Putting The Pieces Together in Gilles de La Tourette Syndrome: Exploring The Link Between Clinical Observations and The Biological Basis of Dysfunction
Putting The Pieces Together in Gilles de La Tourette Syndrome: Exploring The Link Between Clinical Observations and The Biological Basis of Dysfunction
Putting The Pieces Together in Gilles de La Tourette Syndrome: Exploring The Link Between Clinical Observations and The Biological Basis of Dysfunction
DOI 10.1007/s10548-016-0525-z
REVIEW
Received: 6 May 2016 / Accepted: 20 September 2016 / Published online: 25 October 2016
The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract Gilles de la Tourette syndrome is a complex, ulation (DBS) has recently become a viable therapeutic
idiopathic neuropsychiatric disorder whose pathophysio- option. A key factor to attaining optimal results from this
logical mechanisms have yet to be elucidated. It is phe- surgery is target selection, a topic still under debate due to
notypically heterogeneous and manifests more often than the complex clinical profile presented by GTS patients.
not with both motor and behavioral impairment, although Depending on its phenotypic expression and the most
tics are its clinical hallmark. Tics themselves present with a problematic aspect of the disorder for the individual, one of
complex profile as they characteristically wax and wane three brain regions is most commonly chosen for stimula-
and are often preceded by premonitory somatosensory tion: the thalamus, globus pallidus, or nucleus accumbens.
sensations to which it is said a tic is the response. Highly Neurophysiological analyses of intra- and post-operative
comorbid with obsessive–compulsive disorder and atten- human electrophysiological recordings from clinical DBS
tion deficit-hyperactivity disorder, it is purported to be an studies suggest a link between tic behavior and activity in
epigenetic, neurodevelopmental spectrum disorder with a both the thalamus and globus pallidus. In particular,
complex genetic profile. It has a childhood onset, occurs chronic recordings from the thalamus have shown a cor-
disproportionately in males, and shows spontaneous relation between symptomatology and (1) spectral activity
symptomatic attenuation by adulthood in the majority of in gamma band power and (2) theta/gamma cross fre-
those afflicted. Although not fully understood, its neuro- quency coherence. These results suggest gamma oscilla-
biological basis is linked to dysfunction in the cortico-basal tions and theta/gamma cross correlation dynamics may
ganglia–thalamo–cortical network. Treatment modalities serve as biomarkers for dysfunction. While acute and
for Tourette syndrome include behavioral, pharmacological chronic recordings from human subjects undergoing DBS
and surgical interventions, but there is presently no cure for have provided better insight into tic genesis and the neu-
the disorder. For those severely affected, deep brain stim- ropathophysiological mechanisms underlying Tourette
syndrome, these studies are still sparse and the field would
greatly benefit from further investigations. This review
reports data and discoveries of scientific and clinical rele-
A commentary on this review is available at: 10.1007/s10548-016- vance from a wide variety of methods and provides up-to-
0528-9. date information about our current understanding of the
pathomechanisms underlying Tourette syndrome. It gives a
& Rowshanak Hashemiyoon comprehensive overview of the current state of knowledge
row.hashemiyoon@gmail.com
and addresses open questions in the field.
1
Department of Stereotactic and Functional Neurosurgery,
University Hospital of Cologne, Kerpener Strasse 62, Keywords Basal ganglia Tic Oscillation Premonitory
50937 Cologne, Germany urge Centre médian/parafascicular nucleus of the
2
Department of Psychiatry and Psychotherapy, University thalamus (CM/Pf) Deep brain stimulation Gamma
Hospital of Cologne, Cologne, Germany Theta/gamma cross frequency coupling OCD ADHD
3
Johanniter Hospital, EVKLN, Oberhausen, Germany Movement Disorder Genetics
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4 Brain Topogr (2017) 30:3–29
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Brain Topogr (2017) 30:3–29 5
GTS has been genetically linked with OCD and ADHD Mink 2006). Despite significant strides in the field, neither
(suggesting that they are part of a spectrum), although the underlying neuropathological mechanism(s), nor the
their profiles are notably dissimilar (Barkley 1993; Albin primary initiation site(s) of dysfunction are fully
and Mink 2006). The incidence of ‘‘pure’’ or ‘‘uncom- elucidated.
plicated’’ GTS is uncommon, present in only about 10 % GTS may be managed pharmacologically, behaviorally,
of the observed GTS population (Robertson 2000; Faraone or surgically, all of which aim at ameliorating symptoms.
et al. 2003; Mohammadi et al. 2004; Pittenger et al. 2011; Preferred pharmaceutical therapies are comprised of
Eapen and Robertson 2015; Ganos and Martino 2015). In antipsychotics or, in milder cases, amphetamines
contrast, both OCD and ADHD present with low comor- (McNaught and Mink 2011). And while comprehensive
bidity rates, but show a higher prevalence in the general behavioral intervention therapy has shown good success, few
population. Despite the very high comorbidity of GTS trained professionals are available as of yet (Piacentini et al.
with OCD and ADHD, the reverse comorbidity of OCD 2010; Capriotti et al. 2014). Severely afflicted patients tend
and ADHD with GTS is typically reported to be only to be refractory to both behavioral and pharmacological
about 2–7 % (Zohar et al. 1992; Barkley 1993; Denys therapies and thus may opt for surgical intervention (Porta
et al. 2004). et al. 2009a; Hariz and Robertson 2010; Sassi et al. 2011).
Based on clinical characteristics and comorbidities, GTS Historically, medically-refractory patients were treated
may be subtyped into three categories: (1) ‘‘pure’’ GTS, by neurosurgical ablation in a variety of targets with
comprised primarily of motor and phonic tics; (2) ‘‘full diverse results (Hassler and Dieckmann 1970; Temel and
blown’’ GTS, which included copro-, echo-, and paliphe- Visser-Vandewalle 2004; Singer 2010). Despite delivering
nomena; and (3) GTS?, which includes OCD, ADHD, and symptomatic relief in many cases, outcomes include
other severe psychopathologies such as self-injurious complications of mild to severe permanent deficits as well.
behavior, depression, personality disorders, etc.… In 1999, however, deep brain stimulation (DBS) was
(Robertson 2000; Grados and Mathews 2009; Ganos and introduced as a possible alternative treatment (Vandewalle
Martino 2015). Comorbidities may provide the underlying et al. 1999). Since then, over 120 patients worldwide have
structure for the broad range of phenotypic expression, and been reported to have undergone the procedure with
as such, are a key variable to explicating the complexity of varying degrees of success (Sassi et al. 2011; Schrock et al.
the clinical profile. Largely, pure GTS does not typically 2014). While the use of DBS is a relatively new remedy
present with severe motor or executive dysfunction, available for treatment-refractory GTS, successful out-
although these individuals are suggested to exhibit more comes have been reported in many cases (Maling et al.
obsessive–compulsive and self-injurious behavior and are 2012).
more ‘‘delinquent’’ than GTS ? ADHD, likely as a result A key factor to attaining optimal results is target
of rage or anger (Robertson 2000; Rizzo et al. 2007; selection, a topic still under debate due to the complex
Cavanna et al. 2008). GTS comorbid with ADHD presents clinical profile presented by GTS patients (Porta et al.
with appreciable cognitive and behavioral disability, and 2009b; Schrock et al. 2014). The most common target has
GTS co-occurring with both ADHD and OCD presents as been the thalamus, which arguably has also been reported
more heritable with motor tics appearing at an earlier age to deliver the most efficacious overall outcomes in
(Grados and Mathews 2008, 2009). More often than not, it response to stimulation. In fewer cases, the globus pallidus
is the disability resulting from comorbid symptomatology internus has been targeted. Stimulation of this nucleus has
rather than GTS itself which prompts a patient to seek been shown to be effective for tic reduction. In a small
medical attention (Robertson 2000). number of procedures, the anterior limb of the internal
The predominance of comorbidities together with vari- capsule and nucleus accumbens (ALIC/NA) have been
ations in tic phenomenology suggests dysfunction of mul- targeted in order to address the behavioral aspects or
tiple neurotransmitter systems (Buse et al. 2013). Although comorbidities (in particular OCD) associated with GTS
the neurobiological basis of GTS is unclear, the effec- and/or as ‘‘rescue’’ surgeries (Servello et al. 2009). Owing
tiveness of dopamine antagonists in relieving tics has given to its generally successful outcomes and proposed rever-
rise to multiple hypotheses for its role in GTS (Buse et al. sible nature, DBS has become not only a preferred surgical
2013). Further imaging, physiological and pathological technique, but also a promising option for the treatment of
studies have indicated a pivotal role for the re-entrant refractory GTS (Porta et al. 2009b; Maling et al. 2012;
circuits of the cortico-basal ganglia–thalamo–cortical net- Schrock et al. 2014).
work, thus implicating gamma-amino-butyric acid In addition to a direct therapeutic role, the advent of
(GABA) and glutamate as well (Felling and Singer 2011; DBS provides a unique and powerful platform for inves-
Draper et al. 2014), and suggesting the underlying problem tigation. Recordings from DBS targets can provide sub-
may be one of action selection (Mink 2001; Albin and stantial insights into the neuropathophysiological
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6 Brain Topogr (2017) 30:3–29
mechanisms of GTS (Maling et al. 2012; Priori et al. 2013; Overwhelmingly, ticcing is depicted as an action which
Israelashvili et al. 2015). Acute single unit and local field is performed in response to the strong somatosensory
potential (LFP) recordings from the thalamus reveal sensations which generally precede a tic (Leckman et al.
bursting behavior, consistent with reports from thalamic 1993; Woods et al. 2005; Leckman et al. 2010). As such,
nuclei in various other neurological disorders (Priori et al. these premonitory urges are both clinically important and
2013). Chronic recordings from intra-thalamic networks scientifically relevant for understanding GTS. The bodily
demonstrate the effects of DBS on the dynamic changes in sensations of such phenomena correspond with the
the spectral characteristics of LFPs in correlation with anatomical region of the impending tic and are described as
clinical benefit (Maling et al. 2012). For patients a ‘‘need’’, ‘‘itch’’, or ‘‘ache’’ (Woods et al. 2005; Marsh
responding to therapy, a decrease in tic expression has been et al. 2007; Doyon et al. 2009; Leckman et al. 2010).
correlated to an increase in gamma oscillations (Maling Insofar as they are a disturbance heralding an impending
et al. 2012). Additionally, changes in the cross-frequency dysfunctional state, they can be considered analogous to
coupling of theta-gamma band activity have been corre- the aura experienced by epileptics prior to a seizure.
lated with active improvement in symptomatology (un- However, premonitory urges are corporeal sensations
published results). These data provide evidence for the rather than a perceptual disturbance; occur typically on fast
functional relevance of oscillations in the pathophysiology time scales and in circumscribed areas; and elicit bodily
of GTS and support the role of the thalamus as a pivotal responses to relieve them. Such impellent urges are rep-
component in GTS dysfunction. resentatively described by one subject as a feeling that she
would ‘‘burst’’ unless she was able to ‘‘physically tic’’
(Leckman et al. 1993).
