Brain Advance Access published December 3, 2007
Brain (2007) Page 1 of 15
Neural correlates of tic severity and cognitivecontrol in children with Tourette syndrome
C. L. Baym,1,4, B. A. Corbett,1,2,3, S. B. Wright1,5 and S. A. Bunge1,5,6
1Center for Mind and Brain, 2Department of Psychiatry and Behavioral Sciences, 3MIND Institute, University of Californiaat Davis, 4Department of Psychology, University of Illinois at Urbana-Champaign, 5Helen Wills Neuroscience Institute and6Department of Psychology, University of California at Berkeley, USA
These authors contributed equally to this work.
Correspondence to: Silvia A. Bunge, PhD, Department of Psychology &, Helen Wills Neuroscience Institute,University of California, Berkeley, 132 Barker Hall, Berkeley, CA 94720 -3190, USAE-mail: [email protected]
Tourette syndrome (TS) is a neurodevelopmental disorder characterized by involuntary motor and phonic tics.
It is hypothesized that excess dopamine leads to an imbalance in the pathways through the basal ganglia, result-ing in unchecked movements via thalamic disinhibition. It has been unclear whether TS is associated with cogni-tive control deficits as well as pure motor control deficits, or whether cognitive deficits are associated with thepresence of comorbid conditions. Furthermore, little is known about the neural underpinnings of TS in child-hood, prior to the long-term effects of medication on brain function. Here, children withTS and typically devel-oping children performed a cognitive control task during event-related fMRI data acquisition.The study included18 native English-speaking 7 13 -year-old children with TS (M = 10.42; 15 males), and 19 healthy, age-matchednative English-speaking volunteers (M = 10.33; 11 males). The task involved three separate manipulations of cog-nitive control. Behaviourally, higher tic severity was correlated with slower task performance on the mostdemanding task conditions. Neurally, higher tic severity was associated with enhanced activation of dopaminer-gic nuclei (substantia nigra/ventral tegmental area) and cortical, striatal and thalamic regions in the direct path-way. Heightened tic severity was also associated with greater engagement of the subthalamic nucleus area,suggestive of a compensatory mechanism. Overall, patients engaged left prefrontal cortex more strongly thantypicals during task performance. These data suggest that children aged 7 13 unmedicated for TS exhibitincreased activation in the direct pathway through the basal ganglia, as well as increased compensatory activa-tion in prefrontal cortex and the subthalamic nucleus.
Keywords: frontal; striatal; paediatric; brain imaging; disorder
Abbreviations: ADHD = attention deficit disorder; fMRI = functional magnetic resonance imaging;OCD = obsessive-compulsive disorder; PFC = prefrontal cortex; TS = Tourette syndrome
Received June 29, 2007. Revised September 20, 2007. Accepted October 5, 2007
disorder (OCD) and attention deficit disorder (ADHD),
Tourette syndrome (TS) is characterized by the expression
as well as mood disorders, other anxiety disorders and
of tics, or involuntary movements, such as sudden gestures
conduct disorders (Comings et al., 1990; Leckman, 1993).
or facial movements, and vocalizations, such as throat-
The heredity and genetic underpinnings of TS and
clearing or utterances. The diagnostic criteria require the
associated disorders are a subject of active investigation
expression of involuntary tics defined as sudden, rapid,
(e.g. Pauls and Leckman, 1986; Pauls, 2003; Curtis et al.,
recurrent, non-rhythmic, stereotyped motor movements
2004; Abelson et al., 2005).
and vocalizations (APA, 1994). Both the expression of tics,
TS has been associated with a deficit in executive
and the effort expended in suppressing them, result in
function or cognitive control—i.e. the set of cognitive
marked disturbance in the individual's daily functioning.
processes that allow an individual to produce meaningful,
Pure cases of TS are the exception rather than the rule;
goal-directed behaviour by selecting relevant thoughts and
actions. In particular, deficits have been observed in
2007 The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License whichpermits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
C. L. Baym et al.
inhibitory control and cognitive flexibility, two components
PFC, resulting in an amelioration of symptoms later in life
of cognitive control (Bornstein and Baker, 1991; Johannes
(Gerard and Peterson, 2003).
et al., 2001; Watkins et al., 2005). However, these studies do
Consistent with the anatomical findings, functional
not conclusively demonstrate the presence of a cognitive
magnetic resonance imaging (fMRI) studies of TS have
control deficit, for several reasons. First, studies have not
always considered the comorbidity profiles of TS patients.
(e.g. Peterson et al., 2003; Frey and Albin, 2006; Marsh
Some researchers have found that TS patients who do not
et al., 2007). Disturbances in projections from PFC to the
additionally have OCD or another comorbid neurological
caudate nucleus or from caudate to other basal ganglia
disorder like ADHD are not impaired on tests of executive
structures are thought to be responsible for the inability to
function (Ozonoff et al., 1998; Como, 2001; Verte et al.,
suppress tics (Gerard and Peterson, 2003). To date, only a
2005). Second, it is a challenge to find medication-naı¨ve
few studies have examined brain activation of TS patients—
either adults or children—during performance of a
adults, perhaps) are likely to engage in compensatory
cognitive task (Johannes et al., 2001; Hershey et al., 2004;
strategies that diminish their deficits. Indeed, one study
Serrien et al., 2005; Marsh et al., 2007) that is unrelated to
found evidence for enhanced performance on a cognitive
tic generation or suppression (Stern et al., 2000; Bohlhalter
control task in patients with TS (Mueller et al., 2006).
et al., 2006).
