Journal of Psychosomatic Research 67 (2009) 575 584

Review article

Functional neuroimaging in Tourette syndrome

Hugh Rickards
Department of Neuropsychiatry, Birmingham University and BSMHFT, Birmingham, United Kingdom
Received 24 April 2009; received in revised form 24 June 2009; accepted 28 July 2009

Abstract
Functional neuroimaging of neuropsychiatric disorders is a
complex discipline requiring skills in medical science, philosophy,
and technical physics. This review first examines the broad
categories of functional imaging studies that have been utilized in
this area, comparing the strengths and weaknesses of each
approach. This review then looks at much of the available

literature on functional imaging in Tourette syndrome (TS) and

provides a synthesis of data. The review will also examine the
different methodologies employed and will suggest which
methodologies are most likely to lead to elucidation of the
pathophysiology of TS and related conditions.
2009 Elsevier Inc. All rights reserved.

Keywords: fMRI; Functional neuroimaging; PET; Tourette syndrome

Comparing the different approaches utilized in the

functional imaging of TS
Studies probing specific neurotransmitter systems
Studies of this type can utilize single photon emission
computed tomography (SPECT) or positron emission
tomography (PET) procedures with ligands that bind to
specific receptors in the brain. An example of this is the
use of [ 11 C]raclopride to examine the function of
dopamine receptors. A variety of neurotransmitter systems
have been examined, but most of the studies have focused
on the dopamine and serotonin (5HT) systems. The
advantage of probing specific neurotransmitter systems is
that the technique has the potential to be relatively
sensitive and specific, particularly if the disorder in
question is related to a specific neurotransmitter system
(such as dopamine in Parkinson's disease). However, no
clear single neurotransmitter system has so far been clearly

Department of Neuropsychiatry, Birmingham and Solihull Mental

Health Foundation Trust, Barberry Building, 25 Vincent Drive, Edgbaston,
Birmingham B15 2FG, UK.
E-mail address: hugh.rickards@bsmhft.nhs.uk.
0022-3999/09/$ see front matter 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.jpsychores.2009.07.024

identified in TS by cerebrospinal fluid and plasma studies.

There is a response to dopamine antagonists, but this does
not necessarily implicate the dopamine system directly.
Participants in these studies are exposed to small amounts
of ionizing radiation.
Region-of-interest studies
Studies of this type can use SPECT or PET procedures.
The aim is to examine regional brain activity, usually in
relation to glucose metabolism or blood flow. Some studies
have focused on specific regions of the brain that have been
implicated in the pathogenesis of TS (for instance, the
striatum), and other studies have used standard regions of
interest that effectively cover the whole brain. Currently, the
spatial and temporal resolutions of these types of scan are
poor when compared to those of MRI. This leads to
problems with signals from adjacent areas to the region of
interest and problems with averaging of intraregional
differences (for instance, the striatum may contain different
systems, some of which are overactive and some of which
are underactive. The overall function of this area may then
appear to be normal in a region-of-interest study). There
is a small exposure to ionizing radiation in both PET and
SPECT procedures.

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H. Rickards / Journal of Psychosomatic Research 67 (2009) 575584

Types of imaging technique

PET versus SPECT
PET has a resolution greater than that of SPECT
(although PET's resolution is poor compared to that of
MRI). However, radionuclides in PET are expensive to
produce and do not last long (shorter half-life). PET scanners
are not so readily available. Some paradigms require
radionuclides with a longer half-life, making SPECT a
more appropriate investigation tool in some cases. Technetium-99m ( 99m Tc) hexamethylpropyleneamine oxide
(HMPAO) SPECT produces differentiation between gray
matter and white matter and has been shown to reflect
cerebral metabolism in other conditions such as epilepsy [1].
Functional MRI (fMRI) studies
fMRI utilizes the differential magnetic properties of
blood flow to generate information about functions in
specific brain regions.
MRI has generally better temporal and spatial resolutions
than PET or SPECT. However, MRI cannot currently
analyze specific receptor systems. Because of the nature of
image acquisition in fMRI, regions or systems of interest
normally have to be activated using a specific paradigm,
comparing the active state to the resting state. However,
fMRI also has the capacity to examine functional connectivity between brain regions, particularly by looking at
correlations between activities in one region and another.
This potentially powerful methodology relies on relatively
complex mathematics and, often, on multiple comparisons.
The idea of a resting state can be problematic in TS,
as a person is usually ticking or suppressing tics. This has
been addressed in at least one functional imaging study by
using Stage 2 sleep as resting state, creating a number of
logistic problems.
Activation tasks require the participant to activate a part
of the brain that is somehow implicated in the pathophysiology of the disease. Activities may include performing
tic-like voluntary movements, voluntary tic suppression,
performing tics themselves, or stimulation of a specific
system or brain region using either drugs or cognitive tasks,
such as the Stroop test.
Particular problems with the functional imaging of patients
with TS
Head movements in the scanner can be problematic for all
types of brain imaging. Waxing and waning of tics over a
short time can also lead to difficulties. HMPAO is useful as it
is taken up rapidly (so you can measure the tics over the short
period of HMPAO uptake). It remains in the brain without
redistribution long enough to get the person in the scanner,
and you could even give the person a sedative at that time to
reduce any movement artifact.