Tic Expression This brings into sharp focus the dynamics of tic
expression and elucidates the ongoing debate about whe-
The cardinal feature of GTS is tics. As part of the funda- ther tics should be classified as voluntary, involuntary, or
mental dysfunction of the syndrome, they are nearly unvoluntary/nonvoluntary (Singer 2005; Ganos et al.
automatically described as chronic and involuntary; how- 2015b). Although the symptomatology of GTS is conven-
ever, closer examination of when and how they occur tionally characterized as the involuntary expression of tics,
adduces a far more intricate definition. Examination of it is the premonitory urges—which occur in over 80 % of
their transient stability dynamics as well as the volition patients—that are unequivocally involuntary (Leckman
driving the act of ticcing will provide not only a better et al. 1993; Fahn et al. 2011; Cohen et al. 2013). The
understanding, but a more definitive characterization of confounding factor is that the large majority of sufferers
them within the confines of the disorder. ([90 %) report that they partly or wholly respond to these
Tics fluctuate on both a short and long time scale across involuntary premonitory urges with voluntary tics (Leck-
their dimensional features (intensity, frequency and man et al. 1993; Woods et al. 2005; Doyon et al. 2009). In
severity). On short time scales, both motor and phonic tics fact, subjects report voluntary ticcing regardless of tic
(together and independently) exhibit short-term periodicity severity, although a higher incidence of premonitory urges
and ‘‘burst-like’’ behavior, often described as ‘‘bouts’’ has been correlated with an increase in both tic severity and
(Peterson and Leckman 1998). Over longer epochs, these tic complexity (Ganos et al. 2015b). Thus, the conundrum
fluctuations are expressed as waxing and waning. Rather becomes clear: is a voluntary response to an involuntary
than being random, tic intervals exhibit structure in their sensation truly voluntary when the urge is irresistible?
dynamics, such as self-similarity; period doubling; and Perhaps more light can be shed on the topic by
inverse power law scaling of the frequency distribution employing objective electrophysiological measures as
(with tic interval frequency plotted as a function of tic opposed to subjective reporting. The Bereitschaftspotential
duration) (Peterson and Leckman 1998). The ‘‘bouts of (BP) is an electrophysiological recording representing
bouts’’ experienced by GTS sufferers, therefore, are not the ‘‘free will’’ and the initiation of voluntary movement
haphazard events commonly thought, but instead demon- (Kornhuber and Deecke 1965; Libet 1985). It represents
strate the properties observed in non-linear dynamical the cortical contribution to motor planning and precedes
systems. Within this framework, predictions of system movement. Volition is immediately preceded by activation
behavior should be possible, where for example one could of the supplementary motor area (SMA) and premotor
determine the dimensional features of tics across time cortex *1.2 to 0.5 s prior to movement, followed by
scales. Clinically, this is nontrivial as the constant and activation in the primary motor cortex *0.5 s to imme-
seemingly erratic changes in tic expression (frequency, diately pre-action (Shibasaki and Hallett 2006). EEG
type, severity, complexity, number, location) can confound recordings from GTS patients reveal a complete lack of the
therapeutic strategies (Robertson 2000). first phase and often a lack of the second phase of the BP
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during spontaneous ticcing, but express the BP during of simpler motor (dystonic) tics and premonitory urges
imitation tics in all cases (Obeso et al. 1981; Hallett 2001; (Leckman et al. 1993; Jankovic 1997). For example, eye-
van der Salm et al. 2012). This might clarify entirely the blinking and mouth movements have been reported to be
question of voluntariness, but there is a confounding factor: less frequently preceded by premonitory urges (*30 %) as
in some cases, movement made in response to external compared with shoulder jerks or head/neck movements
triggers does not express a BP (Papa et al. 1991). It may (*60 %) (Leckman et al. 1993). This pattern also appears
therefore be possible that the absence of the BP is a result in phonic tics, albeit to a lesser extent, where sniffing has
of tic response to the premonitory sensory urge, which acts been reported at an approximate 30 % frequency of co-
as an internal trigger. occurrence, while vocal tics were around 40 %. Correla-
Ganos et al. show a correlation between increased tions have also been shown between tic frequency, inten-
interoceptive awareness and the intensity of bodily sensa- sity, and complexity and premonitory urges in older youths
tions referred to as premonitory urges in GTS (Ganos et al. but not younger ones (Woods et al. 2005). Premonitory
2015b). One interpretation of this is that the perception of a sensations are overall reported by both genders nearly
premonitory sensation would be oversensitivity to an equally (except notably in association with throat clearing
internal somatosensory signal. Given the theory that the tics where female subjects reported nearly double the fre-
discernment of voluntary action depends on a perceptual quency of males); occur mostly in the palm, shoulder, and
discrimination in relation to a given threshold level, midline abdomen, and throat; and are typically (40 %) felt
internal signals unrelated to volition could be misconstrued in muscle, but can occasionally also be found in joints and
as voluntary movements if the internal somatosensory skin (Cohen and Leckman 1992)..
signal is above said threshold (Ganos et al. 2015a, b). Tic expression can be influenced by contextual variables
Premonitory phenomena have been associated with matu- from either internal or external environmental cues which
ration and an increased awareness of interoceptive sensa- can affect both their frequency and severity (Marsh et al.
tion (Rajagopal and Cavanna 2013; Ganos et al. 2015b). 2007; Conelea and Woods 2008; Capriotti et al. 2014).
Younger children tend to not be aware of premonitory Classically, it has been reported that tic-exacerbating
sensations and also do not report ticcing voluntarily. variables include fatigue, social activities, or any envi-
The insula is implicated in interoception and bodily ronment which increases stress or anxiety (Conelea and
sensations and, together with the somatosensory and Woods 2008). Tic-ameliorating factors include being in a
medial frontal areas, has been consistently shown to be quiet comfortable environment, sleep, and focused atten-
overactive in tic generation in GTS patients (Tinaz et al. tion on a task (such as music or athletic performance, or
2015). It has been suggested by Tinaz et al. in a study math) (O’Connor et al. 2003; Conelea and Woods 2008).
demonstrating differences in the connectivity patterns of These contextual antecedents are reported from case study
the right dorsal anterior insula in GTS versus controls that or descriptive design studies, which do not control for
the insula could be involved in the increased awareness of threats to both internal and external validity and cannot
premonitory sensations, leading to the urge to tic (Tinaz reliably address causal relationship.
et al. 2015). Interestingly, although high interoceptive In contrast, single-case experimental design investiga-
awareness has been associated with greater premonitory tions are inherently constructed to address causality. They
urges, subjects with GTS exhibit lower overall levels of indicate the factors that most influence tic expression: overt
interoceptive awareness as compared with healthy controls observation and the presence of others; reading and aca-
(Ganos et al. 2015b). demic tasks; and tic related conversation and verbal
Given these subjective and objective reports, and the instructions to suppress tics (Conelea and Woods 2008). In
clear struggle nonetheless to check such debilitating sen- the latter case, verbal instructions resulted in reduced tic
sory phenomena, the term unvoluntary seems the most frequency in nearly half of the subjects with no apparent
authentic when describing volition in ticcing. The aware- rebound effects (Meidinger et al. 2005). Interestingly,
ness and role of internal signals in the body and the vocal—but not motor—tics increased in the tic-related talk
accurate characterization of tics—which are identified as condition (Woods et al. 2001). This is consistent with the
unwanted behaviors—have important implications for the suggestion that in some cases, tic location may be func-
biological basis of the disorder and are clinically valuable, tionally related to the engaged activity (O’Connor et al.
in particular when targeting therapies. 2003). Similarly, tics were reported to occur more fre-
There is a disparity in the incidence of premonitory quently during less challenging reading tasks or conditions
urges with respect to tic classification (Jankovic and Stone (Watson et al. 2005), indicating focused attention is in fact
1991; Leckman et al. 1993; Woods et al. 2005). Although relevant for amelioration of tics. Finally, in a large cohort
dystonic tics are most often associated with them, signifi- of individuals with Chronic Tic Disorder, it was shown that
cant differences have been found between the correlation overt observation (with a camera) significantly increased
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tic frequency when compared to covert observation (hidden disorder, both of these genetic anomalies are thus far
camera) (Piacentini et al. 2006). Notably, the overt obser- considered to be rare functional variants found in only a
vation resulted in increased ticcing regardless of the small proportion of the disease population.
physical presence of another. Furthermore, tic expression Looking for more common forms of genetic variation
rates were independent of setting (home vs. clinic), and which distinguish a substantial portion of the Tourette’s
remained remarkably temporally stable across locations. population from the population at large, the first genome
The results of these studies provide empirically confirmed wide association study (GWAS) for GTS was published in
findings which are non-trivial for symptom management 2012 (Scharf et al. 2013). Although some aberrant genes
and evaluation in clinical practice. were found, this investigation could not report any com-
mon genetic variants that could be identified as risk factors
among about 1500 subjects with Tourette syndrome as
Genetic Factors compared to over 5000 without it (Scharf et al. 2013).
These results suggest either a rare single gene or, more
Tourette syndrome likely arises from complex genetic plausibly, a multifactorial genetic effect might be con-
features that interact with environmental factors (Leckman tributing to the etiopathology. A GWAS combining GTS
et al. 1997). Transmission has been shown to be autosomal and OCD published 1 year later confirmed true functional
dominant, polygenic, and bilineal (Pauls and Leckman variants associated with gene expression levels in the brain
1986; Hanna et al. 1999; Ali et al. 2013). One of the main for each disorder (Yu et al. 2015). Interestingly, it proposed
risk factors is male gender, as it is 3–5 times more that these highly comorbid disorders likely do not share a
prevalent in boys as compared with girls (Kadesjo and genetic architecture, but rather have a complex genetic
Gillberg 2000). The disorder is highly heritable: (1) the relationship.
incidence of GTS increases 10–100 fold if a primary rel- There may be inherent difficulties to isolating specific
ative has the disorder, (2) the incidence of GTS increases risk genes which would unequivocally link to a seemingly
5–20 fold if a primary relative has chronic tic disorder, and heterogeneous disorder such as GTS. The alternative
(3) studies of monozygotic and dizygotic concordance have technique of gene network analysis, which reconstructs
reported between 50–94 % and 10–56 %, respectively, if functional gene networks from the susceptible genes in
one sibling had GTS and/or tic disorder (Price et al. 1985; disease-associated loci, may address this issue. A current
Hyde et al. 1992). study using transcriptome analysis of post-mortem striatal
Despite a strong hereditary component, Tourette syn- tissue has identified significant changes in the expression of
drome presents with a range of clinical phenotypes and is gene clusters in the brain tissue of lifelong sufferers with
therefore often considered to be a genetically heteroge- severe GTS (Lennington et al. 2016). Ten modules of co-
neous disorder (Jankovic 2001; Grados and Mathews 2009; expressed genes revealed 309 down-regulated interneuron-
Ali et al. 2013; Cavanna and Rickards 2013). Presently, the related genes and 822 up-regulated immune-related genes.
most prominent chromosome aberration is associated with No significant correlation was found between the expres-
the SLITRK1 gene on chromosome 13 (Abelson et al. sion of the two classes of transcripts, suggesting that they
2005). This gene has been shown to control neurite out- may independently contribute to GTS pathophysiology.
growth and is expressed in the cortex, thalamus and basal Thus, decreases in the signaling of various classes of
ganglia, all areas intimately implicated in the pathophysi- interneurons in the striatum as well as aberrant activation
ology of Tourette syndrome (Abelson et al. 2005; Proenca of the immune system could each be contributing factors to
et al. 2011). Another locus of interest is on chromosome dysfunction.
