It is also possible that the different trajectories
FIGURE 4. Developmental Trajectory of Left and Right Infe-
rior-Posterior Hemispheres in ADHD Patients With Better
and Worse Outcomes and Healthy Comparison Subjects
a
a
For the left inferior-posterior hemisphere, difference between bet-
ter outcome group and worse outcome, p=0.003; between worse
outcome group and healthy comparison group, p=0.008; between
better outcome group and healthy comparison group, n.s. For the
right inferior-posterior hemisphere, difference between better out-
come group and worse outcome group, p=0.01; between worse
outcome group and healthy comparison group, p=0.01; between
better outcome group and healthy comparison group, n.s.
28
29
30
31
32
28
29
30
31
32
8 9 10 11 12 13 14 15 16 17 18 19
Volume (ml)
Age (years)
Right Inferior-Posterior Hemisphere
Left Inferior-Posterior Hemisphere
Healthy
comparison
subjects
(N=36)
ADHD patients
with better
outcome
(N=18)
ADHD patients
with worse
outcome
(N=18)
FIGURE 5. Developmental Trajectory of Left Anterior Hemi-
sphere in ADHD Patients With Better and Worse Outcomes
and Healthy Comparison Subjects
a
a
Difference between better outcome group and worse outcome
group, n.s.; between worse outcome group and healthy compari-
son group, p=0.07; between better outcome group and healthy
comparison group, p=0.001.
8.5
8.0
7.5
7.0
6.5
8 9 10 11 12 13 14 15 16 17 18 19
Volume (ml)
Age (years)
Healthy comparison
subjects (N=36)
ADHD patients with
better outcome (N=18)
ADHD patients with
worse outcome (N=18)
Page 7
654 Am J Psychiatry 164:4, April 2007
CEREBELLAR DEVELOPMENT IN ADHD
ajp.psychiatryonline.org
within ADHD are determined by polymorphisms in
monoaminergic neurotransmitter genes that are ex-
pressed in the cerebellum, such as polymorphisms of the
dopamine D
4
receptor gene, which have been linked with
clinical outcome (53). The rates of oppositional defiant
disorder and anxiety disorders were higher in the worse
outcome group, which raises the possibility that these co-
morbid disorders partly account for the deviant develop-
mental pathways. This is of particular interest given re-
cent suggestions that the presence of conduct disorder
and possibly oppositional defiant disorder defines a phe-
notypic subtype of ADHD (54). However, in all our study
subjects at baseline, the clinical picture was dominated
by ADHD, and the comorbid conditions were not the fo-
cus of treatment. This question will be clarified in future
studies with an expanded sample that includes a larger
proportion of children with a worse outcome and no co-
morbid disorders.
Limitations of this study include problems inherent to
use of a manual region-of-interest method of measuring
the vermis, which is reflected in the ICCs. However, all inter-
rater ICCs were within the range considered good, and all
intrarater ICCs were excellent (greater than 0.8) (55). Our
sample consisted almost entirely of patients with com-
bined-type ADHD, which limits the examination of sub-
types of ADHD. While we did not find any statistical differ-
ence in whole cerebellar size in children with ADHD, the
effect size reflecting the volumetric reduction in ADHD is in
line with previous reports, which suggests that the study
lacked the power to detect a statistically significant differ-
ence. However, by restricting our analysis to children for
whom three or more scans were available, we gained the
perspective of longitudinal growth trajectories, which re-
fine and extend the volumetric differences noted in previ-
ous studies. A large proportion of our subjects were exposed
to stimulant medication both prior to the first assessment
and during the follow-up period, which complicates the in-
terpretation of our findings because stimulants may have
neurotrophic effects (2). However, because the two ADHD
groups had similar histories of exposure to stimulants at
baseline, medication alone is unlikely to account for the dif-
ferential trajectories linked with outcome. It is more diffi-
cult to evaluate systematically the possible trophic effects of
other medications given the rarity of use in our sample.
In summary, we found a fixed, nonprogressive volume
reduction in the superior cerebellar vermis of children
with ADHD, which may prove to be a useful endopheno-
type in future genetic studies. In contrast, cerebellar hemi-
spheres exhibit a trajectory of developmental growth that
is state specific and may represent a potential target for
clinical or pharmacological intervention in ADHD.
Received June 29, 2006; revisions received Aug. 30 and Oct. 4, 2006;
accepted Oct. 12, 2006. From the Columbia University School of Med-
icine, New York, N.Y.; Child Psychiatry Branch, NIMH, Bethesda, Md.;
and the Department of Psychiatry, University of Iowa School of Medi-
cine, Iowa City, Iowa. Address correspondence and reprint requests to
Dr. Shaw, Child Psychiatry Branch, 10 Center Drive, Bldg. 10 3N202,
Bethesda, MD 20892-1600; shawp@mail.nih.gov (e-mail).
Dr. Giedd has received an honorarium from Johnson and Johnson.
All other authors report no competing interests.