The problem with examining the function of the brain at

a single point in time in TS is that any change in function
might be consequential rather than causal. Changes in brain
function may also be epiphenomena. TS is a complex
condition, and tics may involve a number of brain
processes, including premonitory sensation, awareness of
premonitory sensation, attempts to suppress, thinking about
suppression, preparation for movement, the tic itself, and
relief of premonitory sensation. This list only includes
those brain functions that have conscious components.
There are likely to be a range of brain functions related to
tics that have no conscious component and about which we
have little knowledge. Thus, functional changes in the brain
may be demonstrating the TS pathology itself or may
represent the process of tic generation and its accompanying phenomena.
These processes are likely to overlap and can take
variable amounts of time (in some cases, the whole process
can be completed in well under a second). Paradigms for
functional neuroimaging studies need to take these factors
into account.

Summary of recent studies

Studies probing particular neurotransmitter systems
Ligand studies aim to use a radioactive compound that
binds to a specific receptor in order to examine the function
of that receptor system.
The first ligand-based studies in TS were aimed at the
dopaminergic system. This system was targeted for two main
reasons: dopamine was implicated in TS because of response
to treatment, and it was technically possible to study the
dopaminergic system. In addition, a single postmortem study
implicated the dopamine system in TS [2]. Turjanski et al.
[3] studied presynaptic and postsynaptic dopaminergic
functions in TS using [11F]dopa (to assess the integrity of
dopaminergic terminals) and [11C]raclopride (to assess
receptor site density) (Table 1). Both of these ligands are
positron-emitting, so this was a PET study. This study was
limited by the fact that the majority of patients in the
[11F]dopa study were medicated with neuroleptic drugs at
the time of the study. Despite this, there were no clear
differences between patients and controls using either ligand.
This study was the sequel to another study from the same
group using the same methodology and finding the same
results [4], so it is unclear whether it represents a replication
or an extension of the original findings. Ernst et al. [5] used a
similar ligand ([18F]dopa) to study 11 children with TS and
found a higher level of binding in the left striatum of the TS
patients compared to matched controls.
Wong et al. [6] used the dopamine-blocking ligand
[11C]3-N-methylspiperone in a two-stage process. Firstly,
they looked at dopamine receptor density in the striatum
compared to that in the occipital cortex, and, secondly, they

H. Rickards / Journal of Psychosomatic Research 67 (2009) 575584

577

Table 1
PET ligand studies
Authors

Year Nuclide
11

[ F]Dopa
[11C]Raclopride
[18F]Dopa
[11C]Methylspiperone

N (TS) Result

Comments

10
10
11
20

Majority of patients were medicated

Majority of patients were medicated

Turjanski et al. [3]

Turjanski et al. [3]
Ernst et al. [5]
Wong et al. [6]

1994
1994
1999
1997

Singer et al. [8]

2002 [11C]Raclopride

Gilbert et al. [9]

2006 [18F]Fallypride

Behen et al. [25]

2007 [11C]Methyltryptophan

Albin et al. [23]

Albin et al. [23]
Haugbol et al. [26]
Wong et al. [7]

2009
2009
2007
2008

[11C]Dihydrotetrabenazine
[11C]MPH
[11F]Altanserin
Variety of ligands

26
33
33
20
14

No differences
No differences
Higher binding in the left striatum
Subgroup of four patients with
elevated D2 binding

Haloperidol pretreatment; the subgroup

with high binding had higher vocal
tic scores

Baseline scans showed no difference;

amphetamine challenge led to
increased binding
Widespread lower dopamine binding found

Fallypride is used to examine

extrastriatal dopamine binding
Decreased uptake in dorsolateral prefrontal cortex Children
and increased uptake in thalamus
No differences
No differences
Increased 5HT2A binding in striatum
General up-regulation of 5HT systems
Increased dopamine binding in the left
ventral striatum; changes in midbrain
5HT function; amphetamine challenge
increased dopamine release