15, the L-histidine decarboxylase (HDC) gene (Ercan-
Sencicek et al. 2010; Karagiannidis et al. 2013; Castellan
Baldan et al. 2014). The enzyme expressed by this gene Anatomy and Pathophysiology
converts L-histidine to histamine, which in turn regulates
neurotransmission. Clearly, any alteration in this gene In addition to genetic studies, electrophysiological, imag-
could lead to dysregulation of the information processing ing and modeling investigations have provided many new
necessary for proper motor, cognitive, and executive insights into the possible pathomechanism(s) of GTS; still,
function. Indeed, observations of HDC-deficient related its etiopathology has yet to be elucidated. Nonetheless, it is
symptoms in humans were later supported by animal believed that Tourette syndrome results from dysfunction
experiments, in which similar sensorimotor and behavioral in the cortico-basal ganglia–thalamo–cortical network
symptomatology was reproduced in mice (Castellan-Bal- (CBGTC) (Leckman et al. 1997; Mink 2001). The circuits
dan et al. 2014). Although these are the most promising of the CBGTC are reported to control motor, emotional,
leads in the search for the genetic underpinnings of the and adaptive function as well as the ability to reason
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10 Brain Topogr (2017) 30:3–29
GP i /SNr
delivers a net excitatory effect on the GPi/SNr, causing
thalamic inhibition and the suppression of alternate,
Direct pathway
Indirect pathway
unwanted motor behaviors.
Hyperdirect pathway This dualistic model eventually gave way to a new tri-
GABAergic/inhibitory
Brainstem partite theory which includes the ‘‘hyperdirect’’ pathway.
Glutamatergic/excitatory
Dopaminergic/neuromodulatory In the hyperdirect pathway, information is monosynapti-
cally communicated from motor and non-motor cortical
subsequently suggested, and is necessary for the perfor- areas to the STN, bypassing the striatum. Information can
mance of such tasks as the learning and execution of then travel to the thalamus with faster conduction times via
appropriate behavioral responses (Alexander et al. 1986; direct efferents from the STN to the GPi/SNr. This
Joel and Weiner 1994; Haber and Calzavara 2009). Inte- scheme creates a triphasic temporal effect on the thalamus
gration within the network is the foundation upon which (Nambu et al. 2002). Via the fast conducting hyperdirect
motivation is translated into movement-requiring, goal- pathway, the thalamus is initially inhibited; it is then sub-
oriented behavior and, ultimately, habit formation (Frank sequently disinhibited by the direct pathway, with the
2009; Maia and Frank 2011; Moustafa et al. 2014). indirect pathway finally exerting inhibition once more. This
The CBGTC consists of mono- and poly-synaptic ‘‘di- arrangement could allow for precise selection of action,
rect’’ and ‘‘indirect’’ pathways (see Fig. 2b) which are with a circumscribed initiation and termination.
organized topographically and distinguishable histologi- In addition to this temporal organization, communica-
cally (Kalanithi et al. 2005; Haber and Calzavara 2009). tion between nuclei of the CBGTC also exhibits a distinct
Historically, the direct and indirect pathways were believed spatial organization due to differential anatomical con-
to effect the mechanism of motor control by tandem nections. An example of this is the powerful striatal and
operation. In the direct pathway, excitatory input from the STN efferents which are of opposite polarity, but converge
cortex activates inhibitory output from the striatum which upon individual pallidal neurons (in both segments of the
suppresses the spontaneously active basal ganglia output globus pallidus). Although converging on a single cell, the
nuclei’s (GPi/SNr) inhibitory output, thus disinhibiting or STN-pallidum fibers provide broad arborizations synapsing
releasing the thalamus (see Table 1). This is the mecha- onto the proximal dendrites of pallidal neurons with highly
nism suggested for motor program selection. By modulat- branched collaterals closely surrounding their somata,
ing inhibition at multiple levels, the indirect pathway while the distal end of striatal-pallidal fibers closely
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Fig. 2 Anatamo-functional organization of the circuits of the CBGTC illustrated using diffusion tensor imaging. All pathways originate from
network. a Re-entrant circuits of the CBGTC form functionally and the cortex and make variable successive (and some branched) synaptic
anatomically distributed, parallel circuits which integrate to perform connections en route to the GPi/SNr. The thalamus receives organized,
massive processing in different brain areas collectively serving the synthesized information from the GPi/SNr. In turn, it performs further
same function. Disturbances are observed in motor, limbic, and processing and integration of impulses before conveying such to the
associative functions in Tourette syndrome. The motor loop is derived cortex. Arrows indicate excitation while vertical bars indicate
from the primary motor, premotor, and supplementary motor cortex; inhibition. Data collected from thirty subjects participating in the
the associative loop is derived from the dorsolateral prefrontal cortex; human connectome project; rendering generated with TrackVis
the limbic loop is derived from the anterior cingulate and orbitofrontal software with subcortical structures based on the Harvard-Oxford
cortex. Figure modified from (Volkmann et al. 2010). Anatomical and Atlasing of the Basal Ganglia atlases. Modified from Andreas Horn
abbreviations as in Fig. 1b. b Anatomical representation of the human (own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-
motor CBGTC with the direct, indirect and hyperdirect pathways sa/4.0)
embrace pallidal dendrites (see Fig. 3) (Hazrati and Parent actions are allowed by focused activation (via disinhibi-
1992a, b). This contributes to a ‘‘center-surround’’ orga- tion) on a longer timescale of the circumscribed center area
nization (see Fig. 4) (Nambu 2007). of thalamic neurons via the direct pathway. In contrast and
The configuration of this dynamic spatio-temporal in parallel, the hyperdirect and indirect pathways, involv-
model is purported to actualize the coordination of vol- ing subthalamo–pallidal connections, produce extensive
untary actions (Nambu et al. 2002; Haber 2008). Desired activation of the output nuclei of the basal ganglia,
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12 Brain Topogr (2017) 30:3–29
resulting in inhibition of large areas of thalamus and the This imbalance between facilitation and inhibition has
cancellation of unwarranted, competing motor programs. also been implicated in habit formation. The conversion of
The physiology and microanatomy of the circuit provide a a desired motor program (goal-directed behavior) into a
temporal and spatial organization which tightly controls habit (automated responses) requires proactive inhibitory
action gating. Activity imbalance in these pathways is control and the participation of the associative and motor
shown to produce a range of hypo- and hyper-kinetic dis- circuits of the CBGTC, respectively (Aron 2011; Jahan-
orders, such as Parkinson’s and hemiballismus. shahi et al. 2015). The suppression of tics in response to
premonitory urges postulates the imposition of goal-di-
rected inhibition. Investigations of spontaneous versus
imitation tics suggest the former are due to either a
reduction in the activation of the mechanisms of habitual
inhibition or hyper-active generation of habitual actions
(Jahanshahi et al. 2015).
The modulatory role of dopamine (DA) in the CBGTC
is crucial for learning habits and for driving the transition
between goal-directed behavior and habit formation (Wong
et al. 2006). Reinforcement learning is suggested to occur
in part due to the dopaminergic cells of the SNc. These
neurons code reinforcement prediction errors which signal
the difference between observed versus predicted events
(Nambu 2008; Maia 2009). Such salient stimuli direct the
responsiveness of striatal projection neurons, in part due to
the ability also of the SNc to alter synaptic efficacy at the
cortico-striatal synapse (see Fig. 5) (Leckman et al. 2006;
Nambu 2008). This reinforcement of salient stimuli con-
tributes to habit formation.
Children and adults with GTS present with impaired
habit learning such that rate of learning inversely correlates
Fig. 3 Characterization of basal ganglia synapses. The GPi receives with tic severity (Marsh et al. 2004). Perturbation of DA
input from basal ganglia nuclei via the direct and indirect pathways. It
has been shown that both the strongly inhibitory cells of the striatum
neurotransmission and decrease in intrastriatal inhibition
and the powerfully excitatory cells of the STN send efferents are factors that could give rise to each, respectively. Such
converging upon single pallidal cells (Hazrati and Parent 1992a). The pathologies have been reported. The efficacy of DA
micro-architectural arrangement of these inputs is an important antagonists in relieving tics has led to a predominant theory
determinant for the integration and transformation of information.
Direct input from striatal efferents closely embraces distal GPi
of DA dysfunction, and various studies report structural
dendrites (yellow circles) while their polysynaptic input via the GPe changes in the striatum, including a decrease in the number
forms a tight pericellular arrangement on the somato-dendritic of parvalbumin-immunoreactive striatal interneurons
domain (orange circles). The latter produce a strong inhibitory effect (Kalanithi et al. 2005; Kataoka et al. 2010; Buse et al.
because of their size and location on the post-synaptic pallidal
neurons. STN-pallidal (both GPi and GPe) fibers produce a strong
2013).
excitatory effect directly on the cell bodies (red circles), but also exert There is much support for CBGTC in the pathophysi-
some influence on pallidal dendrites with their collaterals that loosely ology of Tourette, but other brain regions may also
entwine them. The small terminals expressed by the STN on distal engender GTS dysfunction. Numerous other areas have
GPi dendrites are much fewer than the striato-pallidal synapses by
comparison. Figure modified from Hazrati and Parent (1992a) (Color
been targeted as regions of interest in GTS, either via direct
figure online) interaction with the CBGTC or through different
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Brain Topogr (2017) 30:3–29 13
Fig. 4 Center-surround model for action selection. Schematic dia- respectively—has broad spatial effects on the GPi/SNr. These
gram represents the contribution of the direct, indirect and hyperdirect pathways are suggested to effectuate precision initiation and termi-
pathways to motor action selection. Cortical input travels serially nation of selected motor programs in addition to inhibiting
from the striatum to the GPi/SNr to the thalamus in the direct pathway unwanted/competing ones. Effects of cortical input on spiking
(center figure). Inhibitory GABAergic input from the striatum to the activity in the hyperdirect and indirect pathways are represented in
spontaneously active pallido-nigral target results in disinhibition of the hypothetical time series in the left panel. The hyperdirect pathway
the thalamus, allowing it to activate the cortex and select the desired is represented to the left of the indirect pathway in both panels to
motor program. Sequential effects of cortical input on the spiking indicate timing effects on the neuronal stream. The physiology and
activity of these structures in the direct pathway are represented in the microanatomy of the circuit provide a temporal and spatial organi-
right panel. Excitatory STN input from the hyperdirect and indirect zation which tightly controls action gating. Figure modified from
pathways—working on both a faster and slower time scale, Nambu (2008)
mechanisms. Foremost among these is the cerebellum, parameters in adults includes changes in both gray and
owing to its role in motor function as well as learning and white matter (Liu et al. 2013). Structural changes have
plasticity (Tobe et al. 2010). Unlike basal ganglia diseases been reported in the prefrontal cortex, limbic structures and
which are associated with impairment of involuntary basal ganglia of individuals with GTS, consistent with the
movement, cerebellar disorders are associated with failing dysfunction and natural history characteristic of the disor-
of voluntary movement. The role of the cerebellum in the der (Singer et al. 1993; Hyde et al. 1995; Peterson et al.