Fourth, it may be that some cognitive control processes are
The first fMRI study involving children with TS was
impaired, whereas others are intact. As such, it is important
recently published by Marsh and colleagues (2007). In this
to determine which cognitive control processes, if any, are
study, children and adults with TS and healthy volunteers
deficient in TS.
performed a Stroop task during fMRI data acquisition. The
Widely characterized as a frontostriatal disorder, TS is
patients and typicals did not differ in terms of performance
believed to involve abnormalities in the neural brain
on this cognitive control task, but did differ in terms of
brain activation patterns. Among patients, stronger behav-
prefrontal cortex (PFC) and the striatum (Albin and
ioural Stroop interference effects were associated with
Mink, 2006). Clues regarding frontostriatal abnormalities
increased activation of dorsolateral PFC (DLPFC) and
in TS—or, more specifically, a disruption in cortico-
ventrolateral PFC (VLPFC), lenticular nucleus, thalamus
striatal-thalamic-cortical circuitry (CSTC; Butler et al.,
and mesial PFC. In contrast, healthy individuals exhibited
2006)—come primarily from anatomical studies in adults
increased activation in right VLPFC with better perfor-
and children (Gerard and Peterson, 2003; Pringsheim et al.,
mance on their task. Interestingly, within the patient group,
2003; Frey and Albin, 2006; Ludolph et al., 2006), positron
greater tic severity was associated with increased activation
emission tomography studies, primarily in adults (Chase
in DLPFC, possibly reflecting an ineffectual compensatory
et al., 1984; Baxter and Guze, 1992; Ernst et al., 1999;
mechanism (Marsh et al., 2007). While this prior study
Gilbert et al., 2006), magnetic resonance spectroscopy
does offer insight into the mechanisms of cognitive control
(DeVito et al., 2005), and neuroscientific research on
across children and adults with TS, it did not examine the
non-human animals (Saka and Graybiel, 2003). Recent
whole brain, leaving open the possibility that there may be
studies have shown promise for the use of deep brain
stimulation of several components of the basal ganglia in
Furthermore, as many of the patients (in particular the
the treatment of patients with severe TS (Mink et al., 2006).
children) were medicated, it remains unclear whether the
Peterson and colleagues (2003) conducted volumetric
differential patterns of activation observed between groups
analyses in a large sample, and showed reduced caudate
were attributable to Tourette syndrome itself or to changes
nucleus volumes in both children and adults with TS.
in brain structure/function as a result of medication.
Notably, smaller bilateral caudate volumes in childhood
A number of lines of evidence point to dysfunctional
have been shown to be predictive of tic severity and
dopamine neurotransmission in TS (Pringsheim et al.,
obsessive compulsive symptoms in adulthood (Bloch et al.,
2003; Albin and Mink, 2006). In particular, medications
2005). Additionally, other anatomical studies have shown
that block dopamine receptors are used to control tics, and
a variety of anatomical measures point to abnormal
(Ludolph et al., 2006), midbrain, potentially including
dopaminergic function in TS (Albin and Mink, 2006). It
dopaminergic nuclei (Garraux et al., 2006), and thalamus
is hypothesized that excess dopamine leads to an imbalance
(Lee et al., 2006). In contrast, smaller volumes in patients
of activity in the direct and indirect pathways through the
with TS have been found in the hippocampus (Lee et al.,
basal ganglia, resulting in involuntary movements via
2006). With respect to PFC volumes, the data have been
disinhibition of the motor thalamus (Albin and Mink,
more mixed (Peterson et al., 2001; Fredericksen et al.,
2006). However, the precise nature of the dopamine
2002). Based on the pattern of findings for PFC volumes in
dysfunction in TS is not yet understood. Some of the
children and adults with TS relative to controls, it has been
brain differences between adults with and without TS, such
hypothesized that children who learn to effectively suppress
as decreased availability of D2 receptors in those with TS
their tics during development show increased growth of
(Gilbert et al., 2006), may be indicative of compensatory
Cognitive control in Tourette syndrome
mechanisms counteracting the underlying disorder. Indeed,
were intentionally minimized on this task by the fact that
some of the differences observed between adults with and
participants had multiple seconds to prepare for an
without TS may be a result of long-term use of
upcoming trial, and that they were explicitly given the
medications, and/or the long-term consequences of volun-
rule at the start of each new trial. Nonetheless, we expected
tary and/or involuntary recruitment of compensatory brain
that children would have greater difficulty when switching
from one rule to the other than when employing the same
Several studies have found evidence of compensatory
rule as on the preceding trial. Based on prior behavioural
mechanisms in adults with TS: i.e. enhanced prefrontal
research (Watkins et al., 2005), we predicted that children
activation in TS patients relative to healthy adults, despite
with TS would exhibit magnified behavioural costs for
similar performance levels (Johannes et al., 2001; Hershey
Switch versus Repeat trials relative to typical children.
et al., 2004). Intriguingly, as noted previously, one study
Finally, the response selection manipulation compared
showed enhanced cognitive control in adults with TS,
Incongruent and Congruent trials, in which the two
possibly as a result of years of tic suppression (Mueller
potentially relevant features of a stimulus—its colour and
et al., 2006). If the compensatory developmental hypothesis
orientation—were associated with different responses or the
of Gerard and Peterson (2003) summarized above is
same response. Based on the prior behavioural research
correct, it would emphasize the point that it is imperative
described previously, we predicted that children with TS
to diagnose TS as early as possible, so as to provide
would exhibit magnified behavioural costs for incongruent
children with coping strategies that could lead to beneficial
versus congruent trials compared with typical children.
long-term brain plasticity and a better long-term prognosis.
The rule manipulation contrasted arbitrary S-R mappings
These studies provide a strong rationale for characterizing
brain anomalies—both anatomical and functional—in
Direction rule). Demands on rule representation were
paediatric patients as well as in adults.
minimal on this task, in that the currently relevant rule
In our event-related fMRI study, we sought to test for
was explicitly indicated on each trial. However, we still
differences between unmedicated children with TS and age-
expected that the Color rule would tax rule representation
matched typically developing children (referred to here as
more strongly than the Direction rule, because it relied on
typicals) in terms of performance and brain activation
newly learned S-R associations. We did not have any
associated with a cognitive control task. We devised a task
predictions regarding group differences in terms of rule
(Fig. 1A) that included manipulations of three separate
representation, but sought to test whether children with TS
aspects of cognitive control: (i) task-switching, or the ability
would exhibit magnified behavioural costs for Color versus
to properly update the currently relevant task information;
Direction trials relative to typical children.
(ii) response selection, or the ability to ignore competing
In terms of brain imaging analyses, we sought to test for
information to select between response options and (iii)
signs of hyperdopaminergic transmission in patients with
rule representation, or the ability to retrieve and use
TS, as indexed by increased activity in the substantia nigra
currently relevant response contingencies. By including
(SN) and/or ventral tegmental area (VTA), dopamingergic
three separate manipulations, we could assess whether
nuclei with neuromodulatory effects on widespread regions
children with TS were impaired on one or more of these
of the brain. These nuclei are located sufficiently close to
facets of cognitive control, and examine the neural
one another that they are difficult to distinguish from one
correlates of task performance. Based on the few behav-
another (Aron et al., 2004). Thus, rather than attempting to
ioural studies of cognitive control that have been conducted
examine the SN and VTA independently from one another,
in children with TS, we predicted that this group would
we sought to test whether the SN/VTA area would be more
have difficulty switching between tasks and selecting
strongly engaged by patients with TS.
between competing response alternatives.