pretreated subjects with haloperidol in 20 TS patients. The

dopamine receptor density was not different between
subjects and controls. However, there was a subgroup of
four TS patients with significantly elevated dopamine 2
(D2) receptor binding. Clinically, this subgroup was only
different in that it had higher vocal tic scores. In a more
recent follow-up to this study, Wong et al. [7] studied 14 TS
adults and 10 healthy controls. They utilized several scans
with different ligands over 3 days to measure a range of
parameters around dopamine and 5HT, including receptor
density and affinity, transporter binding, and dopamine
release following administration of amphetamine. In this
study, D2 binding was increased in the left ventral striatum.
There were changes in midbrain and striatal 5HT functions
(regardless of the presence or the absence of obsessive
compulsive disorder) in TS patients. The amphetamine
challenge led to a greater release of striatal dopamine in
TS subjects.
Singer et al. [8] used [11C]raclopride and a pharmacological paradigm (amphetamine challenge) in seven adults
with TS and controls. Like the study of Turjanski et al.,
the baseline raclopride scans did not differ between
patients and controls, but the amphetamine challenge
resulted in a greatly increased binding in the TS group
compared to controls, replicating the findings of Wong
et al. [7] to some extent.
More recently, a PET ligand that binds to extrastriatal
dopamine receptors ([18F]fallypride) has become available.
Gilbert et al. [9] designed a study specifically to look at
extrastriatal dopamine activity in six TS adults and controls.
Widespread lower dopamine binding was found in the
orbitofrontal cortex, primary motor cortex, anterior cingulate, mediodorsal thalamus, and hippocampus. The relevance
of these findings is not currently very clear.

[123I]Iodobenzamide (IBZM) is a potent D2 antagonist,

and two studies have used this ligand to study postsynaptic
dopamine function in TS. Wolf et al. [10] used a discordant
monozygotic twin methodology to clarify the relationship
between environment and severity of symptoms in TS
(Table 2). Five sets of monozygotic twins (all of whom had
TS, but of differing severities) were studied in a SPECT
scanner. Caudate D2 binding was much greater in all the
more severely affected of the twin pairs, although there was
strong within-pair concordance. The subjects had undergone HMPAO SPECT scanning, which showed no
differences in striatal regional cerebral blood flow (rCBF)
between subjects and controls, and all subjects had been off
medication for an extended period prior to the study.
These findings suggest that absolute levels of dopamine
receptors are genetically determined, but that small changes
could be either the cause or the result of symptom severity.
Mller-Vahl et al. [11] used the same ligand ([123 I]IBZM)
in medicated and unmedicated TS patients and unmedicated
controls. In the seven neuroleptic-treated patients, IBZM
binding was significantly different from that in controls, but
the neuroleptic-naive patients showed no difference from
controls. Further subgroup analysis showed that subjects
who were advanced in their illness had relatively low IBZM
binding in the striatum than controls. Again, this finding
must be viewed with caution as it appears post hoc in a
study with a low number of subjects with TS (N=17).
A further iodine-based isotope [123I]2s-carbomethoxy-3s(4-iodophenyl)-N-(3-fluoropropyl) nortropane (-CIT) is a
SPECT ligand for dopamine transporter (DAT) binding and
has been used in three TS studies. Malinson et al. [12]
studied five adults with TS and matched controls and found
significantly higher striatal [123I]-CIT binding in the
subjects. All subjects had binding higher than that of their

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H. Rickards / Journal of Psychosomatic Research 67 (2009) 575584

Table 2
SPECT ligand studies
Authors

Year

Nuclide
123

N (TS)

Results

Comments

Caudate D2 binding always higher

in the more severely affected twin
Neuroleptic-naive patients showed no
difference from controls
No difference
Higher striatal binding
No differences

Strong within-pair concordance

Wolf et al. [10]

1996

I]IBZM

10

Mller-Vahl et al. [11]

2000

[123I]IBZM

17

Hwang et al. [19]

Malinson et al. [12]
Heinz et al. [13]

2008
1995
1998

[123I]IBZM
[123I]-CIT
[123I]-CIT

10
5
10

Mller-Vahl et al. [15]

Stamenkovic et al. [14]
Serra-Mestres et al. [16]

2000
2001
2004

[123I]-CIT
[123I]-CIT
[123I]FP-CIT

12
20
10

Cheon et al. [17]

Mena et al. [18]
Hwang et al. [19]
Yeh et al. [20]

2004
2004
2008
2007

[123I]IPT-CIT
TRODAT 1-Tc99m
TRODAT 1-Tc99m
TRODAT 1-Tc99m

9
10
10
8

Bohnen et al. [21]

Albin et al. [22]
Berding et al. [24]

1999
2003
2004

[11C]Dihydrotetrabenazine
[11C]Dihydrotetrabenazine
[123I]AM281

8
19
6

Higher striatal binding

No differences
Dopamine binding higher in
caudate and striatum
Dopamine binding higher in basal ganglia
Increased DAT bilaterally in striatum
No differences
Less decline in binding in striatum
related to MPH challenge
No difference
Increased ventral striatal binding
Ligand detectable in people with TS