pathophysiology of GTS was most recently supported in an 2003; Bloch et al. 2005; Plessen et al. 2009). Reduction in
investigation in which vocal and motor tics were induced caudate volume has been correlated with symptomatology
by focal disruption in ventral and motor striatum, respec- in both children and adults (Hyde et al. 1995; Peterson
tively (McCairn et al. 2016). Interestingly, metabolic et al. 2003; Bloch et al. 2005). Childhood caudate volume
observations in those experiments also implicated the was observed to be a predictor of symptom severity in early
hippocampus and amygdala, although the other subcortical adulthood (Bloch et al. 2005). In a longitudinal magnetic
nuclei of the CBGTC were not associated. Additional resonance imaging (MRI) study, Bloch et al. showed a
implicated nuclei include the pedunculopontine, with its strong inverse correlation between caudate volumes in
reciprocal connections to the STN, and dorsal raphe, due to children and tic severity and OCD symptomatology later in
their projections to DA neurons. life. In contrast to this, an MRI study of monozygotic
twins, concordant for the presence of GTS but discordant
Pathology: Anatomic for its severity, while finding a slightly reduced right
caudate volume in the more severely affected twin,
Prevailing theories suggest the disturbances observed in nonetheless emphasized the proportional loss of ventricular
GTS and its associated comorbidities arise as a conse- asymmetry to the degree of clinical severity (Hyde et al.
quence of disturbances in the structural and functional 1995). MRI in a large cohort of GTS sufferers demon-
components of the CBGTC-namely the cortex, basal gan- strated reduced bilateral cerebellar surface volumes pro-
glia and thalamus. Alteration of brain morphological portionally correlated with increased tic severity (Tobe
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14 Brain Topogr (2017) 30:3–29
Fig. 5 Neuromodulation of striatal afferents and efferents. a Medium mechanism by which dopamine exerts modulatory control over the
spiny neuron. Image of medium spiny neuron (MSN) showing activity of the direct and indirect pathways and thus regulates
dendritic spines, with spine neck and spine head clearly identified. behavior. Striatal MSNs of the direct pathway are differentially
Neuron with Enhanced Green Fluorescent Protein imaged using laser excited by D1 receptors which activate adenylyl cyclase, while MSNs
scanning two photon microscope. b Neuromodulation of excitatory of the indirect pathway express predominantly D2 receptors which
glutamatergic cortico-striatal input by dopaminergic nigro-striatal inhibit adenylyl cyclase. Tic expression may be the result of excessive
input. Cortical neurons make excitatory glutamatergic synapses on the activation of the direct versus indirect pathway, explaining the
heads of the dendritic spines of striatal MSNs. The dopaminergic SNc success of D2 antagonists in relieving tics. The interactions of these
neurons exert modulatory control over cortico-striatal connections by neurons at the level of the synapse can result in plasticity, such as
synapsing on the necks of MSN spines, affecting the efficacy of occurs as a result of activation of AMPA/NMDA and DA receptors.
cortical inputs via the widespread distribution of dopaminergic D1R D1 subtype of the dopamine receptor, D2R D2 subtype of the
receptors on the cell membrane. Additionally, the striatum is the dopamine receptor, NMDAR N-methyl-D-aspartate receptor, AMPAR
primary target of dopaminergic signals; thus, it is well-positioned to a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, AC
regulate cortico-striatal plasticity. c Schematic diagram showing adenylyl cyclase, ATP adenosine triphosphate, cAMP 30 ,50 -cyclic
micro-anatomical arrangement and associated biochemical interac- AMP
tions of cortical, SNc and striatal neurons. This organization is the
et al. 2010). For OCD comorbid cases, the results were a 50–60 % decrease in the number of interneurons. In the
reversed with increasing hypertrophy in the lateral cere- pallidum, the GPi has shown increases in the total number
bellar hemispheres bilaterally, correlated with progres- of parvalbumin expressing neurons, while the GPe and
sively more severe OCD symptoms. caudate showed a decrease in the number and density of
Various imaging studies have shown decreases in the these cells (Kalanithi et al. 2005; Kataoka et al. 2010).
volumes of the caudate, putamen, and globus pallidus. Careful examination of the literature reveals some
Neuropathological studies have also shown structural inconsistencies and conflicting results using imaging and
alterations. The sensorimotor caudate and putamen showed other indirect techniques. Such contradictions need to be
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Brain Topogr (2017) 30:3–29 15
examined for matching parameters or confounding ele- Draganski et al. reported a negative correlation between
ments. For example, conflicting reports of volume increase prefrontal cortical thickness reduction and tic severity
in the dorsolateral putamen could be attributed to other (Draganski et al. 2010). In adults, primary somatosensory
qualifying factors, such as comorbid effects (from ADHD, cortex and right dorsal premotor cortex showed increased
for example) or medication (Peterson et al. 2003; Dra- cortical thickness. Increased cortical thickness and grey
ganski et al. 2010). matter volume in the left primary somatosensory cortex
GTS subjects taking neuroleptics had significantly dif- and prefrontal cortex were also positively correlated with
fering basal ganglia volumes when compared to healthy the intensity of premonitory urges. Morphological analysis
subjects or to those not on medication (Peterson et al. of the sensorimotor cortices controlling movement and
2003). Subjects taking typical neuroleptics tended to have vocalization in affected children showed cortical thinning
significantly larger caudate and globus pallidus volumes, in the frontal and parietal lobes positively correlated with
with the putamen and ventral striatum showing the same tic severity (Sowell et al. 2008).
trend (Peterson et al. 2003; Draganski et al. 2010). In Comorbidities and tic severity modulated grey matter
contrast, subjects taking atypical neuroleptics, had slightly volumes (Draganski et al. 2010). In particular, ADHD
smaller caudate and putamen volumes, but larger globus comorbidity conferred significant effects. ADHD comorbid
pallidus volumes. This volume-modifying effect was not subjects were observed to have substantial decreases in the
seen with a-adrenergic agonists, tricyclic drugs, or specific left inferior parietal cortex and posterior hippocampus
serotonin reuptake inhibitors. bilaterally, while OCD comorbidity was not correlated with
These results should be appraised in the context of the any changes. ADHD comorbidity also determined the
known effect of neuroleptics on the basal ganglia. Inde- polarity of correlation between orbitofrontal cortex/ven-
pendent of GTS, they are recognized modifiers of basal trolateral prefrontal cortex thickness and tic severity, as
ganglia structure. For example, first generation (classic) assessed by the Yale Global Tic Severity Scale (YGTSS).
antipsychotics cause increases in caudate volume, while Those with ADHD ? GTS or ADHD ? OCD ? GTS
second generation antipsychotics have the opposite effect. were reported to show a negative correlation between
In fact, switching from the former to the latter can reverse orbitofrontal cortex/ventrolateral prefrontal cortex thick-
the effects of the first generation antipsychotics, bringing ness and tic severity, while those with only OCD ? GTS
volumes back to normal. Such drug-related effects on showed a positive correlation between thickness and tic
anatomical volumes should be considered when reporting severity (Draganski et al. 2010). Nucleus accumbens vol-
and interpreting results, both to temper over-interpretation ume was negatively correlated with severity of OCD.
and to examine for drug-modified interactions with existing White matter analysis has shown widespread abnor-
changes in brain volumes. malities in both children and adults with GTS. Tic severity
As a broad range of motor and limbic cortical regions has been reported to be inversely proportional with white
are implicated in the dysfunctional network associated with matter volume in the right frontal pole and positively
GTS, examination of their morphological changes could correlated with increases in axial diffusivity in children
provide insight into their role in the pathogenesis of GTS (Liu et al. 2013). These subjects also showed a positive
(Peterson et al. 2001; Sowell et al. 2008; Thomalla et al. correlation with mean diffusivity and tic duration. In
2009). Increased volume has been shown in dorsal lateral adults, intensity of premonitory sensations was negatively
prefrontal and parieto-occipital regions with decreases in correlated with fractional anisotropy (FA) values in the
inferior occipital volumes (Peterson et al. 2001). Addi- parietal portion of the superior longitudinal fascicle (Dra-
tionally, decreased grey matter volumes were also observed ganski et al. 2010; Liu et al. 2013). Adults also showed
in the medial orbitofrontal, anterior cingulate and ventro- significant FA decrease in the genu of the corpus callosum,
lateral prefrontal cortices and operculum bilaterally (Dra- and FA increase with mean diffusivity decrease was
ganski et al. 2010). Corpus callosum size was found to be observed bilaterally in the somatosensory area (Draganski
inversely correlated with dorsal lateral prefrontal and et al. 2010). Significant axial diffusivity and mean diffu-
orbitofrontal cortical volumes to a greater magnitude than sivity increases were reported in children in the anterior
found in controls, and positively correlated with tic severity thalamic radiation, right cingulum bundle projecting to the
(Plessen et al. 2004). In these studies, the size of the corpus cingulate gyrus, and forceps minor (Liu et al. 2013).
callosum was shown to be smaller overall in children and In a study using probabilistic tractography, as well as
larger in adults, correlating with the natural history of the FA and radial diffusivity to examine the hypothesis that
disorder. Reduced callosal size would limit interhemi- aberrant brain development affects the structural connec-
spheric communication and result in diminished input to tivity of the CBGTC in adults with GTS, Worbe/Mar-
inhibitory neurons in the prefrontal cortices. rakchi-Kacem et al. reported abnormally enhanced
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Brain Topogr (2017) 30:3–29 17
b Fig. 6 Increased gamma power correlates with symptomatology. showed a broad cross-correlation with the motor cortex in a
Comparative power spectra before and after chronic DBS therapy for natural versus imitation ticcing paradigm, suggesting a
GTS are shown. Bipolar local field potential recordings are taken
from the DBS macroelectrode, chronically implanted in the CM neurophysiological correlate for the premonitory sensations
thalami of five patients. In order to faithfully represent the thalamic that precede and drive tic behavior (Hampson et al. 2009).
network, the largest sampling of the neuronal population is taken This theory is supported by electrical stimulation of the
(channel 4 in all subjects; TS2 has a bilateral stimulator). A SMA with subdural electrodes in human epileptic subjects,
correlation was found between increased synchronization of neuronal
ensemble activity in the gamma band and improved symptomatology. which generated both movement and the urge to move
Figure modified from (Maling et al. 2012). a DBS macroelectrodes. (Fried et al. 1991).