With respect to the relationship between brain activation
The task was intended to be challenging, but not overly
and performance in TS, we entertained three possible
difficult, for children aged 7–13 (Fig. 1A). Prior to MRI
outcomes: namely, that unmedicated children with TS
scanning, participants were taught stimulus-response (S-R)
would (i) exhibit a deficit in cognitive control, associated
mappings based on ‘Direction' and ‘Color' rules. On
with specific differences in brain activation relative to
Direction trials, participants were to press a left button in
typicals; (ii) exhibit no cognitive control deficits and no
response to a leftward pointing stimulus, and to press a
differences in task-related brain activation, after taking into
right button for a rightward pointing stimulus. On Color
account other comorbidities, in particular ADHD or (iii)
trials, participants were to press a left button in response to
exhibit no deficits in performance on a cognitive control
a red stimulus, and a right button in response to a blue
task, but exhibit enhanced brain activation relative to
stimulus, or vice versa.
typicals, suggestive of the engagement of compensatory
The task-switching manipulation compared trials in which
the rule was different from that of the previous trial
A pathway between right inferior frontal cortex (IFC)
(Switch) to those in which the rule was the same as that of
and the right subthalamic nucleus (STN) has recently been
the previous trial (Repeat). Demands on task-switching
characterized in humans (Aron et al., 2007). Through this
C. L. Baym et al.
Fig. 1 Task design and behavioural data. (A) Participants were instructed to respond with a left or right button press to each stimulus,based on the relevant rule for that trial (Color or Direction). Variable ITIs (2 8 s) were interleaved between each trial. (B) Box-and-whisker plots of accuracy and RT showing min/max/first quartile/third quartile/median divided by activation for ConRep and IncSw, and bygroup. (C) Behavioural correlations between estimated IQ and accuracy on IncSw trials, separately for patients and typicals and betweentic severity and RT on IncSw trials for the patients only. RTs are reported for correct trials only. Medication naive patients are indicatedwith circle markers. Patients previously medicated for ADHD symptoms are indicated with triangle markers.
Cognitive control in Tourette syndrome
and/or other hyperdirect pathways to the basal ganglia,
motor inhibition could proceed rapidly, bypassing the
Apart from the 37 participants included in the study, eight
inhibitory indirect pathway through the basal ganglia
additional participants were excluded from the final analysis. Five
(Mink, 2001; Aron and Poldrack, 2006). We hypothesized
patients and one typical were excluded on the basis of excessive
that patients with TS might compensate for weakened basal
head motion during scanning (greater than 5 mm within a run),
ganglia control via increased engagement of a hyperdirect
one patient on the basis of poor task performance, and one typical
pathway. Thus, we sought to test the prediction that
on the basis of low estimated IQ.
children with TS would engage the STN more strongly thantypicals. Such a pattern would be consistent with a
Recruitment and screening
compensatory mechanism; in contrast, stronger STN
Children with TS were recruited via the Tourette Syndrome
activation in typicals than in patients with TS would be
Association based in the United States, clinical referrals, local
consistent with diminished activity in the indirect pathway
advertisements, physician referrals and through the University of
California at Davis. The diagnosis of TS was based on DSM-IV
dopamine transmission and stimulation of D2 receptors
criteria (APA, 1994) and established by: (i) a previous diagnosis of
(Mink, 2001). Like the SN/VTA, the STN is a small nucleus;
TS by a psychologist, psychiatrist, neurologist or behavioural
however, relying on coordinates from prior fMRI studies
paediatrician; (ii) clinical judgment (B.A.C.) and (iii) confirma-tion of the presence of motor and phonic tics by the Yale Global
(Aron et al., 2004, 2007; Aron and Poldrack, 2006), we
Tic Severity Scale (YGTSS). The parents of all the participants also
sought to test our theoretically motivated prediction that
completed a semi-structured interview, the Diagnostic Interview
there would be group differences in the STN area.
Schedule for Children (DISC; Shaffer et al., 2000) to determine theextent of symptomology across other related disorders (e.g. OCD,ADHD, anxiety).
Materials and Methods
Typically developing children were recruited through area
Inclusion and exclusion criteria
schools, fliers and recreational centres. Following initial contact,potential participants were screened via parent interview for the
Children aged 7–13 with TS and healthy age-matched controls
absence of neurodevelopmental disorders. Individuals with a
were recruited for participation in this study, and were
history of serious physical illness (e.g. endocrine, cardiovascular
compensated financially for their involvement. Children with
or neurological disorders) were excluded from enrollment in the
serious neurological, psychiatric or medical conditions, other than
study. The groups were not matched on the basis of intellectual
TS with or without comorbid ADHD or OCD, or with an
functioning (Table 1). After thorough explanation of the study
estimated IQ below 75 were not included in the study. Rather
was completed, informed written consent was obtained from
than considering OCD and ADHD as exclusion criteria for the
parents and verbal assent was obtained from all research subjects
patients, we included scores on standard measures of OCD and
prior to inclusion in the study. This study was approved by
ADHD as continuous variables in multiple regression analyses of
the Institutional Review Board of the University of California
performance and brain activation. Children who had taken
medication to treat tics were excluded from the study.
Each child underwent an extensive clinical evaluation prior toscanning by, or under the supervision of, paediatric neuropsychol-
The study included 18 native English-speaking 7–13-year-old
ogist (B.A.C.). Diagnostic testing was completed following
children with TS (M = 10.42; 15 males, 3 females), and 19 healthy,
informed consent procedures on the first of two visits. The
age-matched native English-speaking volunteers (M = 10.33; 11
Wechsler Abbreviated Intelligence Scale (WASI; Wechsler, 1999) was
males, 8 females). Children in the two groups did not differ in age
used as an estimate of IQ. This measure was administered to all
(P = 0.996). Although the two groups had different proportions of
participants, unless an IQ score from a more comprehensive
males and females, two-sample t-tests revealed no significant
measure had been recently completed (52 years). Children with a
performance differences between males and females (all P40.05).
score of 575 on the WASI were excluded from the study.