matched controls, although there was some overlap in the

data taken as a whole. Heinz et al. [13] failed to replicate this
finding, using an identical methodology, in 10 TS patients
and matched controls. Post hoc findings indicated a negative
correlation between tic severity and binding in the midbrain
and thalamus (where [123 I]-CIT binding may reflect
serotonergic function). Another replication failure was
reported by Stamenkovic et al. [14], who studied 20 TS
patients with the same ligand and looked at DAT binding in
all brain areas compared to the cerebellum. However,
Mller-Vahl et al. [15] also used [123 I]-CIT in 12 TS
patients and controls and found increased striatal activity
(compared to occipital values). Serra-Mestres et al. [16] were
able to use higher-resolution SPECT scanning and to focus
on the different nuclei of the basal ganglia in 10 drug-free TS
patients and matched controls. DAT binding (measured
using [123I]FP-CIT) was higher in caudate and striatum. In
this study, the researchers also considered the effect of the
severity of (motor and behavioral) symptoms and found that
these did not affect binding. This finding was confirmed by
Cheon et al. [17] in nine drug-naive children with Tourette
simplex (i.e., TS without any associated psychopathology)
using a very similar ligand ([123I]PT-SPECT). This group
also replicated the finding that binding was not related to
severity of symptoms.
Technetium DAT SPECT scanning has been shown to
be a useful tool in the diagnosis of akinetic rigid syndromes.
Three studies have utilized this methodology in TS. Mena
et al. [18] used TRODAT 1-Tc99m, a newly developed
technetium-labeled tropane derivative, in 10 TS patients and
normal controls and showed a marked increase in DAT in the
striatum bilaterally. However, all patients were being treated
with neuroleptics. Hwang et al. [19] captured both

Post hoc finding of reduced binding in

midbrain and thalamus

Binding was not affected by symptoms

Binding was not affected by symptoms
All patients treated with neuroleptics

Preliminary study

presynaptic and postsynaptic dopamine functions in the

striatum using both [99mTc]TRODAT-1 and [123I]IBZM
SPECT in 10 adult TS patients and healthy controls and
found no significant differences between the groups. Yeh
et al. [20] examined the effect of methylphenidate (MPH)
pretreatment on DAT scanning. Normally MPH would cause
a decline in DAT binding, and this was seen to a lesser extent
in the TS group only in the right striatum.
Bohnen et al. [21] used a type 2 vesicular monoamine
transporter ligand ([11C]dihydrotetrabenazine), which binds
to monoaminergic neurones in the striatum, in eight adults
with TS and matched controls. They found no differences
between the groups. Albin et al. [22] replicated the
methodology, comparing 19 variously medicated TS patients
with 27 controls, and again found no difference between the
groups in the dorsal striatum, but an increase in ventral
striatal dihydrotetrabenazine binding in the subject group. A
second work by Albin et al. [23] used [11C]MPH (which
binds to plasmalemmal DAT) and [11C]dihydrotetrabenazine
to examine dopamine transport in 33 TS adults and controls.
They found no differences between subjects and controls in
terms of binding.
Berding et al. [24] examined the cannabinoid CB1 ligand
[123I]AM281 in six TS patients before and after exposure to
9-tetrahydrocannabinol. They found that this ligand was
detectable by SPECT in people with TS with an acceptably
low exposure to radiation. This ligand may show promise for
future studies.
A small number of studies have examined the 5HT
system in TS. In addition to the study of Wong et al. [7],
who found nonspecific changes in 5HT function in
the brain of people with TS, Behen et al. [25] used
[11C]methyl-L-tryptophan as nuclide to measure general

H. Rickards / Journal of Psychosomatic Research 67 (2009) 575584

5HT function. They studied 29 children with TS and 9

healthy controls and focused their attention mainly on
structures within the model of corticostriatothalamocortical
(CSTC) circuitry. They showed a decrease in tracer uptake
in the dorsolateral prefrontal cortex bilaterally and an
increase in tracer uptake in the thalamus bilaterally.
Haugbol et al. [26] compared 20 adults with TS and 20
controls. A PET imaging study of [18F]altanserin, which
binds to 5HT2A receptors, was performed. This showed
increased striatal 5HT2A binding in TS patients compared to
controls, but the medication status of the participants was not
clear. A post hoc analysis also suggested global upregulation of the 5HT2A system.
Summary of ligand studies
A number of studies in this area failed to show significant
differences between patients and controls, but this may be a
reflection of the poor spatial resolution of current scanning
procedures. Findings that are starting to emerge include an
increased dopamine activity in the left striatal region, which
may be more pronounced in the ventral striatal area. Two
studies have shown that amphetamine challenge leads to a
relatively overactive dopaminergic system in the striatum.
None of the studies cited so far has indicated a direction of
causation (Are the functional changes causing or reflecting
the symptoms, or are both symptoms and functional changes
a reflection of a third process?).
Region-of-interest studies
[99Tc]HMPAO SPECT
HMPAO is a radionuclide that crosses the bloodbrain
barrier (around 5% of intravenous HMPAO enters the brain
and tends not to redistribute for the first 24 h after injection).
HMPAO is taken up in the brain in proportion to blood flow,
which in turn varies with the metabolism of the region of
interest [27]. Six studies addressed rCBF in TS [2833]. In
the study of Riddle et al. [29], nine TS patients and matched
controls were imaged with HMPAO SPECT, and reduced
rCBF in the left putamen/globus pallidus was noted (a
relative reduction of around 4%) (Table 3). The studies of
George et al. [28] and Kleiger et al. [31] used a slightly
different methodology; they used the occipital lobe as the
comparator area (compared to Riddle et al.'s use of the
region of interest/whole brain minus cerebellum ratio). The
first work of George et al. [28] showed only an increase in
right frontal activity compared with controls, whereas the
second work of Kleiger et al. [31] showed findings similar to
those of Riddle et al. [29] in 50 patients compared to 20
controls; there were reductions in activity in the left caudate
and anterior cingulate gyrus. Moriarty et al. [33] later went
on to study whether HMPAO SPECT could generate an
endophenotype that could distinguish obsessivecompulsive
symptoms from tics in five small Gilles de la Tourette
syndrome pedigrees. They studied 20 subjects in all and