Channel configurations for electrode recordings are shown. Channel Bilateral SMA and lateral premotor cortex, as well as
four has the largest sampling area, representing a larger network of midline activity, were shown to increase in 18F-fluo-
neuronal activity. b Electrophysiological recordings from five patients
1 month post-operatively (stimulator not yet turned on) (left graph) rodeoxyglucose PET measures, which also showed
and after 5 months (right graph). Motor and vocal tics were assessed decreased metabolic activity in the limbic caudate and
using the YGTSS. Patients who responded with significant symp- thalamus (Swain et al. 2007). In a similar study, no changes
tomatological improvements, reflected in lower YGTSS scores, in glucose metabolism overall within and between the
(responders), also showed significant increases in the spectral power
of local field potentials in the gamma range, indicating that GTS is a cerebral cortices were observed; however, the frontal and
disorder of hyposynchronization and that gamma oscillations may be temporal lobes bilaterally showed a relative hyperme-
important to the pathophysiology of GTS. After several months, tabolism in GTS patients (Chase et al. 1984). In particular,
patients one and five did not show significant clinical benefit (or an inverse correlation was shown between cortical meta-
change in YGTSS) and displayed aberrant gamma synchronization (as
evidenced by the continued absence of gamma peaks over time). bolism and severity of vocal tics in the middle and inferior
Variation was found in the final lead (electrode) location as compared portions of the frontal lobes bilaterally, while coprolalia
with the others. The absence of a normal oscillatory regime combined was associated with the left parasylvian region. Addition-
with electrode location disparities suggests that the stimulation of the ally, the basal ganglia—predominantly the striatum—ex-
CBGTC network at the level of the CM thalamus addresses the
pathophysiological basis of GTS and ‘‘corrects’’ the resulting hibited a 16 % greater glucose metabolism in GTS patients
dysfunction in signal transmission. c Acute stimulation correlates than controls.
with increase in gamma synchronization. Immediate increase in An event-related [15O] H2O PET synchronized with
thalamic gamma power was observed in response to acute DBS audio- and video-taping exploring the duration and fre-
stimulation in long term responders, indicating a physiological
importance for the role of gamma oscillations. Because changes in quency of tics showed abnormal brain activation in a dis-
synchrony are immediately observed in those who also derive the tributed neural system including regions in the neocortical,
greatest benefits from therapy chronically, gamma oscillations may be paralimbic and subcortical areas (Stern et al. 2000). Areas
critical to the pathophysiology underlying GTS and might be used as associated with sensorimotor, language, executive, and
a biomarker. Stimulus–response changes in gamma may be useful
intra-operatively in determining optimal target localization limbic functions such as the primary motor, supplementary
motor, premotor, anterior cingulate, and dorsolateral-ros-
tral prefrontal cortices; Broca’s area; insula; claustrum;
putamen and caudate were highly temporally correlated
structural connectivity between the striatum and thalamus with motor and phonic tics. These results support the the-
with primary motor and sensory cortices (Worbe et al. ory that GTS pathophysiology consists of a large scale
2015). The striatum and thalamus also exhibited abnormal network that either spontaneously initiates motor and vocal
connectivity with the paracentral lobule, SMA and parietal behavioral repertoires, or fails to suppress them.
cortices. In the subcortical aspect of the CBGTC, enhanced An investigation which also employed [15O] H2O PET
motor connectivity in the thalamo-putaminal tract showed in which vocal and motor tics were induced in non-human
strong, positive correlation with tic severity. Microstruc- primates reported a much smaller network with different
tural abnormalities of white matter were found in the activated brain regions (McCairn et al. 2016). Injection of
pathways between the cerebral cortex, basal ganglia, and the GABA antagonist bicuculline into the NA or dorso-
thalamus. Interestingly, the microstructural axonal abnor- lateral sensorimotor putamen produced repetitive complex
malities of the cortico-striatal pathways showed gender vocalizations or motor tics in the orofacial and/or the arm
dimorphism as they were more prominent in females. region, respectively. In the limbic circuit, unilateral disin-
hibition of the NA significantly increased regional cerebral
Pathology: Metabolic blood flow bilaterally in the anterior cingulate gyrus, the
amygdala and hippocampus. In the motor circuit, this
Metabolically, fMRI studies have reported increased increase in blood flow was observed ipsilaterally (to
activity in the paralimbic areas, SMA and parietal oper- injection) in M1 and contralaterally in the cerebellum post-
culum prior to ticcing (Bohlhalter et al. 2006; Hampson putamenal injection. Motor tics were not concomitant with
et al. 2009). Of these, only the SMA was activated and vocal tics and each circuit maintained its unique regions of
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18 Brain Topogr (2017) 30:3–29
increased activation for corresponding tic type. These which the CBGTC is implicated, GTS dysfunction is a
results suggest: 1) vocal and motor tics are a resultant result of hyposynchronization in the thalamic network. The
property of the interruption of GABAergic communication results of this investigation help elucidate the role of
in specific striatal regions which produce circumscribed oscillations in GTS and offer insights into the basis of tic
circuit-wide increases in activation and 2) focal interrup- genesis and expression.
tion in the limbic/motor circuit does not necessarily lead to Alteration of the functional connectivity between
widespread shared dysfunction between the circuits in the regions within the CBGTC has also been described in
larger CBGTC. individuals with GTS (Jeffries et al. 2002; Tinaz et al.
2014). Observations from 18F-fluorodeoxyglucose PET
Pathology: Functional showed ventral striatum connectivity to be most prominent,
although changes in the premotor areas, SMA, and insula
Significant alterations in the temporal patterning of neu- were also been reported. Functional connections between
ronal activity in the pathological circuit reflect changes in the motor and lateral orbitofrontal circuits were the same in
information processing and may provide insight into the GTS patients and healthy controls, but the Tourette’s group
underlying neurophysiological mechanisms of dysfunction showed a reverse polarity such that their activity was
in GTS. The use of fractional amplitude of low frequency positively coupled (increased activity in one is correlated
BOLD fluctuations in resting-state fMRI allows a quanti- with increased activity in the other). These data are col-
tative measure with more focus on neuronal fluctuations lected by indirect observations of metabolic coupling
and can be applied in the study of neurophysiology of between brain regions. Electrophysiological measures of
neuropsychiatric disorders (Zou et al. 2008; Lai and Wu the directional neuronal connectivity in the network in
2015). In such an investigation of drug-naı̈ve, pure GTS humans have not been reported to date and would con-
(no comorbidity) children, significant decrease in func- tribute to our understanding of the underlying functional
tional activity was measured in the amplitude of low fre- mechanisms of the pathophysiology of GTS (Hashemiyoon
quency fluctuations (ALFF) (0.01–0.1 Hz) and the et al. 2016).
fractional ALFF (fALFF) in multiple relevant cortical
regions (Cui et al. 2014). Significant increase in the fALFF
was observed subcortically, including in the left putamen Treatment Options
and bilateral thalami. These results are consistent with the
prevailing model of GTS dysfunction of excess striatal There is presently no cure for Tourette syndrome. Fur-
activity leading to increased thalamic activity and an thermore, because almost all cases of GTS are co-occurring
overexcited neocortex. Further support for this was found with neurobehavioral disorders, therapeutic options must
in the observation that tic severity was positively correlated aim at relieving tic severity and frequency in addition to
with increased fALFF in the thalamus, ‘‘confirming its treating the often more troublesome comorbid symptoms.
putative role in the pathogenesis of TS.’’ As such, three features of GTS should be taken into con-
In humans, the centre médian/parafascicular nucleus of sideration when planning ameliorative strategies: (1) indi-
the thalamus (CM/Pf) is the primary source of thalamo- vidualized patient portrait, due to the variability of
striatal projections, sending massive efferents to the dorsal symptom profiles that arise from a range of comorbidities;
striatum. The primate CM/Pf, via innervation of the (2) the waxing and waning of the location, frequency, and
nucleus accumbens; caudate; putamen; and cortex, is part intensity of symptoms, which can occur over a range from
of an extensive functionally-organized network with the minutes to months; and (3) the natural history of symp-
capacity to affect a broad range of basal ganglia functions tomatology, which increases then decreases from early
(Smith et al. 2014). childhood to adulthood. Treatment options are behavioral,
The physiological contribution of the human thalamus to chemical and/or surgical as symptom severity increases or
the network pathophysiology of GTS was elucidated in a as needed.
longitudinal study which recorded changes in thalamic Due to new data on the efficacy of behavior therapy
physiology over the course of DBS therapy (Maling et al. (especially ‘‘habit reversal training’’), it is now recom-
2012). Local field potential (LFP) recordings from the CM/ mended as a first-line intervention treatment for GTS
Pf revealed a correlation between tic symptomatology and (Verdellen et al. 2011; van de Griendt et al. 2013). While
spectral activity in the gamma band (see Fig. 6b). In these therapies are becoming increasingly more favorably
patients responding to therapy, a clear correlation was recognized as treatment options (in particular as safe and
shown between a decrease in tic severity and an increase in effective for children), results are comparatively slow onset
the power of synchronized gamma oscillations. This study and require further investigation to establish persistence of
demonstrated that, unlike other movement disorders in ameliorative effects. As side effects are not an issue with
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Brain Topogr (2017) 30:3–29 19
this option, it could be recommended as a supplemental DBS is FDA-approved and carries the CE-mark for
add-on treatment, to be offered alongside other therapies. movement disorders such as Parkinson’s disease and
Pharmacological interventions are typically introduced essential tremor and has been recently approved in a neu-
in moderate to severe cases. In such indications classic ropsychiatric indication, OCD. Although it is not yet
neuroleptics, which work as DA-antagonists, are still the approved in the treatment of GTS, the procedure has been
most commonly prescribed because of their ability to performed in over 120 patients in 25 centers across 14
relieve tic burden (Eddy et al. 2011). These drugs include countries since the first surgery in 1999 (Vandewalle et al.
pimozide and haloperidol, which are FDA-approved 1999; Müller-Vahl 2013; Schrock et al. 2014). The vast
antipsychotics, or risperidone, which is first-option in majority of the 48 studies published since then target only a
Europe (Roessner et al. 2011). For milder cases—if treat- single brain structure, with two targets in 10 cases and
ment is recommended—a2-adrenergic agonists are indi- three targets in one case (Schrock et al. 2014). The first
cated, in particular where ADHD comorbidity occurs DBS surgery for GTS was performed in a 42 year-old male
(Robertson and Orth 2006; Singer 2010; McNaught and whose tics decreased from 38 per minute to zero at
Mink 2011). For isolated motor tics, botulinum neurotoxin 12 months post-operatively (Vandewalle et al. 1999).
injections have been shown to be effective and well-tol-
erated (Kwak et al. 2000; Marras et al. 2001). Targeting: Surgical
No tailored drug therapy has been developed for GTS;
therefore, pharmacotherapy consists of remedies borrowed The target described by Vandewalle et al. in this inaugural
from other disorders, such as schizophrenia (McNaught case was in the medial part of the thalamus (Vandewalle
and Mink 2011). The use of antipsychotics, while effective et al. 1999). The selection of this surgical focus was
in alleviating motor symptoms, also gives rise to consid- motivated by the thalamotomies described by Hassler in
erable side effects (McNaught and Mink 2011; Ganos and 1970 (Hassler and Dieckmann 1970; Temel and Visser-
Martino 2015). This is due to their interaction with a range Vandewalle 2004; Singer 2010). The rationale for selection
of neurotransmitter systems, including the histaminergic, was to obtain the same clinical effect on GTS symptoms
serotonergic, cholinergic and alpha-adrenergic. This is a with the bilateral high frequency stimulation of DBS.
