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Regional Brain and Ventricular Volumes in Tourette Syndrome
Bradley S. Peterson, MD;
Lawrence Staib, PhD;
Lawrence Scahill, MSN, PhD;
Heping Zhang, PhD;
Carol Anderson, PhD;
James F. Leckman, MD;
Donald J. Cohen, MD;
John C. Gore, PhD;
John Albert, BA;
Rebecca Webster, BS
Arch Gen Psychiatry. 2001;58:427-440.
ABSTRACT
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Background The pathophysiology of Tourette syndrome (TS) is thought to involve
disturbances in cortico-striato-thalamo-cortical circuitry. The morphological
characteristics of the cortical and associated white matter portions of these
circuits have not been previously examined in TS subjects.
Methods High-resolution anatomical magnetic resonance images were acquired in
155 TS and 131 healthy children and adults. The cerebrums and ventricles were
isolated and then parcellated into subregions using standard anatomical landmarks.
Results For analyses that included both children and adults, TS subjects were
found to have larger volumes in dorsal prefrontal regions, larger volumes
in parieto-occipital regions, and smaller inferior occipital volumes. Significant
inverse associations of cerebral volumes with age were seen in TS subjects
that were not seen in healthy controls. Sex differences in the parieto-occipital
regions of healthy subjects were diminished in the TS group. The age-related
findings were most prominent in TS children, whereas the diminished sex differences
were most prominent in TS adults. Group differences in regional ventricular
volumes were less prominent than in the cerebrum. Regional cerebral volumes
were significantly associated with the severity of tic symptoms in orbitofrontal,
midtemporal, and parieto-occipital regions.
Conclusions Broadly distributed cortical systems are involved in the pathophysiology
of TS. Developmental processes, sexual dimorphisms, and compensatory responses
in these cortical regions may help to modulate the course and severity of
tic symptoms.
INTRODUCTION
TOURETTE SYNDROME (TS) is a chronic, childhood-onset neuropsychiatric
illness. It is characterized by motor and vocal tics that fluctuate in severity,
and it frequently co-occurs with obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity
disorder (ADHD), or other social and behavioral disturbances.1, 2
This structural imaging study of cerebral and ventricular volumes in 286 TS
and healthy control subjects tests several previously formulated hypotheses
that derive from studies of the natural history and pathophysiology of TS.
First, we hypothesize that some but not all regional brain volumes will
differ between TS and healthy control groups.3
This hypothesis follows immediately from a model of TS pathophysiology that
postulates anatomical and functional disturbances in particular components
of the multiple circuits that loop between the cortex and subcortex (the cortico-striato-thalamo-cortical
circuits).3, 4 Motor portions of
these circuits are believed to subserve tic behaviors,3, 5
whereas other components are thought to modulate activity in motor circuits
and thereby influence the severity of tic symptoms.6, 7, 8
Components of these neuromodulatory circuits in subjects who voluntarily suppress
their tics, for example, include the frontal, temporal, and parietal cortices.9 Anatomic and functional variability in the brain regions
that compose these circuits may contribute to between-subject variability
in symptom severity and to differences between TS and control groups in regional
brain volumes.
Second, we hypothesize age-specific differences in volume between TS
and healthy control subjects (ie, group differences in some brain regions
vary according to age of the subjects).10 This
hypothesis is based on studies of the natural history of TS that demonstrate
a typical, gradual diminution in severity of tics during adolescence. These
studies indicate that the persistence of severe tics into adulthood is relatively
unusual.11, 12 Studies that include
adults as well as children can therefore yield clinically important information—they
may, for example, point to the neural systems that change with age and that
thereby influence the severity of symptoms and natural history of TS.