Three patients and one typical child included in the study were
On the first visit, each child completed a psychological
left-handed. One patient had a history of epilepsy, but was not an
assessment that included 15 subsections of the DISC (Shaffer
outlier relative to the other patients on any of our other measures.
et al., 2000), the YGTSS (Leckman et al., 1998), and the ChildYale-Brown Obsession and Compulsion Scale (CY-BOCS; Scahillet al., 1997). Additionally, parents were given the following
measures to complete at home, prior to the scanning visit: the
Sixteen out of 18 patients were medication-naı¨ve, as per parental
Behavior Rating Inventory of Executive Function (BRIEF; Gioia
reports. The other two children had taken atomoxetine (brand
et al., 2000), Conners' Parent Rating Scale-Revised (Short) (CPRS-
name StratteraTM) to treat ADHD symptoms. One child had
R:S; Conners, 2001), Child Behavior Checklist (CBCL; Achenbach
ended treatment approximately 1 month prior to testing; the other
and Rescorla, 2001), Social Communication Questionnaire (SCQ;
had been off atomoxetine for 40 h prior to testing. Behavioural
Rutter et al., 2003), Multidimensional Anxiety Scale for Children
and fMRI analyses performed with and without these two children
(MASC; March, 1999) and Parenting Stress Index (PSI; Abidin,
indicated that they were not outliers.
1995). More details regarding each of the assessments are provided
C. L. Baym et al.
Table 1 Results of psychological assessments
Social communication problems
Table of mean scores for assessment results, ordered from most to least significant difference between groups. P-values indicate level ofsignificance of unpaired comparisons between groups. Standard deviations are reported in parentheses. Test results are ordered from mostto least significant effect.
in the Supplementary Material. Questionnaires filled out at home
(ITIs) interspersed between them. The order of trial type
were properly and entirely completed for 29/37 participants (14
presentation and jittered fixation was determined using Optseq2,
patients and 15 typicals); for the remaining participants, 1–4 of
an optimizing program designed to allow for maximal efficiency
the questionnaires could not be scored.
in deconvolving trials from each condition and baseline activation(Dale, 1999). Jittered fixation lasted from 2 to 8 s and was
interspersed throughout the functional runs.
Participants were instructed on a trial-by-trial basis to use one oftwo visually presented rule cues (‘Color' or ‘Direction') to
determine the appropriate response for a given target stimulus
Prior to MRI scanning, children were introduced to the scanner
(Fig. 1A). The target stimuli were cartoons from the Disney movie
environment through the use of a mock scanner. They were asked
‘Finding Nemo'; the colour and orientation of these stimuli were
to lie down in the mock scanner, listen to prerecorded sounds of
manipulated in Adobe Photoshop CS2. Participants were taught
the pulse sequences, and practice lying still and making button
the relevant stimulus-response (S-R) mappings for the two rules
presses. After participants were familiarized with the scanning
prior to scanning (Fig. 1A). On Direction trials, participants were
procedure, they learned S-R mappings for the Color and Direction
to press a left button in response to a leftward pointing stimulus,
rules, and practiced applying them both on paper and in a 3 min
and a right button for a rightward pointing stimulus. On Color
computerized session. During this training session, participants
trials, half of the participants were taught that a red stimulus
provided 1 ml saliva samples at 20 min intervals following initial
indicated a left-button press and a blue stimulus indicated a right-
exposure to the mock scanner as part of a study on the biological
button press, and half were taught the reverse S-R mapping.
response to stress in patients with TS.
Participants used the index and middle fingers of their right handto respond.
MRI data acquisition
Imaging was performed using an 8-channel phased-array coil on a3-Tesla Siemens Trio MRI scanner (Siemens Medical Solutions,
The experimental task followed a 3 2 factorial design, enabling
Erlangen, Germany) at the University of California at Davis
the assessment of independent contributions of rule difficulty,
Imaging Research Center (Sacramento, CA). Participants viewed
task-switching and interference suppression. The rule difficulty
visual stimuli on a projection screen using an angled mirror and
manipulation contrasted arbitrary S-R mappings learned on theday of testing (Color) with previously learned S-R mappings
responded using a button box in the right hand.
After acquisition of a T2 localizer scan, four functional runs
(Direction). The task-switching manipulation compared trialsinvolving a rule switch relative to the prior trial (Switch) with
were collected, each 4.5 min long (TR = 2000 ms, TE = 25 ms, 34
those in which the rule was the same as on the previous trial
axial slices, no interslice-gap, 3.4 3.4 4 mm3 voxels, flip
(Repeat). The interference suppression manipulation compared
angle = 90, field of view = 220 mm, 135 volumes per run).
trials in which two features of a stimulus were associated during
training with different responses (Incongruent) or the same
Correction (3D-PACE) sequence was used to minimize motion
artifacts during fMRI data acquisition. The 3D-PACE sequenceprospectively adjusts scan parameters throughout a run on thebasis of real-time assessment of head motion (Siemens Medical
Solutions; Thesen et al., 2000). Four volumes from the start of
On each trial of the event-related fMRI paradigm, a fixation cross
each functional scan were removed from analysis to account for
appeared for 200 ms, followed by an instructional cue (‘Color' or
magnetic field equilibration. Following the functional scans, high-
‘Direction') for 2300 ms, and a target stimulus for 1500 ms
resolution T1 MPRAGE anatomical images were acquired.
(Fig. 1A). Color and Direction trials were pseudorandomly
Across the four functional scans, participants completed 48
ordered throughout a scan, with variable intertrial intervals
trials of each of the following conditions: Congruent Repetition
Cognitive control in Tourette syndrome
(ConRep), Congruent Switch (ConSw), Incongruent Repetition
basal ganglia and thalamus. Voxel-based analyses were restricted to
(IncRep) and Incongruent Switch (IncSw) trials. For each of these
voxels within two anatomical masks created in the MarsBar
conditions, an equal number of trials involved the Color rule and
toolbox for SPM2 (Brett et al., 2002): a lateral prefrontal mask
the Direction rule. Each scan included six trials of each of the
including 4816 voxels (bilateral B.A. 6, 8, 9, 10, 44, 45, 46, 47),
eight resulting trial types. The order of the functional scans was
and a subcortical mask including 1475 voxels (bilateral caudate,
counterbalanced across subjects.
putamen, globus pallidus and thalamus). We report results forcontiguous clusters of 5 or more voxels within one of these masks
meeting an uncorrected threshold of P50.005. At this threshold,41 cluster would be expected by chance alone within either the
Data were analysed using SPM2 (Wellcome Department of
prefrontal or subcortical mask.