major complication of the available pharmacotherapy and Hassler performed between ten and fourteen coagulations
thus compromises its practical effectiveness. The devel- in each hemisphere, in the medial, intralaminar and ven-
opment of neuroleptics with high efficacy and low side trolateral thalamic nuclei. In order to be able to stimulate
effects, such as the now molecule-of-choice, Aripiprazole, the three groups of nuclei targeted by Hassler, the strategic
would greatly improve the options for pharmaceutical point chosen was located at the intersection between the
intervention in GTS (Hartmann and Worbe 2013). anteromedial border of the centre médian nucleus of the
In medically refractory cases, where pharmacological thalamus (CM), as part of the intralaminar thalamic nuclei;
intervention cannot provide relief, surgery is an option. the periventricular substance (substania periventricularis
Historically, surgical lesioning in a variety of target sites (Spv)), as part of the medial thalamic nuclei; and the
has been performed in debilitating cases. These included nucleus ventralis oralis internus (Voi), as part of the ven-
ablations in the thalamus, globus pallidus, frontal lobe trolateral thalamic nuclei. The trajectory for the electrode is
(bimedial frontal leucotomy and prefrontal lobotomy), ideally along the longest axis of the Voi. Based on the
limbic system (anterior cingulotomy and limbic leuco- Schaltenbrand-Wahren atlas, the coordinates for this target,
tomy), and cerebellum (Hassler and Dieckmann 1970; in relation to the line connecting the anterior with the
Temel and Visser-Vandewalle 2004; Singer 2010). posterior commissure (AC–PC line), are: 5 mm lateral to
the AC–PC line, 4 mm posterior to mid AC–PC line, and at
the level of the AC–PC line (depth coordinate).
DBS and Electrophysiology This target has been adopted by some centers, and
slightly modified by others. For example, based on their
History positive clinical results, Servello et al. utilize a target
which is 2 mm more anterior, while others stimulate the
More recently, a safer surgical option, DBS, has been center of the CM (Welter et al. 2008; Maling et al. 2012;
introduced (Vandewalle et al. 1999; Sassi et al. 2011). The Servello et al. 2016).
procedure, which remains largely unchanged since its Including the thalamus, target selection for DBS in GTS
inception, requires the electrical stimulation of deep brain has totaled nine distinct brain regions, aligned with the
structures by chronically implanted electrodes which functional neurobiopathology in the CBGTC circuit (Hariz
receive high-frequency pulses from an often subcuta- and Robertson 2010; Sassi et al. 2011). Although the
neously implanted pulse generator. therapeutic potential of these targets is an area of active
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20 Brain Topogr (2017) 30:3–29
investigation, three brain regions are commonly implanted: more inclusive range of symptoms related to motor func-
(1) the medial thalamic region with 70 reported cases, (2) tion as well as emotion and cognition.
the GPi, with 30 cases reported (14 anteromedial (topo- Targeted stimulation in alternative deep brain areas
graphically limbic area), 16 posteroventral) and (3) the should nonetheless be considered for highly circumscribed
ALIC/NA with 6 reported cases (Schrock et al. 2014). disease dimensions. Due to its various and high number of
Additionally, the GPe and the STN have each been comorbidities, GTS presents with a broad phenotypic
reported once as a target, the latter in a Parkinson’s patient range. For patients with a stronger functional bias, other
with tics. The most efficacious target appears to be the targets may be more therapeutically sensible for the relief
thalamus, but it is also the region most often targeted for of specific symptoms. For example, the posteroventrolat-
surgical intervention. eral part of the GPi could be selected for patients seeking to
relieve robust motor symptoms, while the ALIC/NA would
Targeting: Functional address neurobehavioral concerns such as obsessions and
compulsions.
In addition to the reasoning mentioned above, Vandewalle
et al. based their choice of target on the hypothesis that the Intra- and Peri-Operative Recordings
application of DBS to it would lead to the modulation of:
(1) motor symptoms via stimulation of the CM, which Despite a considerable body of work from imaging,
projects to the motor striatum (motor feedback circuit); (2) pathological and other studies to suggest mechanisms for
behavioral symptoms via stimulation of the Spv, which the pathophysiology of GTS, important questions still
projects to the ventral striatum (limbic circuit); and (3) remain. DBS has offered the opportunity for acquiring
facial tics (a predominant GTS symptom) via stimulation direct evidence of the activity in one or more component
of the Voi, because of its direct projections to the facial regions of the suspected pathophysiological pathway from
part of the (pre-) motor cortex. in vivo electrophysiological recordings in human patients.
In the neurobiological dysfunction of GTS, the thalamus Intra-operative recordings from drivable microelectrodes
is a key component both anatomically and functionally present an opportunity for single unit recordings, while
(Haber and Calzavara 2009). It is intimately involved in post-operative recordings of local field potentials can be
both the processes (such as emotions, motivation and made from implanted macroelectrodes. In 2010, the first
cognition) that lead to movement and the goal-directed thalamic physiological data from seven GTS patients
behaviors that require movement. It is well connected to undergoing DBS were reported from seven patients (Mar-
both the cortex and striatum. Located in the caudal part of ceglia et al. 2010). Action potentials from single neurons in
the intralaminar thalamus, the CM/Pf diffusely innervates the trajectory targeting the Vo complex revealed irregular
the motor, premotor and the prefrontal cortices (Parent and firing and oscillatory bursting at 4–6 mm and 1–3 mm
Parent 2005). Furthermore, in addition to being the target above target respectively. At target, a quiet zone was
of integrated basal ganglia output, it projects dense clusters reported although the authors suggest this may be due to
of axon terminals to focally innervate the striatum (Mat- the activity of the zona incerta which is actually below
sumoto et al. 2001). Beyond these, a third set of projection target.
neurons jointly innervates both the cortex and the striatum Intra-operative single neuron recordings characterized
(Parent and Parent 2005). These tightly connected func- bursting in the posterior Vo region of the thalamus in
tional circuits signify the importance of the CM/Pf, which anaesthetized patients, consistent with low frequency tha-
has a pivotal role in the state setting modulatory system of lamic bursting reported in the thalamic nuclei of various
the brain (where it affects both arousal and attention) and is other neurological disorders (Marceglia et al. 2010; Priori
intimately associated with the basal ganglia action-gating et al. 2013). Analysis of local field potential (LFP)
circuit (Matsumoto et al. 2001; Parent and Parent 2005). recordings in the same region in the same patients—while
The CM/Pf is well-situated to synthesize, organize and not ticcing—2 days post-operatively exhibited prominent
control the information transmitted to both the cortex and oscillations in the delta, theta, and alpha range (Marceglia
striatum. In other words, the parallel and ‘segregated’ et al. 2010).
pathways of the CBGTC create a rich network with the In eight patients undergoing pallidotomy, similar
thalamus potentially ‘‘in the driver’s seat’’, modulating bursting activity, in addition to pauses in tonic activity, was
other structures. The regulatory functions of the thalamus observed in the GPi in 45 % of recorded neurons (Zhuang
are already well-documented in other systems (e.g. visual et al. 2009). Most of this activity was predominantly syn-
and auditory). With the thalamus strategically positioned in chronous (*71 %). A little over 25 % of these occurred
this widely distributed, finely tuned, complex network, its prior to EMG onset, mostly with increased activity
use as a target for therapeutic DBS for GTS could resolve a (*78 %), although some exhibited decreased activity
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Brain Topogr (2017) 30:3–29 21
(22 %). A very small percentage of recorded neurons study also exhibited the largest increases in gamma power
(*3 %) followed EMG onset. Pallidal neurons also at 6 months2 (see Fig. 6b). Non-responders to DBS did not
showed decreased neuronal firing rate and irregular pattern. show significant improvement clinically and did not exhibit
gamma oscillations. Gamma band activity is characteristic
Acute and Chronic Recordings of normal thalamic information processing (Llinas and
Ribary 1993; Steriade et al. 1993, 1996). The therapeutic
Recordings from intra- and peri-operative studies offer a effect of DBS may be the functional restoration of effective
precious opportunity to extract information directly from communication. This is reflected in the increased syn-
the human brain in vivo. By themselves, however, they chronization of neurons contributing to gamma synchro-
face severe limitations. While the thalamic study reported nized activity.
for the first time the electrophysiology of the Vo, the The short term effect of DBS on the thalamic network
neurophysiological properties described were neither was also tested. One minute DBS-OFF recordings were
unique to the target nor to the disorder, GTS (Marceglia taken during a relaxed awake state before and after 30 s
et al. 2010; Priori et al. 2013). Additionally, no other stimulation at the therapeutic settings. Spectral difference
measures were taken to assure correlation to tic expression, plots showed a statistically significant increase in gamma
and LFPs were taken in the absence of ticcing. The power in the right hemisphere of three patients, two of
recordings of GPi neurons from patients undergoing pal- them also responders in the chronic DBS data set (see
lidotomy addressed this issue by utilizing EMG to show Fig. 6c). No significant changes were seen in any of the
correlation between neurophysiological behavior and tic patients’ left hemispheres.
behavior. As the first ever longitudinal study of the effects of DBS
These studies provide first approaches to gaining a better on the dynamic changes in specific frequency bands in
understanding of the neurophysiology of relevant deep human GTS patients, this study addresses a vital gap in our
brain nuclei in the human GTS brain; however, such acute knowledge of the neural correlates of symptomatology as
studies suffer from two major failings. First, they are well as dynamic physiological responses to DBS therapy
potentially confounded by the notable microlesion effect, over time. The results of this study suggest that dynamic
which can induce biochemical responses in neurons and changes in gamma band power are relevant to the patho-
persist up to 2–3 months post-operatively (Granziera et al. physiology underlying GTS, and support the hypothesis
2008; Pourfar et al. 2009; Tykocki et al. 2013). Second, that the CM thalamus is an important therapeutic focus in
they do not explain the underlying neurophysiological its pathological circuit dysfunction.
dynamics that support the pathology and how these are
altered as a result of therapy. Such information must come Network Dynamics
from chronic recordings from in-dwelling electrodes.