579

found decreased perfusion in the striatal, frontal, and

temporal regions in affected individuals regardless of
symptoms or syndrome.
A single case reported by Sieg et al. [34] using HMPAO
showed a focal reduction in perfusion in the left basal
ganglia. This was a clinical case report rather than a
controlled study.
Kleiger et al. [31] studied six drug-free adults with TS
using HMPAO SPECT. The activity was recorded in
proportion to cerebellar activity (although the cerebellum
has previously been shown to be active in relation to tics).
Contrary to previous HMPAO studies, they found hypoperfusion in the right basal ganglia.
Chiu et al. [32] used [99mTc]HMPAO brain single-photon
emission tomography to try to delineate differences in
perfusion between children with chronic tic disorder and
children with TS. Visual interpretation and semiquantitative analysis were used to compare perfusion between the
two groups (27 children with TS and 11 children with
chronic tics). Visual interpretation of the scans indicated that
82% of patients with TS had abnormal perfusion compared
to none of the patients with chronic tics. Abnormalities
tended to be located in the left lateral temporal lobe. This
study illustrates some of the fundamental issues that hamper
functional neuroimaging research. The two categories being
studied are not necessarily discrete natural entities, and the
imaging studies may reflect symptoms rather than causes.
The findings may also be epiphenomena in relation to other
factors (particularly comorbid conditions, which were not
controlled for in this study).
Diler et al. [35] studied 38 children with TS and 18
controls. The group used [99mTc]ethyl cysteinate dimer
(ECD) to study regional cerebral perfusion and found a
variety of differences between patients and controls, in
particular lower perfusion in the left caudate, cingulum, right
cerebellum, left dorsolateral prefrontal region, and left
orbital region.
[11F]Fluorodeoxyglucose (FDG) PET studies
PET studies can examine regions of interest, as well as
specific receptor ligands. FDG-PET studies measure the
glucose uptake of the brain, which is used as a proxy for
function or activity. The first recorded study [36] was
performed in five patients and found no differences between
subjects with TS and controls. A similar group performed
the same study with a higher number of participants (n=11)
and an improved scanner [37]. This group was the first to
identify a reduction of around 15% of activity in the frontal,
cingulate, and insular cortices and in the ventral striatum.
Braun et al. [38] performed FDG-PET on 16 TS patients
who were drug-free. They looked at the function of specific
regions of interest, as well as differences in function
between regions. Generally, their findings showed a
reduction in glucose uptake in the inferior limbic cortex
(particularly the insula) and the striatum and a relative
hypermetabolism in the sensorimotor cortices. This was

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H. Rickards / Journal of Psychosomatic Research 67 (2009) 575584

Table 3
Region-of-interest studies
Authors

Date Nuclide

Scanner N (TS)

Riddle et al. [29]

1992 HMPAO

SPECT 9

Compared to cerebellum

George et al. [28]

Moriarty et al. [30]

1992 HMPAO
1995 HMPAO

SPECT
SPECT

Compared to occipital lobe

Compared to occipital lobe

Moriarty et al. [33]

1997 HMPAO

SPECT

Sieg et al. [34]

Kleiger et al. [31]
Chiu et al. [32]

1993 HMPAO
1997 HMPAO
2001 HMPAO

SPECT
SPECT
SPECT

Diler et al. [35]

2002 [99mTc]ECD SPECT

Chase et al. [36]

Brooks et al. [37]

1984 FDG
1985 FDG

PET
PET

Braun et al. [38]

1993 FDG

PET

Stoetter et al. [39]

1992 FDG

PET

Reduced rCBF in left putamen/

globus pallidus
20
Increase in right frontal rCBF
50
Reduced rCBF in left caudate
and anterior cingulate
20
Decrease in striatal, frontal, and
temporal regions
1
Focal reduction of rCBF in left basal ganglia
6
Hypoperfusion in right basal ganglia
27 TS, 11 CMT Left-sided abnormalities more common
in TS
38
Lower left caudate perfusion and
other changes
5
No difference
11
15% reduction in frontal cortex,
cingulate cortex, insular cortex,
and ventral striatum
16
Reduction in limbic cortex and striatum;
hypermetabolism of sensorimotor cortex
18
Similar to above finding