Third, we hypothesize that regional sex differences in brain volume
will be seen in healthy controls and that those sex differences will be attenuated
in TS subjects.6 This hypothesis is based on
the well-documented observation that TS is 4 to 10 times more common in males
than in females.7, 13, 14, 15
Although the determinants of these sex-specific differences in rates of illness
are unknown, they seem not to include sex-linked transmission of the putative
TS vulnerability genes.16, 17, 18, 19, 20
We and others6, 21 have hypothesized
that these differences in rates of illness instead have their neural basis
in regions of the brain that are sexually dimorphic. Anatomical and functional
disturbances in these regions may be responsible for the more frequent expression
of TS in males and for the overt expression of symptoms in the relatively
few women who would otherwise not express their inherent genetic diathesis
to TS.6, 21 This proposal is supported
by findings that hormonal manipulations can influence the severity of tic
and OCD symptoms.6, 22, 23, 24, 25
Candidate regions where group differences in volumetric sexual dimorphisms
might be expected to differ between TS and healthy subjects include the parietal
region. This area exhibits volumetric differences between sexes in normal
individuals26 and, based on the well-replicated
finding that men on average perform better than women on a variety of visuospatial
tasks that require an intact parietal lobe,27, 28, 29, 30
the region was hypothesized by some investigators to be functionally sexually
dimorphic even before the anatomical sex differences were first described.31
Fourth, we hypothesize that hemispheric asymmetries will be observed
in healthy subjects and that those asymmetries will be reduced in TS subjects
in some brain regions.32, 33 This
hypothesis is based on previous reports of altered basal ganglia asymmetries
in TS.32, 34, 35, 36
These basal ganglia findings motivated the measurement of the corpus callosum
in TS, which suggested the presence of disturbances in the structural integrity
of interhemispheric connections.33, 37
Reasoning that altered structural lateralization would not be limited to the
basal ganglia and corpus callosum, we have predicted that imaging studies
will demonstrate disturbances in cortical asymmetry.33, 38
To examine these hypotheses, we conducted a magnetic resonance imaging
(MRI) study of 155 TS and 131 healthy children and adults. Subregions of the
cerebrum were compared between groups using multivariate models that tested
each of our hypotheses concurrently. Similar comparisons were conducted for
subregions of the cerebral ventricles to complement these analyses, as abnormal
ventricular volumes have long been thought to reflect abnormalities in the
surrounding cerebral tissue.
SUBJECTS AND METHODS
SUBJECT RECRUITMENT AND CHARACTERIZATION
Tourette syndrome subjects were recruited from the Tic Disorders Specialty
Clinic at the Yale Child Study Center. Normal controls were recruited from
a list of 10 000 names purchased from a telemarketing company. They were
identified by the company as having individuals in specified age ranges and
as living in the same neighborhoods (based on ZIP code) as the TS subjects.
Individuals from the list were selected for contact by the investigators using
a random number generator. Introductory letters were followed by screening
telephone calls. Of the eligible control families contacted, approximately
10% participated. Written informed consent was obtained for all participants.
Subjects were aged 6 to 63 years, and they were predominantly right-handed
according to a standardized questionnaire.39
Tourette syndrome subjects had to meet DSM-IV criteria
for this diagnosis.40 Exclusionary criteria
for TS subjects included another movement disorder, or a major psychiatric
disorder other than OCD or ADHD that antedated the onset of TS. For control
subjects, exclusionary criteria included any history of tic disorder, OCD,
ADHD, or current Axis I disorder. Additional exclusionary criteria for both
groups included any prior seizure, a history of head trauma with loss of consciousness,
ongoing substance abuse or previous substance dependence, or an IQ below 80.
Neuropsychiatric diagnoses were established through clinical evaluation
and administration of the Schedule for Tourette Syndrome and Other Behavioral
Disorders,41 a structured interview that has
been used extensively in TS family studies. The Schedule for Tourette and
Other Behavioral Syndromes includes the Kiddie-Schedule for Affective Disorders
and Schizophrenia Epidemiologic Version for diagnoses in children,42, 43 the Schedule for Affective Disorders
and Schizophrenia for diagnoses in adults,44
and more detailed sections on TS and OCD for both age groups. Diagnoses were
established through a best-estimate consensus procedure performed by 2 child
psychiatrists (B.S.P. and J.F.L.) using all available clinical and investigational
materials.45 Ratings of current and worst-ever
severity of tic symptoms were obtained using the Yale Global Tic Severity
Scale46 and either the adult or child version
of the Yale-Brown Obsessive Compulsive Scale.47, 48
Socioeconomic status was estimated with the Hollingshead Index of Social Status.49
MRI SCANNING
Magnetic resonance imaging scans were obtained using a single 1.5-T
scanner (GE Signa; General Electric, Milwaukee, Wis). Head positioning was
standardized using canthomeatal landmarks. A 3-dimensional spoiled gradient
echo sequence was obtained for the morphometric analyses (repetition time,
24 milliseconds; echo time, 5 milliseconds; flip angle, 45°; frequency
encoding superior/inferior; no wrap; 256 x 192 matrix; field of view,
30 cm; 2 excitations; slice thickness, 1.2 mm; and 124 contiguous slices encoded
for sagittal slice reconstructions).
MORPHOMETRIC PROCEDURES
Morphometric analyses were performed on Sun Ultra 10 workstations using
ANALYZE 7.5 software (Rochester, Minn) while blind to subject characteristics
and hemisphere (images were randomly flipped in the transverse plane before
region definition). A second operator confirmed the accuracy of all procedures.
Preprocessing
Large-scale variations in image intensity were removed before the images
were reformatted.50, 51 Head flexion/extension,
rotation, and tilt were corrected before to region definition using the anterior-posterior
(AC-PC) commissure and standard midline landmarks.