Recordings from electrodes implanted inside the human The functional relevance of the thalamic network is sug-
brain offer a rare opportunity to observe neuronal behavior gested by both the gamma amplitude and its correlation
correlated with disease state. In 2012, Maling/Hashemiy- strength to improved symptomatology when comparing
oon et al. reported on the first and only study to date from results from more circumscribed bipolar electrode record-
direct, chronic recordings in the human CM thalamus over ings to that of the largest sampling area. Although all
the course of DBS therapy (Maling et al. 2012). This channels showed changes in gamma power correlated with
investigation in a cohort of five subjects tracked over decreased tic severity, the fluctuations were greatest in
6 months focused on the pathophysiological dynamics of channel four. This channel represented the largest sampling
the thalamic network in response to a therapeutic modality. of population activity because it had the largest spatial
Using the NeuropaceTM system, LFP recordings were made sampling area (the greatest possible lead distribution,
from the implanted macroelectrodes of the DBS device and across contacts 1–4) (see Fig. 6a).
analyzed in relation to GTS symptomatology. Temporal The collective activity of neuronal ensembles gives rise to
analysis of the spectral characteristics of LFP recordings in neuronal oscillations, which reflect the specific temporal
the CM thalamus was correlated with the clinical benefit coordination of the population. There is extensive evidence
derived by each subject, typically tracked on a monthly that this coordinated activity (synchronized oscillations) is
basis. The results of this study showed the first clinical associated with a wide range of functions as part of the normal
correlation between GTS symptomatology and a band- communication found in healthy brain processes. Pathologi-
specific oscillatory frequency. A clear correlation was cal states of brain dysfunction are expressed as altered coor-
shown between a decrease in tic severity and an increase in dination states, represented neurophysiologically as perverted
the power of gamma synchronized oscillations. Patients
2
with the best clinical outcomes over the duration of the One patient was presented at 5 months.
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22 Brain Topogr (2017) 30:3–29
rhythms. Aberrant oscillations have been associated with a are a reflection of network activity and thus, some func-
variety of disorders and have become the focus of intense tional parameter of information processing in the thalamus.
examination over the last years (Llinas et al. 1999; Brown As there is a close correlation between aberrant oscillatory
2003; Uhlhaas and Singer 2006; Maling et al. 2012). activity and variation in the disease state (e.g. Parkinson’s
One theory which sparked the movement towards disease (aberrant beta) versus GTS (aberrant gamma)),
understanding neurological and neuropsychiatric disorders dynamic changes that occur in neuronal networks in
in terms of abnormal synchronization patterns is that of response to DBS therapy contribute specific information to
thalamocortical dysrhythmia (TCD) (Llinas et al. 1999; the possible pathological mechanism of impairment among
McCormick 1999). TCD suggests that the mechanism that other things in the coherence matrix. The results of this
produces disorders from Parkinson’s disease to depression study, therefore, suggest that oscillations have a functional
is the same and that it is functionally based on the elec- role in the pathophysiology of GTS.
trophysiological properties of the thalamocortical loop. The
two main tenants of TCD are (1) a shift to persistent theta
oscillations and (2) large-scale coherence that unremit- Conclusions, Discussion and Future Directions
tingly restricts and alters the dynamic reorganization of the
brain. This widespread activity results in an ectopic gamma There is at present no scientifically described category for
that arises from ‘‘an edge effect’’. Gilles de la Tourette syndrome (Cavanna and Rickards
So influential was this theory that it was purported to be 2013). While there is much contributory information
the mechanism underlying tic genesis in GTS by one of the accounting for it, there is an enormous explanatory gap
most renowned figures in the field (Leckman et al. 2006). between the descriptive definition presently available and a
In the absence of any direct, electrophysiological record- true neurobiological understanding of it. Like other psy-
ings to the contrary, this hypothesis of hypersynchroniza- chiatric disorders, diagnosis is ‘‘restricted to subjective
tion was entirely plausible. In order to test the theory and symptoms and observable signs’’ (Insel and Cuthbert
definitively determine its validity, similar analyses were 2015). The rigorous application of behavioral, biological
performed using the chronic LFP recordings of the and computational measures to the dysfunctional brain
thalamus. states giving rise to GTS and other psychiatric disorders
The first line of comparison was a determination of theta will not only offer a more complete characterization of
behavior in GTS. To adhere to the most important char- them, but also provide firm, scientifically quantifiable cri-
acteristic distinguishing theta rhythmicity, theta power terion for them. This lays the foundation for precision
would have to be either consistently high, or increase with medicine, where distinct aspects of underlying dysfunction
increased severity of symptoms. Neither was the case. In can be targeted to deliver consistently successful therapies
fact no consistent correlation was observed between the for optimized patient care.
theta band and changes in symptomatology, its behavior Because definitive diagnostic tests are as of yet still
seemed independent of such changes (Maling et al. 2012). lacking, GTS is presently classified by the observation of
The second and perhaps most telling analysis was of symptoms. As comorbidities can be exceedingly high (up
spectral power correlation plots. Using the nearly identical to 90 % in specialized clinics), in particular with OCD and
algorithm described in the original paper, frequencies were ADHD, it becomes nontrivial to establish the etiological
plotted to find the cross-frequency coherence between theta basis of the wide range of phenotypes observed in such
and gamma power. Here the results were quite interesting. patients (Grados and Mathews 2009). The complex profile
Increased theta-gamma correlations were not linked to regularly—and rightfully—attributed to these individuals
greater dysfunctional state, but rather the contrary (un- has led to the practical consideration of typing GTS. When
published results). They were observed to be increasing in the typing includes OCD, three classes emerge: TS only,
coherence in correlation with improving symptomatology. TS ? OCD, and TS ? OCD ? ADHD. Of these, the first
However, similar to fluctuations purely in the gamma band, and the last are considered authentically heritable. This is
the results were non-linear. Rather, the largest power particularly interesting—and confounding—when one
changes occurred when the greatest change in tic severity considers how intimately compulsions are related to tics;
occurred as indicated by a decrease inYGTSS scores. Thus, and yet, it is the addition of ADHD that provides evidence
it wasn’t the lowest score that showed the highest coher- of a shared genetic foundation.
ence, but rather the greatest drop in score (D). It has been suggested that GTS is a neuropsychiatric
Additionally, dynamic patterning was observed in the spectrum disorder. While it shares many commonalities
coherence matrix between frequencies which fluctuated with OCD and ADHD—and all three are disorders
with behavioral state (personal observation). These alter- exhibiting excessive activity—the strong asymmetries
ations in the coordination matrices of recorded ensembles between their profiles are a red flag. Of particular note is
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Brain Topogr (2017) 30:3–29 23
the extremely low comorbidity of OCD/ADHD with GTS. symptoms of various disorders including Parkinson’s disease,
This small percentage may represent where the true heri- Huntington’s disease, GTS, OCD, ADHD and others.
tability between these groups can be found, substantiating Intrinsic or extrinsic mechanisms, like plasticity or DBS,
the conclusions of the GWAS of GTS and OCD: that these may be employed to recalibrate the neuronal equilibrium of
highly comorbid disorders have a complex genetic rela- network interactions (McIntyre et al. 2004; Babadi and
tionship but do not share a genetic architecture. This could Abbott 2010; Maling et al. 2012; Hashemiyoon 2013). This
be expressed as similarities and differences in pathophys- could be quantitatively measured by analysis of the chan-
iological mechanisms and neural networks circuits. The ges in the activation of neuronal ensembles, such as indi-
correlations and asymmetries observed in GTS comor- cated by alteration in their levels of synchronization. Such
bidities could be a staple for gene studies which go beyond calculations directly address important questions about the
the simple phenotypic expression of observable traits. underlying mechanisms of GTS pathophysiology.
Exploration of the genetic basis of certain endopheno- Aberrant oscillatory behavior has been suggested to
types may be profitable (Gould and Gottesman 2006). GTS subserve various neuropsychiatric disorders and has been
presents with a broad range of phenotypes which may arise reported in GTS (Llinas et al. 1999; Uhlhaas and Singer
from a heterogeneous genetic profile. Plausibly, the trans- 2006; Maling et al. 2012). Changes in the synchronized
lation of such varied genetic expression is the variety of rhythms of specific frequency band activity (such as
structural and functional abnormalities detected in the gamma) are reflected as neurophysiological fluctuations
Tourette brain. Such a complex clinical and biological that could be correlated with alterations in motor and/or
picture is especially challenging for the discovery of risk- behavioral impairment, measurable by a relevant clinical
conferring common genetic variants. It is unsurprising metric (such as the YGTSS). DBS offers the unique
then, that GWAS have thus far not reported any. A opportunity to take direct electrophysiological recordings
promising method for addressing these issues is gene net- from the purported areas of dysfunction in neuropsychiatric
work analysis. Analyses based on differential gene disorders in humans. By tracking specific neurobiological
expression with gene co-expression allow the identification changes in dysfunctional networks, potential biomarkers
of relevant gene networks of the disease state to be dis- for GTS could be revealed.
tinguished. By examining co-regulated patterns of gene Unfortunately, there are precious few direct investiga-
expression, gene network analysis can link the translational tions of the dynamic changes in pathology in humans. To
changes in the expression of gene clusters with clinical date, there is only one longitudinal study reported in human
reports of the observed endophenotypes. subjects to quantify the underlying neurophysiological
GTS has been studied extensively using imaging and dynamics as correlated with therapeutic effect (Maling
other indirect techniques that have shown structural and et al. 2012). That study revealed changes in the synchro-
functional abnormalities in the contributors to the CBGTC nization of gamma oscillations in the thalamic network of
circuit. However, results of these studies are conflicting GTS patients in correlation with changes in symptomatol-
and/or have not been replicated, in addition to being ogy resulting from DBS therapy. Furthermore, changes in
inherently more circumstantial. Moving forward, these theta/gamma coherence have been correlated with changes
studies would benefit from increased parameter control, in therapeutic benefit. The discovery of these neuromarkers
which includes behavioral states, therapeutic effects (such is non-trivial, both scientifically and clinically.
as neuroleptics), and comorbidities. Linking observations from different methodologies
Individuals with GTS necessarily suffer from abnormal could provide some requisite quantifiable results. Demon-
brain organization. As a self-limiting neurodevelopmental strated here for the first time is a mechanism by which
disorder, examination of the alterations in the connectivity alteration in the genetic domain generates a neuropatho-
dynamics of the CBGTC over the natural history of the dis- physiological modification of network dynamics correlated
order would reveal the dynamic spatiotemporal equilibrium with tic expression in GTS. Combining results from genetic
states of the network correlating with its dictated emergent network analyses revealing changes in interneuron-related
behavioral state. Perturbations in the balance of the anatomi- genes with results from the longitudinal DBS study indi-
cal and functional connections in the circuits of this ever- cating changes in oscillatory synchronization illustrates a
important, delicately-poised yet robust network manifest as translational effect from molecular mechanisms to network
the cognitive, motor, and/or limbic deficits in dysfunctional neurophysiology which correlates with tic symptomatol-
disease states. Fluctuations in the coordination matrices of the ogy. The down-regulation of hundreds of interneuron-re-
CBGTC network likely actualize as the biological basis of a lated genes affects the balance of excitation/inhibition
wide range of behaviors associated with the signs and necessary for proper information processing in the brain.
123
24 Brain Topogr (2017) 30:3–29
This imbalance in turn alters the structural and functional link to the Creative Commons license, and indicate if changes were
organization of the ensembles giving rise to synchronized made.
oscillatory behavior. Such changes are expressed as an
increase or decrease in the coordinated activity of neuronal
ensembles which manifests as hyper- or hypo-synchronized
References
oscillations. Thus, results from a genetic study substantiate
Abelson JF, Kwan KY, O’Roak BJ et al (2005) Sequence variants in
the findings from a DBS investigation concluding that SLITRK1 are associated with Tourette’s syndrome. Science
hyposynchronization of oscillations are correlated with tic 310:317–320. doi:10.1126/science.1116502
expression. These combined approaches offer powerful Albin RL, Mink JW (2006) Recent advances in Tourette syndrome
research. Trends Neurosci 29:175–182. doi:10.1016/j.tins.2006.
insights into tic genesis in GTS and the functional role of
01.001
oscillations in its dysfunction. Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of
Studies in human subjects are especially important for functionally segregated circuits linking basal ganglia and cortex.
psychiatric disorders, such as GTS, which suffer from Annu Rev Neurosci 9:357–381. doi:10.1146/annurev.ne.09.