Eidelberg et al. [40] 1997 FDG

PET

10

Stern et al. [41]

2000 [15O]H2O

PET

Jeffries et al. [43]

2002 FDG

PET

18

Lerner et al. [42]

2007 [15O]H2O

PET

Results

Comments

Did not correlate with symptom

type or severity
Case report (no control)
Compared to cerebellum
Visual interpretation of scans only

Drug-free patients

May have been a re-publication of

the same data set
Increase in sensorimotor activity; decrease in Scaled subprofile mapping to
caudate and thalamic activity
identify networks of activity
Tics activated the sensorimotor, language,
Serial scanning to improve
executive, and paralimbic regions
temporal resolution
Ventral striatal connections were most
different from those of controls
The main abnormal area in tic release
Used Stage 2 sleep as control situation
was the cerebellum

particularly pronounced in the ventral part of the striatum.

A similar finding was reported by the same group [39], but
it is unclear whether or not this is a replication of the
finding or a republication of the same data set. Turjanski
et al. [3] reported on FDG-PET in 15 patients who were
also in a raclopride study (vide supra). They specifically
looked at caudate and putamen and found no differences
between patients and controls.
Eidelberg et al. [40] used the same methodology in 10 TS
patients and found that, globally, there were no differences
between patients and controls. However, they used a
technique called Scaled Subprofile Modeling to identify
networks involved in TS. This method is akin to factor
analysis and identified two factors: an increase in activity
in sensorimotor cortices and midbrain, and a decrease in
caudate and thalamic metabolism.
PET has also been used to elucidate the pathophysiology of tics themselves. Stern et al. [41] performed serial
scanning on six adults with TS. The radionuclide in this
study was [15O]H2O. The patients were all videotaped and
audiotaped during the scanning process, and each patient
was scanned 12 times. Tics produced widespread
activation in the sensorimotor, language, executive, and
paralimbic regions of the brain. One patient with
coprolalia demonstrated that a different group of regions
was activated by his coprolalia compared to the group of
regions activated by his vocal tics. These regions included

prerolandic and postrolandic language areas, insula,

caudate, thalamus, and cerebellum.
Lerner et al. [42] used [15O]H2O as PET nuclide to look at
the neural mechanisms around tic generation in nine TS
patients and matched controls. They used sleep as control to
minimize the effect of wanting to tic or tic suppression as
background noise. This condition has previously been used
in imaging studies of dystonia. The active paradigm for the
patients was tic release. The main areas associated with tic
release were cerebellum and insula, and the authors go on to
suggest that cerebellar abnormality may be the primary
problem in TS. They then go on to support their idea by
suggesting that the reason that deep brain stimulation in the
thalamus may be effective is that it interrupts the major
connections between the cerebellum and the striatum.
As imaging techniques become more sophisticated, one
area of great promise is that of imaging paradigms that
examine the relationship between regions of interest. Jeffries
et al. [43] used [18F]deoxyglucose and compared 18 TS
patients (off drugs) with 16 controls. They were looking
particularly at connectivity between regions. Using Pearson
ProductMoment Correlation Coefficient, they ascertained
which areas of the brain had connectivities that were most
unlike those of the controls. Interestingly, the area of the
brain that was connected most differently in the TS groups
was the ventral striatal area (this was the only area where the
connectivity was more than 3 S.D. from the mean of the

H. Rickards / Journal of Psychosomatic Research 67 (2009) 575584

normal distribution in controls). The main differences in

striatal connectivity were in relation to motor cortices, but
also to the cerebellum, pons, and caudal part of the
orbitofrontal cortex. The insula also appeared to be
significantly differently connected in the TS group. An
overview of the whole study suggests a broad range of
differences between the functional connectivity of TS brains
and the functional connectivity of normal brains. The fact
that the differences were most pronounced in the ventral
striatum fits well with the idea of TS being a disorder that
crosses over the boundary between motor and emotional
functions. In addition, the involvement of the cerebellum in
this study casts doubt over the utility of using the cerebellum
as a control region when looking at the activity of
other regions.
Summary of region-of-interest studies
There are no specific replicated findings in this series of
studies. However, a general overview of all studies points
towards a general reduction in the activity of the striatum in
TS when compared to controls. This applies particularly to
the left striatal structures. Two studies indicate increased
higher levels of activity in the sensorimotor cortices, which
are not particularly surprising in a motor disorder. The
connectivity study indicated that the brain areas involved
may center on the ventral striatum but include a number of
areas and pathways outside the CSTC pathways.
fMRI studies
There are a number of fMRI studies, all using slightly
different but specific paradigms. These are described below.
Peterson et al. [44] used the paradigm of tic suppression to
study adults with TS using fMRI (Table 4). They found 22