Cerebral Tissue
An isointensity contour function was used in conjunction with manual
editing to isolate the cerebrum. The cerebrum (exclusive of cerebellum) was
then parcellated into 8 anatomical subunits using orthogonal planes. The cerebral
hemispheres were first divided using a curved Hermite spline surface interpolated
from 100 points placed at standard midline landmarks. Each of the cerebral
hemispheres was subdivided using 1 axial plane placed through the AC-PC line
(tangent to the top of the AC and bottom of the PC) and 3 coronal planes—1
tangent to the genu of the corpus callosum, 1 tangent to the anterior border
of the AC, and 1 through the PC at the midline.52
These planes divided each hemisphere into 8 regions: dorsal prefrontal, orbitofrontal,
premotor, subgenual, sensorimotor, parieto-occipital, midtemporal, and inferior
occipital (Figure 1). The validity
of related parcellation schemes have been previously documented.53, 54, 55, 56, 57
Parcellated cerebral tissue volumes included both gray and white matter but
not cerebrospinal fluid (CSF).
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Figure 1. The abscissa represents the dichotomous
variable of diagnosis (Tourette syndrome [TS] or controls) and the ordinate
represents regional volume. The graphs present, for each cerebral parcellation
unit, the least squares mean values and SEs for males and females in each
diagnostic group. The means are adjusted for all other terms of the statistical
model (shown in Table 1). Significant
effects for diagnosis are seen in the dorsal prefrontal, premotor, and subgenual
regions. A significant TS x sex x region interaction is evident
in the parieto-occipital region. The larger volumes for women in some brain
regions are not absolute, but only proportional to the whole brain volume
covariate used to correct for the smaller overall brains in women and for
overall scaling effects in the statistical model.
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Table 1. A Priori Hypothesis Testing for the Parcellated Cerebrum*
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Cerebral Ventricles
An isointensity contour function was used to define the contours of
the cerebral ventricles. The ventricular system was subdivided by first manually
isolating the third and fourth ventricles. Each of the lateral ventricles
was then divided into 3 sections—the frontal horns, midbody, and occipital
horns—using 2 coronal planes, one passing tangent to the anterior-most
point of the AC and the other through the PC as those commissures crossed
midline.52 The temporal horn was separated
from the lateral bodies of the ventricles using an axial plane containing
the AC-PC line (Figure 2). The interrater
reliability of the measurements was assessed on 20 scans each measured by
4 raters. Intraclass correlation coefficients calculated using a 2-way random-effects
model58 were greater than 0.98 for each of
the cerebral and ventricular subdivisions, with the exception of the third
ventricle, which had an intraclass correlation coefficient of 0.88.
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Figure 2. The parcellation units defined
using axial and coronal planes through standard anatomical landmarks of the
reformatted brain, as described in the text. The medial view is a parasagittal
slice (ie, lateral to the interhemispheric fissure and true midline) to permit
visualization of structures within the cerebral hemisphere.
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Whole Brain Volume
To control for generalized scaling effects within the brain,59 we measured whole brain volume (WBV) for use as a
covariate in statistical analyses.60 This measure
included cerebral tissue (gray and white matter), ventricular CSF, and CSF
spaces within the brain (cisterns, fissures, and cortical sulci). The CSF
spaces were added to the volume of cerebral tissue using a connected components
analysis (the ANALYZE subroutine "delete holes"). These spaces were included
to minimize the effects of age-related cortical atrophy on this covariate
in older subjects and other possible neurodegenerative effects in the patient
group. Covarying for WBV in the presence of these effects can either covary
out similar effects in brain subregions or make volumes of unaffected subregions
seem artifactually larger.60, 61
STATISTICAL ANALYSES
A Priori Hypothesis Testing
All statistical procedures were performed in SAS version 8.0 (SAS Institute
Inc, Cary, NC). A priori hypotheses were tested using a mixed models analysis
(PROC MIXED) with repeated measures over a spatial domain (regional brain
volumes).
The cerebral and ventricular parcellations were entered as dependent
variables into 2 separate models. The model for the cerebrum included 2 within-subjects
factors—"region," which had 8 levels (the 8 cerebral parcellations listed
above) plus the cerebellum, and "hemisphere," which had 2 levels ("left" and
"right" for the 8 cerebral parcellations) plus a "midline" specification for
the cerebellum. The model for the ventricles also included a region factor
with 4 levels (frontal, midbody, occipital, and temporal horns) plus the third
and fourth ventricles; it also included a hemisphere factor with 2 levels
(left and right for the 4 components of the lateral ventricles) plus a midline
specification for the third and fourth ventricles. Diagnosis was a between-subjects
factor, and covariates included age, sex, WBV, socioeconomic status, and lifetime-diagnoses
OCD or ADHD.