Cognitive Neurology, London, UK). Functional volumes from
Region-of-interest (ROI) analyses were performed to further
each participant were corrected for interleaved slice acquisition,
characterize the activation profile across all four task conditions
and were translated using a rigid-body motion correction.
for regions of a priori interest. ROIs in lateral PFC were defined
Functional volumes were normalized to an EPI template using
functionally from a voxel-based t-test (patients4typicals for all
correct trials4baseline). ROIs in SN/VTA and nucleus accumbens
3 3 4 mm3 voxels. The SPM EPI template has been validated
were defined functionally from a voxel-based multiple regression
for use in normalization of brain volumes for children aged 56
analysis used to identify activations positively correlated with
(Burgund et al., 2002; Kang et al., 2003). Finally, functional
YGTSS. For basal ganglia structures and the thalamus, we used
volumes were smoothed using an 8 mm full-width at half
anatomical ROIs from the MarsBar toolbox. Mean parameter
maximum isotropic Gaussian kernel.
estimates for a given ROI were computed for each participant and
To examine individual movement, we computed root mean
condition, and were submitted to repeated measures ANOVAs and
square (RMS) values for translation for each participant across
post-hoc comparisons. For anatomical ROIs, both left- and right-
sided regions (e.g. left and right putamen) were submitted to
(M = 0.398; range = 0.567). As expected, patients exhibited more
analysis, and hemisphere was included as a within-subject variable.
head movement than typicals (t = 2.82, P50.009). However,
In total, eight different regions from lateral PFC, basal ganglia
multiple steps were taken to ensure that the fMRI data were not
and the thalamus were submitted to ROI analyses (Table 2).
compromised by excessive head motion, as noted above. First, we
Taking into account this number of ROIs, the corrected statistical
used a 3D-PACE prospective acquisition sequence during data
threshold would be P50.00625 with an alpha of 0.05. None of
acquisition, so as to minimize the impact of head motion on our
our ROI-based results met correction for multiple comparisons.
results. Secondly, we excluded participants for whom head motion
However, the pattern of results observed in these ROIs were highly
was greater than 5 mm within a run. Finally, we included motion
consistent with our predictions, and are featured here as initial
regressors as covariates of no interest in the analysis of individual
findings regarding the neural mechanisms of cognitive control in
unmedicated children with TS.
Single-subject fMRI analysesStatistical analyses were performed using the general linear model
in SPM2. FMRI time-series data were modeled as a series of
events, time-locked to the onset of each trial, and were convolvedwith a canonical hemodynamic response function. The resulting
The TS group differed from the typical group in terms of
functions were used as covariates in a general linear model, along
tic severity, as measured by YGTSS. Indeed, this was the
with a basis set of cosine functions that high-pass filtered the data,
factor that most prominently distinguished the two groups
as well as a covariate for session effects. Six motion regressors
(Table 1). However, the groups differed in other ways as
(indicating amount of translation and rotation in the x, y and z
well. Listed in order from strongest to weakest group
dimensions for each 2 s TR) were included in the analysis as
differences, the TS group also scored higher on a parental
covariates of no interest. The least-squares parameter estimates of
assessment of executive dysfunction (BRIEF), Attention
height of the best-fitting synthetic hemodynamic response
Deficit Hyperactivity symptoms (Conners'), Obsessive-
function for each condition were used in pair-wise contrasts,
Compulsive symptoms (CY-BOCS), behavioural problems
and the resulting contrast images, computed on a subject-by-
(CBCL), social communication problems (SCQ) and
subject basis, were submitted to group analyses. Incorrect trialswere modeled separately, and were not included in the fMRI
anxiety levels (MASC). Although the patients with TS in
our sample were high-functioning (mean estimated IQscore SD: 106 14), they had lower estimated IQ scores
Group fMRI analyses
than our sample of typicals. Indicative of the fact that TStakes a toll on the family rather than merely the individual,
Several analytic approaches were used to characterize differences
parents of children with TS scored higher on a parental
in brain activation between children with and without TS. First,
stress index than parents of typical children (mean SD for
voxel-based two-sample t-tests were used to directly compare thegroups. Second, voxel-based multiple regression analyses were
parents of patients versus typicals: 76 21 versus 57 16;
used to assess the effects of various factors both within and across
groups. For these two types of analyses, we limited the search
Because of the strong prevalence of obsessive-compulsive
space to regions for which we had specific predictions: lateral PFC,
and attention-deficit symptoms in patients with TS, and
C. L. Baym et al.
Table 2 Results of multiple regression analyses conducted on ROIs
Bilateral globus pallidus
YGTSS R2 = 0.27, P50.04
YGTSS R2 = 0.32, P50.02
YGTSS R2 = 0.39, P50.009
EstIQ R2 = 0.34, P50.017
BRIEF R2 change = 0.177, P50.033
YGTSS R2 = 0.32, P50.02
EstIQ R2 = 0.36, P50.011
EstIQ R2 = 0.46, P50.003
YGTSS R2 = 0.39, P50.007
Estimated IQ, YGTSS, CY-BOCS, Conners', MASC, BRIEF and age were included as independent variables. All correlations were in thepositive direction. No hemispheric differences were observed in the regions noted as bilateral; average R2- and P-values are reported forvariables that account for a significant portion of the between-subject variance of activation for an ROI (P50.05).
because these symptoms are not always severe enough to
placed increased demands on both task-switching and rule
meet full diagnostic criteria for OCD or ADHD, we
purposefully used continuous measures of ADHD and
Taken as a whole, the two groups did not differ
OCD rather than categorical ones. However, using con-
significantly from one another in performance (accuracy:
servative cut-offs (t-score 570 for the Conners' and raw
F1,35 = 1.6, P = 0.21, RTs: F1,3551, P = 0.99), and there were
score 5 8 for the CY-BOCS), seven patients scored in the
no significant interactions involving Group. However,
clinical range for TS + OCD, one for TS + ADHD and two
because our TS group exhibited a range of tic severity,
for TS + OCD + ADHD. The remaining eight patients and
from mild to marked (total YGTSS scores ranged from
all typical participants scored in the normal range on both
8 to 31), we sought to examine more closely the relation-
the Conners' and CY-BOCS.
ship between tic severity and task performance.