581

adults without significant head tics and who could

voluntarily suppress their tics. They scanned them during
tic suppression and free expression of tics. The results
showed widespread differences between the suppression
and the free expression. Post hoc analyses of basal ganglia
structures indicated decreased activity in the ventral globus
pallidus and putamen. Increased activity was seen in the
ventral head of the right caudate nucleus.
Biswal et al. [45] used a finger-tapping test to examine the
organization of the sensorimotor cortex in TS. The task
involved tapping the thumb and forefinger together in a
rhythmic self-paced fashion. Only the sensorimotor and
supplementary motor cortices were examined on a pixel-bypixel basis. Only five patients with TS were examined
alongside five matched controls, but the TS patients tended
to activate more pixels and over a wider geographical area
than the controls. It is difficult to see what conclusion can be
drawn from these data, except to say that cortical motor
organization is somehow different in people with TS.
Hershey et al. [46] attempted to stimulate dopaminergic
activity in the brain by utilizing the Working Memory Test
(WMT), as well as levodopa stimulation, individually and
combined. This complicated design showed that brain areas
responded differently to the WMT according to whether or
not the subject had been pretreated with levodopa,
although in only eight patients. In general, levodopa
served to normalize the exaggerated WMT responses seen
in the TS group, although there were no clear group
differences found.
Gates et al. [47] studied a single 15-year-old patient with a
matched control who had regular phonic tics but no head tics.
The control mimicked tics at roughly the same interval as the
patient. A variety of areas were preferentially activated by
the patient, including caudate, cingulate, cuneus, left angular
gyrus, left inferior parietal gyrus, and occipital gyrus. The

Table 4
fMRI studies
Authors

Date

N (TS)

Paradigm

Result

Comments

Peterson et al. [44]

1998

22

Tic suppression

Biswal et al. [45]

1998

Finger tapping

Hershey et al. [46]

2004

WMTlevodopa

Gates et al. [47]

2004

Control mimicked tics

Fattaposta et al. [48]

Marsh et al. [49]

2005
2007

1
66

Regular and unusual motor tasks

Stroop test

Recovery of fMRI 15 s after

vocal tics
Subject was a skilled kickboxer
Cross-sectional study

Bohlhalter et al. [51]

2006

10

Event-related

Baym et al. [52]

2008

18

Cognitive task

Church et al. [53]

2009

33

Functional connectivity

Suppression related to decreased activity in

globus pallidus and putamen; increase in
ventral right caudate activity
Greater activation of sensorimotor cortex
with motor task
L-Dopa normalized exaggerated WMT
responses in TS cases
Activation in caudate, cingulate, cuneus,
and other areas
SMA activation in both tasks in TS patients
Subjects failed to activate frontostriatal
systems with age
Paralimbic and sensory areas associated
with urge to tic
Activation of direct pathway in TS; prefrontal
area activated by task
Failure of TS patients to develop
age-appropriate connectivity

First image 2 s before tic

Not controlled for sex

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H. Rickards / Journal of Psychosomatic Research 67 (2009) 575584

researchers used fuzzy clustering analysis. Of greater

interest were the data about signal decay that this study
developed following a vocalization. It took between 10 and
15 s after vocalization for the fMRI to normalize.
Another study with a single patient and a control utilized
an unusual patient with TS who was also an expert kickboxer
[48]. The participants were asked to perform a regular task
(index finger tapping) and an unusual task (little finger
tapping). The supplementary motor area (SMA) was
expected to be activated during relatively unusual tasks.
However, the TS patient showed SMA activation in both
usual task and unusual task. However, the unusual skills of
the subject may have acted as a confounder.
The largest fMRI study to date was published by Marsh
et al. [49]. They used the Stroop test [50] as an activation
task. The rationale behind this choice was that the Stroop test
preferentially activates frontostriatal systems, it improves
with age, and deactivations of the default mode system
(governed by the ventral and posterior cingulate cortices)
became more prominent with age. The researchers used a
cross-sectional sample of 66 people with TS to examine
whether the normal changes with age are also seen in the TS
group. Their rationale is slightly undermined by the lack of
any evidence for impairment in people with TS in the Stroop
test. However, there were clear age-related differences
between subjects and controls. In particular, the posterior
cingulate cortex became relatively deactivated with age in
controls, but not in TS patients. Also, the frontostriatal
circuits became more activated with age in controls, but not
in the subjects, indicating a possible problem with
maturation and lending support to their a priori hypothesis.
The cross-sectional design of this study limits the validity of
the findings, but nevertheless suggests future avenues for
research (ideally, serial scanning of a cohort of TS patients
into adulthood).
Bohlhalter et al. [51] used a creative methodology to
ascertain the neural substrate of the period just before tics are
clinically apparent. The aim of this study was to look at two
time periods (2 s prior to the tic compared to the tic itself).
Just prior to the tic, a group of areas, including the anterior
cingulate, insula, and parietal operculum, was activated.
During the tic itself, the activity was relatively high in the
superior parietal area and cerebellum on both sides. One
possible criticism of this study is that, clinically, 2 s is quite a
long time to experience a premonitory sensation; many
people experience premonitory sensations for between 0.5
and 1 s.
Baym et al. [52] used a cognitive control task to
compare subjects with TS to matched controls (although
they were not matched for sex). The cognitive task
involved set shifting, response selection, and rule representation, and those with severe tics found these tasks to be
more difficult. The TS subjects engaged the prefrontal
cortex more actively while performing the cognitive tasks
than did the controls, although there were no group
differences in the striatum.