In addition to the covariates described above, we considered for inclusion
in the model all 2- and 3-way interactions of diagnosis, sex, hemisphere,
region, and age, because these terms all had potential biological relevance
and were readily interpretable. We also considered the 2-way interactions
of WBV with hemisphere or region because these terms too were readily interpretable
and seemed likely to be associated with parcellated volumes. Terms that were
not significant were eliminated via backward stepwise regression, with the
constraint that the model at each step had to be hierarchically well-formulated
(ie, all possible lower order terms had to be included in the model, regardless
of their significance).62
Tests of the significance of 4 statistical interactions—TS x
region, TS x age x region, sex x TS x region, and
TS x hemisphere x region—were used to test the 4 respective
a priori hypotheses. Applied to the analysis of cerebral and ventricular volumes
in separate statistical models, these hypotheses required 8 tests of significance;
therefore, values of P<.006 for each interaction
to survive strict Bonferroni correction were required for multiple comparisons.
Hypothesis testing was performed on volumes from all 286 subjects. However,
results of identical analyses are presented for volumes from children and
adults alone to help clarify whether significant effects derived from one
or both age groups.
Tests of Fixed Effects
To identify the component terms that contributed most to the significance
of higher order interactions, we examined the parameter estimates, 95% confidence
intervals, and P values of the component terms in
an analysis of fixed effects for the final mixed models. Least squares means
and SEs were calculated in the mixed models and plotted to assist in the interpretation
of significant interactions (Figure 1).
Assessment of Possible Confounding Factors
We also included in the initial models minority status, height, weight,
and handedness index.39 However, these variables
had negligible effects on the parameter estimates. Consequently, they were
not included in the final models for hypothesis testing.
Associations With Symptom Severity
In the TS group, we explored the associations of regional volumes with
the severity of tic symptoms, either at the time of scanning or when the symptoms
were at their worst in the patient's lifetime. Associations of symptom severity
with regional volumes were performed using linear regression with WBV and
sex as covariates. We anticipated that worst-ever ratings would be more strongly
associated with regional brain volumes than ratings of current severity, as
suggested in our prior TS structural imaging studies.32, 33
RESULTS
SUBJECTS
We acquired high-resolution anatomical MRI scans on 155 TS and 131 normal
control subjects. The TS and control groups were of comparable mean ±
SD ages (18.7 ± 13.4 vs 20.8 ± 13.4 years, respectively; t284 = 1.3, P = .18).
Of the 286 participants, 177 (61.9%) were children (age, <18 years) and
109 (38.1%) were adults, with a similar age distribution between groups. The
TS group compared with the controls had a significantly higher percentage
of males (114 [73%] vs 72 [55%];  21 = 10.2, P = .002) and significantly fewer minorities (7 [5%] vs
16 [12%]; 2 = 5.69, P = .02). Socioeconomic
status did not differ significantly between groups (45.5 ± 11.5 vs
47.6 ± 9.8; t284 = 1.67, P = .10).
Based on the structured interviews, lifetime diagnoses in the TS cohort
included OCD in 62 (40%) and combined-type ADHD in 36 (23%). At the time of
the study, 72 TS subjects (46%) were taking medication, stimulants (N = 3
[2%]), traditional neuroleptics (haloperidol or pimozide, N = 20 [12.9%]),
risperidone (N = 7 [4.5%]),  -adrenergic agonists (clonidine or guanfacine)
(N = 29 [18.7%]), selective serotonin reuptake inhibitors (N = 19 [7.5%]),
or tricyclics (N = 11 [4.3%]).
HYPOTHESIS TESTING
Cerebrum
Statistical tests for each term in the final models are presented in Table 1.
Region-Specific Differences
The TS x region interaction was significant, confirming our first
hypothesis. The fixed effects (Table 2)
and least squares means (Figure 1)
indicated that the strongest contributions to this effect came from larger
dorsal prefrontal volumes in TS males (1.7%, P =
.0004) and females (3.3%, P = .01), smaller premotor
volumes in TS females (-3.0%, P = .04), larger
parieto-occipital volumes in TS males (2.1%, P =
.0002), and smaller inferior occipital volumes (-1.9%, P = .03) in TS males.
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Table 2. Selected Fixed Effects for the Parcellated Cerebrum*
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Children Only.
Compared with normal children of the same sex, the fixed effects and
least squares means indicated larger dorsal prefrontal volumes in TS boys
(5.7%, P = .0007) and TS girls (5.8%, P = .003), smaller premotor volumes in TS boys (-4.8%, P = .02), larger parieto-occipital volumes in TS boys (0.5%, P<.0001) and TS girls (0.5%, P
= .002), smaller orbitofrontal volumes in TS boys (-4.8%, P = .001), smaller subgenual volumes in TS boys (-5.5%, P = .03), and larger inferior occipital volumes in TS boys
(2.4%, P = .05) and TS girls (2.5%, P = .02).