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    • "In addition, the absence of a deficit in non-cortical resting state connectivity does not imply the absence of any cerebellar or subcortical deficits, as other neural properties can be affected. For example, volumetric differences in cerebellar and subcortical regions have been related to ADHD pathology (Mackie et al., 2007; Seidman, Valera, & Makris, 2005; Valera et al., 2007). Furthermore, an increasing number of studies does not point to one core brain deficit in ADHD, but instead describes widespread neural abnormalities associated with the disorder (Bush, 2010; Coghill, Hayward, Rhodes, Grimmer, & Matthews, 2014; Durston, 2003; Fair, Bathula, Nikolas, & Nigg, 2012; Sonuga- Barke, 2005). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: One neurodevelopmental theory hypothesizes remission of attention-deficit/hyperactivity disorder (ADHD) to result from improved prefrontal top-down control, while ADHD, independent of the current diagnosis, is characterized by stable non-cortical deficits (Halperin & Schulz, 2006). We tested this theory using resting state functional MRI (fMRI) data in a large sample of adolescents with remitting ADHD, persistent ADHD, and healthy controls. Methods: Participants in this follow-up study were 100 healthy controls and 129 adolescents with ADHD combined type at baseline (mean age at baseline 11.8 years; at follow-up 17.5 years). Diagnostic information was collected twice and augmented with magnetic resonance imaging (MRI) scanning at follow-up. We used resting state functional connectivity (RSFC) of the executive control network to investigate whether improved prefrontal top-down control was related to a developmental decrease in ADHD symptoms. In addition, we tested whether non-cortical RSFC, i.e., cerebellar and striatal RSFC, was aberrant in persistent and/or remittent ADHD compared to controls. Results: Higher connectivity within frontal regions (anterior cingulate cortex) of the executive control network was related to decreases in ADHD symptoms. This association was driven by change in hyperactive/impulsive symptoms and not by change in inattention. Participants with remitting ADHD showed stronger RSFC than controls within this network, while persistent ADHD cases exhibited RSFC strengths intermediate to remittent ADHD cases and controls. Cerebellar and subcortical RSFC did not differ between participants with ADHD and controls. Conclusions: In line with the neurodevelopmental theory, symptom recovery in ADHD was related to stronger integration of prefrontal regions in the executive control network. The pattern of RSFC strength across remittent ADHD, persistent ADHD, and healthy controls potentially reflects the presence of compensatory neural mechanisms that aid symptomatic remission.
    No preview · Article · Sep 2015 · Cortex
  • Source
    • "For example, anti-Yo normally causes paraneoplastic cerebellar degeneration (PCD) in women with breast or ovarian cancer. However, cerebellar dysfunction has also been suspected in ADHD (S. Mackie et al. 2007). The study by Passarelli et al. (2013) suggests that Yo antibodies may be associated with ADHD and without cancer. "
    [Show abstract] [Hide abstract] ABSTRACT: A high seroprevalence of Yo antibodies targeting cerebellar Purkinje cells was recently reported in children with attention deficit/hyperactivity disorder (ADHD). We investigated the presence of 8 paraneoplastic neurological syndrome (PNS)-associated antibodies including anti-Yo in 169 adult ADHD patients. No associations between ADHD and serum Yo antibodies or other antibodies associated with PNS were found. However, 10 out of 48 ADHD patient sera analyzed by immunofluorescence presented antibodies targeting cerebellar Purkinje cells. This reactivity probably represents the presence of low levels of antibodies against multiple cellular hitherto unknown antigens with little to no clinical significance.
    Full-text · Article · Sep 2015 · Journal of Neuroimmunology
    • "Although the link between ADHD and DCD in terms of motor, attentional, hyperactive and impulsive problems has been discussed in various reviews [22] [23] and studies [24] [25] [26] [27] [28] [29], the neurological basis and its association with cognitive and motor problems has rarely been addressed. Numerous morphometric and neuroimaging studies have been conducted in individuals with ADHD, and have identified brain regions with abnormalities which may explain their cognitive and motor deficits [30] [31] [32] [33]. Contrary to ADHD, there are few studies, with small sample sizes and divergent findings, investigating the neurobiology of DCD [34] [35] [36]. "
    [Show abstract] [Hide abstract] ABSTRACT: Attention deficit hyperactivity disorder (ADHD) has been described as the most prevalent behavioral disorder in children. Developmental coordination disorder (DCD) is one of the most prevalent childhood movement disorders. The overlap between the two conditions is estimated to be around 50%, with both substantially interfering with functioning and development, and leading to poorer psychosocial outcomes. This review provides an overview of the relationship between ADHD and DCD, discussing the common presenting features, etiology, neural basis, as well as associated deficits in motor functioning, attention and executive functioning. It is currently unclear which specific motor and cognitive difficulties are intrinsic to each disorder as many studies of ADHD have not been screened for DCD and vice-versa. The evidence supporting common brain underpinnings is still very limited, but studies using well defined samples have pointed to non-shared underpinnings for ADHD and DCD. The current paper suggests that ADHD and DCD are separate disorders that may require different treatment approaches. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Behavioural brain research
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