Recently developed fMRI techniques have enabled

functional connectivity between regions to be established.
Church et al. [53] looked at resting-state functional
connectivity MRI in 33 adolescent TS patients. This is a
way of looking at changes in brain systems rather than
areas. There are two networks involved with task control.
These are the cingulo-opercular network and the frontoparietal network. Control work has shown how these
networks mature normally, and this can be used as control
data. A general finding from this type of research is that
specific brain regions can move from one network to
another through the process of maturity. According to the
study of Church et al., these developmental transitions do not
appear to take place in TS; this means that TS brain
connectivity looks younger than the age of the patient
would suggest. A typical adolescent TS brain would have the
connectivity of a 7- to 9-year-old. When you compare
adolescents with TS to age-matched controls, frontoparietal
connectivity is most different between the groups. These
differences have also been reported in autism and attention
deficit/hyperactivity disorder.
Summary of fMRI
In the author's view, the fMRI studies do not provide a
clear and consistent picture of brain activity in TS. Studies
of connectivity implicate regions of the brain well outside
those of conventional CSTC circuits and should lead to a
reappraisal of these circuits as being central in the
pathogenesis of TS. fMRI work that is focused on the
developmental aspects of connectivity shows a great deal
of promise and indicates that TS brains are immature. In
an ideal world, serial scanning of at-risk individuals
throughout development would provide the clearest
window on the brain, but this is logistically complex
and prohibitively expensive.

Conclusions
Generally, functional neuroimaging in TS is in its
infancy. Spatial resolution is poor on the whole but
improving, particularly with coutilization of functional and
structural methodologies. It is unlikely that TS is a
manifestation of a specific malfunction of a detectable
neurotransmitter or its receptors. Therefore, summary
comments are largely restricted to generalities; there is a
preponderance of changes on the left side of the brain. Most
brain regions have been implicated, but more commonly the
striatum, particularly the ventral portion. In general, there is
evidence of hypoactivity of the basal ganglia and hyperactivity of the motor/premotor areas, which fits in with
structural neuroimaging findings.
Within the basal ganglia, there is insufficient acuity of the
scanning process to test models such as Mink's model of
dysfunctional striatal matrisomes [54]. However, many

H. Rickards / Journal of Psychosomatic Research 67 (2009) 575584

studies contained subtle biases that favored the discovery of

basal ganglia abnormalities over abnormalities in other
regions (particularly the use of other regions as control
areas, the specific use of slices that contain predominantly
basal ganglia, and the restriction of areas of interest to the
basal ganglia only). No clear endophenotype has emerged
from scanning studies, which could be correlated to factor
analyses of symptom clusters or to genetic data. So far, no
single finding has been reliably replicated in this area. TS is a
dynamic illness involving different systems of the brain, so
studies that use specific pharmacological or cognitive
stimulation paradigms are more likely to yield success in
the future.
Although the pathology of TS may be focal, functional
brain changes are widespread, involve many different areas
and systems, and are extremely complex. The only study to
timelock tics to brain function [37] clearly shows this.
Although a number of studies implicate the basal ganglia in
the pathogenesis of TS, no study clearly implicates the CSTC
circuitry as a whole, and some studies implicate completely
different areas such as the cerebellum.
Further studies that are likely to yield fruitful results in the
future will involve better temporal resolution (to timelock
tics or tic suppression), better spatial resolution (to subdivide
the striatum and other brain areas and to examine pathways
that connect regions), and specific targeting of brain systems
using cognitive or pharmacological stimulation. It looks
likely that MRI will be the most useful scanning modality in
the foreseeable future.
In the future, these designs may lead to better
classification and subgrouping of TS. The design of
imaging studies will, in turn, be influenced by the current
work on factor analysis, in an iterative process. Clearer
clinical phenotypes or endophenotypes could feed into
genetic studies. Imaging could lead to better prediction of
treatment response and could also be used to explore the
neural substrate of people with TS. Finally, multimodal
imaging (e.g., fMRI and magnetoencephalography) may
increase resolution.
However, it may be that our current processes lack
sufficient acuity to answer the basic etiological questions
about TS. We may still have a long walk through the
foothills before the real mountains appear in front of us.
Acknowledgments
I would like to thank Dr. Andrea Cavanna for help with
the discussion and for his endless enthusiasm.
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