Adults Only.
Compared with normal adults of the same sex, the fixed effects and least
squares means indicated smaller dorsal prefrontal volumes in TS women (-3.4%, P = .06), larger premotor volumes in TS men (3.4%, P = .01), larger parieto-occipital volumes in TS men (2.8%, P = .0008), and smaller parieto-occipital volumes in TS
women (-2.7%, P = .005).
Age-Specific Differences
The TS x age x region interaction was significant, confirming
our second hypothesis. The fixed effects indicated the greatest contributions
from the dorsal prefrontal (P = .003) and inferior
occipital (P = .004) regions. Graphical representation
(Figure 3) indicated that dorsal
prefrontal volumes in TS children were larger than those in controls, but
by midadulthood those volumes were smaller in TS than in control subjects.
In inferior occipital regions, volumes were positively associated with age
in the normal controls and negatively associated with age in the TS group
(data not shown).
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Figure 3. Significant age x diagnosis
x region interactions in post hoc testing were seen in the dorsal prefrontal
(DPFC) region. The residual volumes of those regions after partialling out
whole brain volume, sex, socioeconomic status, obsessive-compulsive disorder,
and attention-deficit/hyperactivity disorder in a repeated-measures analysis
of variance are plotted against age. Because these are residual volumes, they
can take positive or negative values.
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Age-specific group differences in volume were more prominent in children
than in adults, and they were especially strong in dorsal prefrontal, orbitofrontal,
and parieto-occipital regions (Table 1
and Table 2). In the TS children,
the associations of age with regional volumes were in the same direction as
those in the combined age groups (Figure 3); inverse associations with age were present in all 3 regions in
the TS group, but negligible age effects were detected in normal controls.
Sex-Specific Differences
The TS x sex x region term was significant. Fixed effects
indicated the strongest contributions from parieto-occipital regions (P = .0002). Here, volumes in healthy females were considerably
larger than in healthy males, whereas volumes in TS females and males were
similar to one another (Figure 1).
Sex-specific group differences were more prominent in adults than in children
(Table 1 and Table 2), with sex differences in healthy adult subjects absent
in the TS adults. In the prefrontal area of adults, reduced sex differences
were largely caused by reduced volumes in TS women (3.5%, P = .02), whereas in the premotor region it was mostly caused by larger
volumes in TS men (3.4%, P = .02) (data not shown).
The findings in the parietal region of adults were nearly identical to those
when all subjects were included (P<.0001) (Figure 1).
Hemisphere-Specific Differences
The TS x hemisphere x region term was not significant in
any of the age groups examined.
Ventricles
Multivariate statistical testing is presented in Table 3. The TS x region, TS x age x region, and
TS x hemisphere x region interactions were not significant and
therefore did not support the first, second, or fourth hypotheses for the
ventricles. The significant TS x sex x region interaction (P = .002), however, confirmed the third hypothesis. The
fixed effects (Table 4) (Figure 4) indicated a sex difference in the
occipital horns of TS subjects (larger volumes in males) that was not present
in normal controls (P = .03).
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Table 3. A Priori Hypothesis Testing for the Parcellated Ventricles*
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Table 4. Selected Fixed Effects for the Parcellated Ventricles*
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Figure 4. Only the Tourette syndrome (TS)
x sex x region interaction was significant, and this effect derived
primarily from the parieto-occipital region.
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Associations With Tic Severity
Ratings of worst-ever tic severity correlated more robustly and consistently
with regional volumes than did ratings of current tic severity (data not shown).
For the cerebral parcellations, correlations were strongest in the left (ß
= -0.26, P = .002) and right (ß = -0.20, P = .02) orbitofrontal region, and in the left (ß
= -0.20, P = .03) and right (ß = -0.29, P = .002) parieto-occipital region, where increasing volumes
were associated with fewer symptoms. Weaker, positive associations were seen
between tic severity and volumes of the left sensorimotor and left midtemporal
regions (ß = 0.17, P = .05) (Figure 5). For the cerebral ventricles, correlations with symptom
severity were uniformly positive and strongest with the volumes of the midbodies
of the lateral ventricles (ß = 0.21-0.23, P
= .02 to P = .008) and with volumes of the third
(ß = 0.19, P = .03) and fourth ventricles (ß
= 0.24, P = .004). These correlations of tic severity
with regional volumes were more robust in adults (eg, orbitofrontal and parieto-occipital ß -0.44
to -0.46, P = .01 to P
= .009) and they were negligible in children.