Multiple regression analyses of behavioural
Repeated-measures ANOVAs were performed on accuracy
and response time (RT) data from the Nemo task. We
We performed stepwise multiple regression analyses to
examined the between-subjects effect of Group (Patients,
examine the effects on performance of age, estimated IQ
Typicals), and the within-subjects effects of Congruency
and total scores on the YGTSS, BRIEF, Conners', MASC
(Congruent, Incongruent), Switching (Switch, Repeat) and
and CY-BOCS. These regression analyses were performed
Rule (Color, Direction).
separately for accuracy and RTs on the more difficultcondition in each of the three task manipulations:
Effects of task manipulations on
Incongruent, Color and Switch trials. Taking into account
performance across all participants
the number of whole-brain regressions computed (four-
Across groups, accuracy and RTs were affected by each of the
teen), the corrected statistical significance was P = 0.0036
three task manipulations (Fig. 1B). Children performed worse
with an alpha of 0.05. Correlations that met correction for
when they had to switch from one rule to another (Switch
multiple comparisons are noted with an asterisk (). Given
versus Repetition trials; accuracy: F
the dearth of behavioural data on cognitive control
1,35 = 71, P50.001; RTs:
paradigms for unmedicated children with TS, correlations
1,35 = 48, P50.001). Additionally, performance was worse
when the irrelevant dimension of the stimulus was associated
that did not meet correction for multiple comparisons are
with the opposite response from the relevant dimension
also listed below.
Across all children, accuracy was positively correlated with
P50.001; RTs: F1,35 = 30, P50.001). Finally, performance
IQ for Incongruent trials (R = 0.50; P50.003), Switch trials
was worse for the arbitrary rule than for the non-arbitrary
(R = 0.46; P50.006), and Color trials (R: 0.37; P50.03)
one (Color4Direction trials; accuracy: F1,35 = 43, P50.001;
(Fig. 1C). Additionally, Switch accuracy was correlated with
age (R2 change = 0.13; P50.02). A stronger correlation
(F1,35 = 18, P50.001) and
between accuracy and estimated IQ across the entire group
Congruency Rule (F1,35 = 24, P50.001) were observed in
was observed for IncSw trials (R = 0.54; P50.0001) than for
terms of accuracy. In terms of RTs, there was a significant
ConRep trials (R = 0.282; P50.05). RTs were positively
interaction of Congruency Rule (F1,35 = 13, P = 0.001).
correlated with Age for Incongruent trials (R = 0.40;
These results indicate that the congruency manipulation
P50.02), and for Switch trials (R = 0.35; P50.05), but not
Cognitive control in Tourette syndrome
Fig. 2 Voxel-based activation across all correct trials relative to fixation, shown across all participants (P50.005, 5 -voxel extent, withinlateral prefrontal and subcortical masks). Regions within the lateral PFC mask are shown in magenta and regions within the subcorticalmask are shown in cyan. Top row: axial slices for z-coordinates of +48, +32 and 0, and coronal slice for y-coordinate of
sagittal slices for x-coordinates of
17 and +42. Numbers correspond to approximate Brodmann areas. C = Caudate nucleus.
for Color trials (P40.05). Thus, performance on Incongruent
and Switch trials, but not Color trials, was correlated with IQand age across the whole group.
Task-related activation across groups
Focusing on the patient group only, we again found that
As a first pass, we conducted voxel-based contrasts within
accuracy was positively correlated with IQ for Incongruent
our anatomical masks to identify regions in lateral PFC,
trials (R = 0.55; P50.023), and Switch trials (R = 0.61;
basal ganglia and/or thalamus that were generally engaged
P50.009), but not for Color trials (all P40.05). RTs
during task performance across the two groups, collapsing
were positively correlated with tic severity (as measured by
across conditions (Fig. 2). For correctly performed trials
YGTSS) across the TS group for Incongruent trials
relative to fixation, clusters of activation included bilateral
(R = 0.51; P50.037) and Switch trials (R = 0.52; P50.04),
middle and inferior frontal gyri (BA 6, 8, 9, 10 and 46), and
but not for Color trials (P40.05) (Fig. 1C). The strongest
bilateral caudate nucleus.
correlation between task performance and YGTSS wasobserved for the IncSw trials (R = 0.53, P50.02); a slightlyweaker
Comparisons between patients and controls
(R = 0.42, P50.04).
Voxel-based two-sample t-tests were performed to identify
regions in PFC, basal ganglia and/or thalamus that were
Conners' and BRIEF) were not significantly correlated
engaged differentially by the two groups. No regions were
with RTs for the TS group (all P40.05). This latter finding
engaged more strongly by typicals than patients. As
does not necessarily mean that performance on this task is
predicted, greater activation for patients than typicals was
correlated with TS but not with other disorders, such as
observed in lateral PFC. Two small clusters were located in
ADHD or OCD; rather, it is likely to be related to the fact
left middle frontal gyrus (MFG; BA 8, 46) and left superior
that we recruited children with a primary diagnosis of TS.
frontal gyrus (SFG; BA 9).
The exclusion of the two participants who had been
Follow-up ROI analyses revealed that the left SFG cluster
medicated for ADHD symptoms only slightly weakened
was engaged relative to baseline by patients but not typicals,
the behavioural correlations with YGTSS for Incongruent
in a manner that was insensitive to our task manipulations
trials (R = 0.44) and Switch trials (R = 0.45). In summary,
(all P40.13). In contrast, the left MFG cluster exhibited
we found that (i) overall, better performance on the
significant effects of both switching (F1,35 = 5.4, P = 0.027)
Incongruent and Switch trials was associated with higher IQ
and rule (F1,35 = 4.3, P = 0.046) (Fig. 3). Thus, patients
and older ages and (ii) children with TS who responded
exhibited overall greater activation in two focal regions of
most slowly on Incongruent and Switch trials tended to
PFC, one of which was specifically associated with rule
have the highest tic severity.
representation and task-switching.
C. L. Baym et al.
accumbens (Fig. 4; Supplementary Table 1). The SN/VTA,an a priori predicted region that was not included in themask of subcortical regions created with Marsbar, alsoexhibited a positive correlation with YGTSS. These findingsindicate that patients with more severe TS symptomsexhibited heightened task-related activation in a number ofregions in the CSTC loop.
To test whether the regions identified as showing a
positive correlation with YGTSS could have been correlatedinstead with ADHD or OCD symptoms, an additionalmultiple regression analysis was performed on the fMRIdata, including YGTSS, Conners', CY-BOCS and IncSwaccuracy as regressors. In effect, none of the activationsidentified as being associated with tic severity could beattributed to either OCD or ADHD severity. Further, theexclusion of the two children who had been medicated forADHD symptoms did not change the set of regions foundto be correlated with YGTSS.