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Figure 5. Regions where the associations
of volume with symptom severity were strongest are shown. Whole brain volume
and sex were first partialed out of both volume and symptom severity, so that
the associations of the residual values plotted here represent partial correlations.
Because these are residual volumes and severity ratings, they can take positive
or negative values.
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FURTHER EXPLORATORY ANALYSES
Cerebrum
Diagnoses of OCD or ADHD in the TS subjects were associated as covariate
main effects with larger volumes at trend levels of significance (P = .09 and P = .06, respectively) (Table 1).
Ventricles
A diagnosis of ADHD in TS subjects was associated with smaller ventricular
volumes at a trend level of significance (P = .06).
Medication Effects in the TS Group
Medication effects on regional volumes were tested separately for the
current use of neuroleptics, selective serotonin reuptake inhibitors, or -adrenergic
agonists using the same statistical models as those employed for the post
hoc testing of diagnostic effects. In no regions were medication effects significant
at a value of P<.05.
Neuroleptic-Naïve, "Pure" TS Children
In a separate mixed-model analysis of children (age <18 years), 42
pure TS subjects (no lifetime diagnosis of OCD or ADHD) who had no prior exposure
to typical or atypical neuroleptics were compared with 67 healthy controls.
Results were similar to those obtained for the comparison of all TS and control
children (Table 1), suggesting
that these comorbidities and prior neuroleptic exposure did not significantly
influence the findings.
COMMENT
We were able to confirm region, age, and sex differences, but not hemisphere-specific
differences in cerebral volume between TS and healthy control subjects. Group
differences were much less prominent for ventricular volumes.
HYPOTHESES
Region Specificity
The most prominent regional effect in TS subjects was a larger dorsal
prefrontal volume. However, this effect derived primarily from larger prefrontal
volumes in TS children. Group differences were less prominent in older children
because of an inverse association of age with prefrontal volumes in the TS
group. In fact, by adulthood, the TS subjects tended to have smaller dorsal
prefrontal volumes, an effect that reached significance in TS women. Similar
effects that were specific to age group were observed in the parieto-occipital
region, where volumes were larger in younger TS children but negligibly larger
by late adolescence. In adults, parieto-occipital volumes were still significantly
larger in TS men but were significantly smaller in TS women. Group differences
in inferior occipital regions were similar to those in parieto-occipital regions,
except that volumes were not significantly larger in TS men.
Separate analyses of children and adults revealed additional group differences
that were more widespread and generally of larger magnitude in the children.
Effects were significant for TS boys, who had smaller orbitofrontal, subgenual,
and premotor volumes. In adults, effects in the premotor region were opposite
in direction and were significantly larger in TS men. Group effects were therefore
opposite in direction for TS children and adults in dorsal prefrontal, premotor,
and parieto-occipital regions, and contributed to age-specific regional differences
in the analysis of the combined age groups (below). Of these various regions,
parieto-occipital and orbitofrontal volumes in the TS group were significantly
and negatively associated with the severity of tic symptoms.
These various brain regions subserve diverse functions. The prefrontal
region is believed to mediate performance in tasks that require decisions
of whether, when, and how to act across a time delay, as needed for working
memory, go–no go, and behavioral inhibition tasks.63
The premotor region defined here includes the supplementary motor area, the
cortical recipient of motor pathways in the cortico-striato-thalamo-cortical
circuits that participate in planning and executing motor tasks. Electrical
stimulation of this region produces complex movements, vocalizations, and
urges to move a contralateral body part,64, 65
urges similar to those that accompany tics.66
The subgenual region defined here contains inferior, dysgranular cortices
that connect the orbitofrontal cortex, temporal pole, and amygdala with the
ventral striatum and hypothalamus.67 It is
regarded as an anatomical crossroad that contributes to affective and motivational
processing.63, 68, 69, 70
The premotor, prefrontal, and subgenual regions therefore together contribute,
among other things, to the motivation, planning, and execution of normal behavioral
repertoires, of the sort that have gone awry in persons with TS. Functions
of the parietal and occipital regions include visuospatial and attentional
processing, disturbances of which are the most reliable findings in neuropsychological
studies of TS subjects, particularly when these functions must be integrated
with motor performance.71
Age Specificity
The associations of dorsal prefrontal and inferior occipital volumes
with age differed significantly between TS and healthy controls because of
inverse associations with age in the dorsal prefrontal, parieto-occipital,
and inferior occipital regions of TS subjects (Figure 3). These group-specific age associations were strongest
in children. Premotor volumes, in contrast, were significantly smaller in
TS boys and larger in TS men. In the ventricular system, strong associations
with age were seen throughout all subregions, but especially in the frontal
horns, midbodies, and temporal horns of the lateral ventricles. These age
effects, however, did not affect the TS group disproportionately.