ROIs in SN/VTA and nucleus accumbensAs noted previously, we sought evidence suggestive ofelevated dopaminergic activity in patients relative tocontrols. To this end, ROI analyses were performed tofurther characterize the activation profile and groupdifferences in the nucleus accumbens and SN/VTA area,as identified from the positive correlation with YGTSS(Fig. 5). To isolate the SN/VTA area from a larger cluster ofactivation, we masked the cluster with 5 mm spherescentered on MNI coordinates of 9,
these regions were identified from a positive correlation ofIncSw4fixation brain activation with YGTSS among
Fig. 3 Lateral prefrontal ROI (BA 8/46;
48, 23, 24; 16 contiguous
patients, multiple regression analyses were performed to
voxels) derived from all correct trials 4 fixation for patients 4typicals. Box-and-whisker plot showing min/max/first quartile/third
determine whether additional behavioural variables modu-
quartile/median divided by activation for ConRep and IncSw, and by
lated activation in either the patient or typical group
(Table 2). The following variables were included in theregression analyses: YGTSS, CY-BOCS, Conners' andBRIEF, as well as three additional covariates of no interest:
Regions exhibiting correlations with tic
MASC, estimated IQ and age.
severity within the patient group
In addition to being correlated with YGTSS, activation in
Because the patient group varied considerably in terms of
bilateral SN/VTA on IncSw trials was also correlated across
tic severity, we sought to identify brain regions in PFC,
patients with scores on the BRIEF, a parental-report
basal ganglia and/or thalamus for which level of activation
measure of executive dysfunction, such that patients with
on the challenging Incongruent Switch trials was either
higher scores—indicative of worse executive function—
positively or negatively correlated with tic severity. To this
engaged this region more strongly (right: R2 change = 0.186,
end, a multiple regression analysis was performed in SPM,
P50.02; left: R2 change = 0.17, P50.05; Fig. 5). Although
including YGTSS scores as the covariate of interest, and Age
SN/VTA activation was positively correlated with both
and Incongruent Switch accuracy as covariates of no
YGTSS and BRIEF, scores on these two questionnaires were
interest. No regions were observed for the negative
not correlated with one another (R2 = 0.009). For typicals,
correlation with YGTSS. In contrast, several regions
by contrast, greater SN/VTA activation was associated with
within our anatomical masks were engaged more strongly
as a function of higher tic severity, including premotor
P50.03). Thus, greater SN/VTA activation was associated
cortex (bilateral BA 6), superior frontal gyrus (left BA 9,
with greater tic severity and executive dysfunction in the
right BA 8), inferior frontal gyrus pars triangularis (right
patient group, but higher intellectual functioning in
BA 45), middle frontal gyrus (left BA 9, right BA 8, 46),
the typical group. In contrast to SN/VTA, nucleus accumbens
Cognitive control in Tourette syndrome
Fig. 4 Regions correlated with tic severity (YGTSS) for patients during performance of IncSw trials (covariates of no interest: IncSwaccuracy and age). Clusters of activation within the lateral prefrontal mask are shown in magenta, and clusters within the subcortical maskare shown in cyan. Within the masks, clusters are shown if they met a statistical threshold of P50.005 with a 5 -voxel extent. Top row:sagittal slices for x-coordinates of
52, 14 and +18. Lower row: axial slices for z-coordinates of +64, +32, 0 and
8. Numbers correspond
to approximate Brodmann areas. Th = thalamus; P = putamen; NA = nucleus accumbens.
Fig. 5 Bilateral ROIs in the SN/VTA are shown (spheres with 5 mm radius centered at 9,
8). Left graph: correlation plot for tic
severity versus right SN/VTA parameter estimates for patients demonstrating that increased tic severity is positively correlated withactivity in this region. Right graph: correlation plot for executive dysfunction (BRIEF) versus right SN/VTA parameter estimates in thepatient group.
C. L. Baym et al.
activation was not correlated with other variables; higher
conditions (ADHD, OCD or other anxiety disorders or
levels of nucleus accumbens activation was associated only
conduct disorders). The finding that children with more
with increased tic severity.
severe TS have greater difficulty than their peers whenforced to switch between tasks or select between competingresponses underscores the point that TS is not simply a
ROIs in basal ganglia and thalamus
movement disorder, but a cognitive one as well.
Anatomical ROI analyses were conducted on regions of the
Children with TS may compensate for underlying
basal ganglia (caudate nucleus, putamen and globus
difficulties with cognitive control. Consistent with this
idea, we observed that children with TS, particularly those
Additionally, because of our predictions relating to the
with greatest tic severity, engaged lateral PFC more strongly
STN, we conducted an ROI analysis for a region in the STN
than typically developing children. This finding is consistent
area (Fig. 6B), defined anatomically based on the studies of
that of Marsh and colleagues (2007), who reported
Aron and Poldrack (2006, 2007).
increased activity in bilateral PFC (left BA 9/46, 10 and
For each ROI, we compared activation values between
right BA 45, 10) with increasing tic severity across a large
groups, separately for IncSw and ConRep trials (Fig. 6 for
sample of children and adults. Several studies have provided
plots of putamen, thalamus and STN area). These plots
evidence of compensatory prefrontal activity in adults with
revealed greater individual variability in the TS group than
TS (Johannes et al., 2001; Hershey et al., 2004); the present
the typicals, particularly on IncSw trials. We then
study is suggestive of the early stages of a compensatory
conducted multiple regression analyses for these regions,
mechanism present already in childhood and in the absence
to identify factors that could account for the large
of tic medication. The possibility that this enhanced PFC
individual differences in activation observed for IncSw
recruitment is part of a compensatory mechanism, rather
trials in the patients. These analyses included YGTSS,
than being a consequence of heightened dopaminergic
CY-BOCS, Conners', MASC, BRIEF, estimated IQ and age
activity in TS, is bolstered by our finding of increased
as independent variables, and average parameter estimates
activation in the STN (an inhibitory nucleus linked to the
for ConRep and IncSw as dependent variables. These
ability to suppress inappropriate responses) as a function of
tic severity, as described below.
because of the number of regressors included. However,
While the current data suggest that children with TS only
we sought to test the specific prediction that YGTSS was
weakly engaged compensatory mechanisms, more dramatic
correlated with activation in the ROIs, specifically or most
compensation may be observed over development or with
prominently on IncSw trials; the other regressors were
included to ensure that our findings were not misattributed
Our fMRI data revealed that tic severity scores were
to tic severity.