Cross-sectional, age-related differences between groups in regional
cerebral volumes have several possible interpretations. One is that they represent
pathological associations of volume with age that are representative of the
longitudinal trajectories of regional brain volumes in most TS subjects. This
seems unlikely, given the nonrepresentativeness of clinically identified TS
adults who remain symptomatic (such as the subjects in this study) and given
the inherent difficulty of inferring longitudinal course from a cross-sectional
study such as this.72 A second interpretation,
which we favor, is that the group differences in adulthood represent regional
markers for morphological traits that contribute to the relatively unusual
persistence of symptoms into late adolescence and adulthood, and that contribute
to the clinical identification and study of these still-symptomatic subjects.
These traits might be long-standing from childhood (and would therefore constitute
a marker of risk for future symptom persistence) or they might be acquired
in adolescence or adulthood (and thereby represent a second process that influences
the natural history of the primary tic disorder).73
Longitudinal studies could help to confirm this explanation directly, and
they would help to assess the utility of regional volumes as putative developmental
markers for symptom persistence. A third possible explanation of the age associations
is that they represent long-term activity-dependent plastic changes (presumably
adaptive or compensatory in nature) caused by the lifelong presence of tics.
Long-term, activity-dependent effects may include the larger dorsolateral
prefrontal volumes in TS children and larger premotor volumes in TS men. Again,
a longitudinal study would help to address these possibilities more directly.
A fourth explanation is that the age-related changes are nonspecific responses
to the presence of chronic illness.
Most TS imaging studies thus far have been of adult subjects. In radioligand
and radiotracer studies, the exclusive study of adults has been necessary
because of the ethical concerns of exposing children to the radioactivity
of tracers. The age-related findings of the present study, however, suggest
that findings of prior adult studies may not generalize to pediatric populations
or to TS adults who are less symptomatic.10
Sex Differences
Group-specific sex differences derived largely from the parieto-occipital
region, where prominent sex differences were seen in normal but not in TS
subjects. This group-specific sex difference was caused by relatively larger
volumes in TS males and smaller volumes in TS females (Figure 1). In the ventricles, a sex difference in occipital horn
volume was seen in TS subjects but not in normal subjects. It derived from
larger volumes in TS males but smaller volumes in TS females (Figure 4). Altered sex differences in TS subjects therefore involved
primarily posterior brain regions, where the directional effects of abnormalities
in cerebral tissue and ventricular CSF paralleled one another—volumes
of each were larger in TS males and smaller in TS females than in their healthy
control counterparts. In the posterior compartment of TS subjects, this may
have reduced sex differences that would otherwise have been prominent, and
in the posterior ventricular system, it may have introduced sex differences
that would not have otherwise existed.
Altered Asymmetries
Our hypothesis concerning altered cerebral and ventricular asymmetries
was not supported by the present findings. This suggests that the prior findings
of altered asymmetries in the basal ganglia do not generalize to cortical
regions, that the cortical regions defined here were too coarse to detect
altered asymmetries, or that the basal ganglia findings represented type I
errors in studies with small numbers of subjects.
AN INTEGRATIVE MODEL: THE NEUROMODULATION OF TIC SYMPTOMS
The greatest group differences in this study were found in dorsal prefrontal,
parieto-occipital, and inferior occipital regions. We suspect that these regional
abnormalities in TS subjects derived in part from the participation of the
heteromodal frontal and parietal regions in a broadly distributed action-attentional
system that must be engaged for the successful inhibitory control of tic symptoms.9, 63, 74, 75, 76
This network also includes the orbitofrontal and midtemporal regions, which,
along with volumes of the parieto-occipital regions, correlated significantly
with the severity of tic symptoms.
Smaller orbitofrontal and parieto-occipital volumes were associated
with worse tic symptoms, suggesting that smaller volumes in this portion of
the action-attentional system may provide insufficient inhibitory reserve
to help suppress these unwanted behaviors. Larger prefrontal volumes in the
TS subjects may represent an activity-dependent structural plasticity that
could help to suppress tics. Consistent with this hypothesis are numerous
preclinical and clinical studies suggesting that the orbitofrontal region
in particular plays an important role in inhibitory control.63, 77, 78, 79, 80, 81, 82, 83, 84
Also consistent is the prior finding that as TS subjects suppress tics, activation
of the ventral prefrontal cortex is signficantly correlated with decreases
in activity of basal ganglia nuclei, the putative neural substrate of tics.9 Larger premotor regions in men compared with smaller
volumes in TS boys may represent long-term, activity-dependent effects in
the motor system associated with the presence of tics.