strongly associated with elevated activation in a number of
These ROI analyses revealed that tic severity among
brain regions aside from lateral PFC. Notably, these
patients was positively correlated with IncSw activation in
correlations were observed primarily for the most cogni-
bilateral putamen and thalamus (Table 2), as well as in the
tively challenging trials (Incongruent Switch), strongly
right STN area. This finding for the right STN ROI is
suggesting that they are not the result of a confound,
consistent with the results of the regression with YGTSS
such as increased movement artifacts in the TS group.
reported above. Additionally, bilateral STN activation in the
Rather, these results indicate that children with TS, in
typical group was positively correlated with IQ (averaged
particular those with higher tic severity, engage a number of
across hemispheres; R2 = 0.43, P50.007). No significant
regions more strongly than do typical children when asked
correlations were observed for ConRep activation in these
to perform a cognitively challenging task. Below we discuss
regions, or for the caudate or globus pallidus.
four sets of brain regions for which a positive correlationwas observed with tic severity.
First, greater tic severity was correlated with stronger
activation of the SN/VTA, consistent with the dopamine
Overall, the children with TS in our study performed the
hypothesis of TS (Nomura and Segawa, 2003; Yoon et al.,
cognitive control task as well as age-matched children.
2007; Fig. 7). To our knowledge, this is the first functional
However, our sample included children with a range of tic
brain imaging study to provide evidence of elevated
severity. Our behavioural data revealed that greater tic
activation in the SN/VTA, although this finding fits well
severity among patients was associated with dispropor-
with other results, such as the PET finding of higher [18F]
tionate slowing of responses in both the switching and
fluorodopa accumulation in the caudate nucleus of children
response selection manipulations, but not the rule manip-
with TS than typicals (Ernst et al., 1999).
ulation. Unlike prior studies examining performance of
Second, tic severity was positively correlated with
patients with TS on cognitive tasks, we have shown that this
activation of regions involved in the direct pathway through
cognitive deficit can be attributed to TS, rather than to the
the basal ganglia (striatum, globus pallidus interna,
symptoms of any of the most common comorbid
thalamus and motor cortex). These findings provide
Cognitive control in Tourette syndrome
Fig. 6 (A) Subcortical ROIs in the right basal ganglia and thalamus. C = caudate; P = putamen; GP = globus pallidus; Th = thalamus. Box-and-whisker plots for right putamen and thalamus, showing min/max/first quartile/third quartile/median divided by activation for ConRep andIncSw, and by group. Plots for maximally active voxel in this ROI from IncSw-fix correlated with YGTSS (additional regressors: IncSwAccuracy and age). (B) ROI of STN, including box-and-whisker plots and correlation plot.
support for the idea that TS involves an imbalance between
mesoaccumbens pathway (Saka and Graybiel, 2003; Albin
the direct and indirect pathways, whereby excess dopamine
and Mink, 2006). It should be noted that our results
leads to elevated activity in the direct pathway through
provide evidence for elevated mesolimbic activity as a
stimulation of D1 receptors, resulting in unchecked move-
function of tic severity specifically during performance of
ments via disinhibition of the motor thalamus (Fig. 7). The
the most cognitively challenging trials, and are therefore
disinhibition of motor pathways in TS is nicely illustrated
indicative of transient rather than sustained elevation of
by the observation that tic severity was positively correlated
mesolimbic activity in TS (this same observation holds for
with regions in the corticospinal tract, including primary
the other regions whose activation levels were correlated
with tic severity). Even though our study does not focus on
Third, we showed that tic severity was positively
tic production per se, our findings provide insight into the
correlated with activity in the nucleus accumbens. Given
mechanism by which spontaneous motor acts may be
the role of the nucleus accumbens in the reinforcement of
reinforced in TS.
behaviour, this finding suggests that tics, as habitual motor
Finally, tic severity was positively correlated with
activation of the STN, consistent with our prediction that
C. L. Baym et al.
Supplementary materialSupplementary material is available at Brain online.
AcknowledgementsThis study was supported by a Merck Scholarship in theBiology of Developmental Disorders. Additional support forBlythe A. Corbett was provided by a mentored clinicalresearch award NIMH K08 MH072958. We thank J. Pinter,MD for clinical referrals, M. Souza, S. Donohue andR. Libove for assistance with data collection and analysis,D. Galik for participant recruitment, C. Wendelken forcontribution to the experimental design and analysis code,
Fig. 7 Model of CSTC pathways affected in TS. Neural circuitry
F. Sharp for collaboration on a larger Tourette syndrome
showing dopaminergic, GABAergic and glutamatergic pathways
project, and M. D'Esposito, B. Voytek, R.Cools and R. Ivry
through the basal ganglia. The current study supports the
for helpful feedback. Funding to pay the Open Access
hypothesis that patients exhibit increased activity in the directpathway as well as increased compensatory activation of the
publication charges for this article was provided by a John
hyperdirect pathway (both pathways bolded). The indirect pathway
Merck Scholarship in the Biology of Developmental
is shown with dotted lines. Arrows indicate excitatory connections
Disabilities in Children.
and circles indicate inhibitory connections.
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AUS KLINISCHER UND Petra Vetter Kontakt e-mail: [email protected] Inhalt Seite 2. Zur Begrifflichkeit.3 3. Probleme der diagnostischen Abklärung.4 3.1. Erklärungsansätze.4 3.2. Methoden.5 3.4. Conners Skala.5 4. Therapeutische Ansätze.6 4.1. Pädagogische Maßnahmen.6 4.2. Psychotherapien.6 4.3. Medikamentöse Behandlung.6
Elschner et al. BMC Veterinary Research 2014, 10:283http://www.biomedcentral.com/1746-6148/10/283 Isolation of the highly pathogenic and zoonoticagent Burkholderia pseudomallei from a pet greenIguana in Prague, Czech Republic Mandy C Elschner1*, Jan Hnizdo2, Ivonne Stamm3, Hosny El-Adawy1, Katja Mertens1 and Falk Melzer1 Background: Melioidosis caused by Burkholderia (B.) pseudomallei is an endemic zoonotic disease mainly reportedfrom northern Australia and Southeast Asia. In Europe, cases of human melioidosis have been reported only frompatients travelling to endemic regions. Besides humans, B. pseudomallei has a very broad host range in domesticand wild animals. There are some reports about importation of B. pseudomallei-infected animals from endemicareas into Europe. The present report describes the first case of B. pseudomallei infection of a pet iguana in Europe.