The inverse association of parieto-occipital volumes with age in TS
subjects was disproportionately represented in TS females, and in the TS group
this resulted in a reduced volume difference between sexes compared with normal
controls. Neuroimaging and behavioral studies together suggest that sexual
dimorphisms in the parietal region may contribute to sex differences in visuospatial
task performance and other sexually dimorphic behaviors. The most robust sexually
dimorphic behavior in normal children and adults is a reduced inhibitory control
in males compared with females that is manifested as an innate predisposition
to more aggressive behavior,85, 86
a frequently reported difficulty in TS clinic populations.2
Because smaller volumes in the parieto-occipital region were associated with
more severe tic symptoms in TS subjects, it is possible that a profile more
like normal males (smaller volumes) in this portion of the action-attentional
system predisposes TS subjects to more severe tics. This is consistent with
our previously stated hypothesis that sexually dimorphic brain regions may
contribute to symptom expression.6
As noted above, the stronger inverse association of dorsal prefrontal
volumes with age in the TS group may have resulted from the presence in the
TS adults of a morphological trait (smaller prefrontal volumes) that predisposes
to more severe or more chronic symptoms. Smaller prefrontal volumes could
have contributed to the relatively unusual persistence of their symptoms in
adulthood and to the subsequent clinical identification and inclusion of the
adults in this study. The age-specificity of regional findings thus further
supports the possibility that larger prefrontal regions in TS subjects are
an adaptive, compensatory response that helps to attenuate tic symptoms. Smaller
prefrontal volumes might then constrain the magnitude of those adaptive reserves
and, if present in childhood, would then be a promising marker for predicting
the future course of illness.
Identifying neuromodulatory systems such as these may be more clinically
relevant in TS than defining the neural basis of the origin of tics per se.
Many younger children, for example, have transient or chronic tics,87, 88, 89, 90 but
few will have tics of sufficient number or severity to cause functional impairment.
Relatively few of the children who have severe tics, moreover, will continue
to have severe tics into early adulthood. Neuromodulatory systems may therefore
determine whether and for how long tics have a functional impact on a child's
life.
LIMITATIONS AND FUTURE DIRECTIONS
Localization of the morphological correlates of TS was no doubt impaired
in this study by the relative coarseness of the cerebral parcellation scheme.
Regional cerebral volumes included both gray and white matter, and the region
definitions all subsumed numerous cytoarchitectonic and functional areas.
The coarseness did provide the advantage, however, of reducing the number
of statistical comparisons and the risk of type I error, while also helping
to guide future hypothesis-driven studies using finer-grained parcellation
schemes.56, 91 The parcellation
also relied on landmarks (the AC-PC line and the anterior border of the corpus
callosum) that are assumed to be anatomically invariant between diagnostic
groups, and this is an untested assumption. Nevertheless, the same parcellation
scheme has been applied in the study of other conditions where the size of
the corpus callosum is reduced by more than 30%, without producing patterns
of group difference in regional volume that resembled those seen here.92 In addition, the effects of prior medication use
on regional brain volumes in the TS group cannot be entirely discounted by
the absence of discernible effects of medication on the statistical analyses.
Nevertheless, tests of a priori hypotheses and the parameter estimates for
those subjects who had no prior medication use were similar to estimates for
the entire group, suggesting that medication exposure did not unduly influence
the findings.
The most limiting feature of this study is its cross-sectional design.
The static view of the brain provided by cross-sectional imaging studies insufficiently
constrains the possible interpretation of the correlation analyses that are
needed to understand the direction of group differences.72
In the present study, for example, it is impossible to say decisively whether
observed group differences in regional volume contributed to the production
of tics or whether they were somehow a plastic or compensatory response to
the presence of the unwanted behaviors. If we are to be confined to study
designs that are naturalistic and observational, as the vast majority of imaging
studies are, then longitudinal studies should be undertaken to generate change
scores that will at least help to further constrain the interpretation of
critical brain-behavior associations.
AUTHOR INFORMATION
Accepted for publication October 10, 2000.
Supported in part by grants MH01232 (Dr Peterson), MH59239 (Dr Peterson),
and MH49351 and MH30929 (Dr Zhang), from the National Institute of Mental
Health, DA12468 from the National Institute for Drug Abuse (Dr Zhang), AA12044
from the National Institute on Alcohol Abuse and Alcoholism (Dr Zhang), and
AG16996 from the National Institute on Aging (Dr Zhang), Bethesda, Md, and
a grant from the Charles A. Dana Foundation, New York, NY (Dr Peterson).
We thank Liliya Katsovich, MA, for her help with database management,
and Michael Kane, BS, and Aaron Dolberg, BA, for their assistance with morphometric
procedures.
ANALYZE software was developed by the Biomedical Imaging Resource, Mayo
Foundation, Rochester, Minn.
From the Yale Child Study Center, the Department of Diagnostic Radiology,
and the Department of Epidemiology and Public Health, Yale Scho |