030186.002041
insufficient animal models (Salgado and Sandner 2013).
Ali F, Morrison KE, Cavanna AE (2013) The complex genetics of
Results from human investigations can be apparently and Gilles de la Tourette syndrome: implications for clinical
swiftly applicable to the understanding and treatment of the practice. Neuropsychiatry 3:321–330. doi:10.2217/npy.13.25
associated disorders, and effect the development of American Psychiatric Association (2013) Diagnostic and statistical
manual of mental disorders, 5th edn. American Psychiatric
improved therapeutic interventions.
Publishing, Arlington
Knowledge of biomarkers and their specific character- Aron AR (2011) From reactive to proactive and selective control:
istic involvement in the disease state are valuable for the developing a richer model for stopping inappropriate responses.
development of next-generation technologies such as Biol Psychiatry 69:e55–e68. doi:10.1016/j.biopsych.2010.07.024
Aylward EH, Reiss AL, Reader MJ, Singer HS, Brown JE, Denckla
closed-loop stimulation. Patient care would greatly benefit
MB (1996) Basal ganglia volumes in children with attention-
because of: (1) on-board improvements in target localiza- deficit hyperactivity disorder. J Child Neurol 11:112–115
tion intra-operatively, (2) tailored treatment postopera- Babadi B, Abbott LF (2010) Intrinsic stability of temporally shifted
tively, and (3) objective therapeutic assessment of the spike-timing dependent plasticity. PLoS Comput Biol
6:e1000961. doi:10.1371/journal.pcbi.1000961
efficacy of stimulation parameters.
Bar-Gad I, Bergman H (2001) Stepping out of the box: information
Further improvement of therapeutic strategies for patient processing in the neural networks of the basal ganglia. Curr Opin
care will come from studies which expand their scope. In Neurobiol 11:689–695
order to elucidate the role of the various structures in the Barkley R (1993) Attention-deficit hyperactivity disorder: a handbook
for diagnosis and treatment. Guilford Press, New York
complex network giving rise to GTS, simultaneous
Baron-Cohen S, Scahill VL, Izaguirre J, Hornsey H, Robertson MM
recordings from subcortical networks concomitant with (1999) The prevalence of Gilles de la Tourette syndrome in
cortical recordings are needed. The inclusion of modern children and adolescents with autism: a large scale study.
electrical neuroimaging methods with DBS studies is piv- Psychol Med 29:1151–1159
Bloch MH, Leckman JF (2009) Clinical course of Tourette syndrome.
otal to a more comprehensive explanation of the mecha-
J Psychosom Res 67:497–501. doi:10.1016/j.jpsychores.2009.09.
nisms subserving GTS (Michel and Murray 2012; 002
Hashemiyoon et al. 2016). Further investigations into Bloch MH, Leckman JF, Zhu H, Peterson BS (2005) Caudate
oscillations and their aberrations in the larger networks of volumes in childhood predict symptom severity in adults with
Tourette syndrome. Neurology 65:1253–1258. doi:10.1212/01.
the CBGTC and brain are essential for understanding
wnl.0000180957.98702.69
causality, function and the regulation of information inte- Bohlhalter S, Goldfine A, Matteson S et al (2006) Neural correlates of
gration. Investigation of these networks on a patient-by- tic generation in Tourette syndrome: an event-related functional
patient basis using combined cortical-subcortical record- MRI study. Brain 129:2029–2037. doi:10.1093/brain/awl050
Brown P (2003) Oscillatory nature of human basal ganglia activity:
ings delivers an improved estimation of the communication
relationship to the pathophysiology of Parkinson’s disease. Mov
between the circuit nodes for each individual and provides Disord 18:357–363. doi:10.1002/mds.10358
a platform for personalized medicine. Burd L, Freeman RD, Klug MG, Kerbeshian J (2005) Tourette
syndrome and learning disabilities. BMC Pediatr 5:34. doi:10.
Acknowledgments The authors acknowledge and offer their sincere 1186/1471-2431-5-34
appreciation to Mr. Hans-Jürgen Stoffels for his significant contri- Buse J, Schoenefeld K, Munchau A, Roessner V (2013) Neuromod-
bution and tireless efforts in creating figures and their modifications. ulation in Tourette syndrome: dopamine and beyond. Neurosci
Biobehav Rev 37:1069–1084. doi:10.1016/j.neubiorev.2012.10.
Open Access This article is distributed under the terms of the 004
Creative Commons Attribution 4.0 International License (http://crea Capriotti MR, Himle MB, Woods DW (2014) Behavioral treatments
tivecommons.org/licenses/by/4.0/), which permits unrestricted use, for Tourette syndrome. J Obs Compuls Relat Disord 3:415–420
distribution, and reproduction in any medium, provided you give Castellan Baldan L, Williams KA, Gallezot JD et al (2014) Histidine
appropriate credit to the original author(s) and the source, provide a decarboxylase deficiency causes tourette syndrome: parallel
123
Brain Topogr (2017) 30:3–29 25
findings in humans and mice. Neuron 81:77–90. doi:10.1016/j. Frank MJ (2009) Slave to the striatal habit (Commentary on Tricomi
neuron.2013.10.052 et al.). Eur J Neurosci 29:2223–2224. doi:10.1111/j.1460-9568.
Cavanna AE, Rickards H (2013) The psychopathological spectrum of 2009.06799.x
Gilles de la Tourette syndrome. Neurosci Biobehav Rev Freeman RD (2007) Tic disorders and ADHD: answers from a world-
37:1008–1015. doi:10.1016/j.neubiorev.2012.10.011 wide clinical dataset on Tourette syndrome. Eur Child Adolesc
Cavanna AE, Cavanna S, Monaco F (2008) Anger symptoms and Psychiatry 16(Suppl 1):15–23. doi:10.1007/s00787-007-1003-7
‘‘delinquent’’ behavior in Tourette syndrome with and without Freeman RD, Fast DK, Burd L, Kerbeshian J, Robertson MM, Sandor
attention deficit hyperactivity disorder. Brain Dev 30:308. P (2000) An international perspective on Tourette syndrome:
doi:10.1016/j.braindev.2007.08.012 selected findings from 3500 individuals in 22 countries. Dev
Chase TN, Foster NL, Fedio P, Brooks R, Mansi L, Kessler R, Di Med Child Neurol 42:436–447
Chiro G (1984) Gilles de la tourette syndrome: studies with the Freeman RD, Zinner SH, Muller-Vahl KR et al (2009) Coprophe-
fluorine-18-labeled fluorodeoxyglucose positron emission tomo- nomena in Tourette syndrome. Dev Med Child Neurol
graphic method. Ann Neurol 15(Suppl):S175 51:218–227. doi:10.1111/j.1469-8749.2008.03135.x
Coffey BJ, Biederman J, Smoller JW, Geller DA, Sarin P, Schwartz S, Fried I, Katz A, McCarthy G, Sass KJ, Williamson P, Spencer SS,
Kim GS (2000) Anxiety disorders and tic severity in juveniles Spencer DD (1991) Functional organization of human supple-
with Tourette’s disorder. J Am Acad Child Adolesc Psychiatry mentary motor cortex studied by electrical stimulation. J Neu-
39:562–568. doi:10.1097/00004583-200005000-00009 rosci 11:3656–3666
Cohen AJ, Leckman JF (1992) Sensory phenomena associated with Ganos C, Martino D (2015) Tics and tourette syndrome. Neurol Clin
Gilles de la Tourette’s syndrome. J Clin Psychiatry 53:319–323 33:115–136. doi:10.1016/j.ncl.2014.09.008
Cohen SC, Leckman JF, Bloch MH (2013) Clinical assessment of Ganos C, Asmuss L, Bongert J, Brandt V, Munchau A, Haggard P
Tourette syndrome and tic disorders. Neurosci Biobehav Rev (2015a) Volitional action as perceptual detection: predictors of
37:997–1007. doi:10.1016/j.neubiorev.2012.11.013 conscious intention in adolescents with tic disorders. Cortex
Conelea CA, Woods DW (2008) The influence of contextual factors 64:47–54. doi:10.1016/j.cortex.2014.09.016
on tic expression in Tourette’s syndrome: a review. J Psychosom Ganos C, Garrido A, Navalpotro-Gomez I et al (2015b) Premonitory
Res 65:487–496. doi:10.1016/j.jpsychores.2008.04.010 urge to tic in Tourette’s is associated with interoceptive
Cui Y, Jin Z, Chen X, He Y, Liang X, Zheng Y (2014) Abnormal awareness. Mov Disord 30:1198–1202. doi:10.1002/mds.26228
baseline brain activity in drug-naive patients with Tourette Ghanizadeh A, Mosallaei S (2009) Psychiatric disorders and behavioral
syndrome: a resting-state fMRI study. Front Hum Neurosci problems in children and adolescents with Tourette syndrome.
7:913. doi:10.3389/fnhum.2013.00913 Brain Dev 31:15–19. doi:10.1016/j.braindev.2008.03.010
Denys D, Tenney N, van Megen HJ, de Geus F, Westenberg HG Goetz CG, Tanner CM, Stebbins GT, Leipzig G, Carr WC (1992)
(2004) Axis I and II comorbidity in a large sample of patients Adult tics in Gilles de la Tourette’s syndrome: description and
with obsessive–compulsive disorder. J Affect Disord risk factors. Neurology 42:784–788
80:155–162. doi:10.1016/S0165-0327(03)00056-9 Goldenberg JN, Brown SB, Weiner WJ (1994) Coprolalia in younger
Doyon J, Bellec P, Amsel R et al (2009) Contributions of the basal patients with Gilles de la Tourette syndrome. Mov Disord
ganglia and functionally related brain structures to motor learning. 9:622–625. doi:10.1002/mds.870090607
Behav Brain Res 199:61–75. doi:10.1016/j.bbr.2008.11.012 Gould TD, Gottesman II (2006) Psychiatric endophenotypes and the
Draganski B, Martino D, Cavanna AE et al (2010) Multispectral brain development of valid animal models. Genes Brain Behav
morphometry in Tourette syndrome persisting into adulthood. 5:113–119. doi:10.1111/j.1601-183X.2005.00186.x
Brain 133:3661–3675. doi:10.1093/brain/awq300 Grados MA, Mathews CA (2008) Latent class analysis of Gilles de la
Draper A, Stephenson MC, Jackson GM, Pepes S, Morgan PS, Morris Tourette syndrome using comorbidities: clinical and genetic
PG, Jackson SR (2014) Increased GABA contributes to implications. Biol Psychiatry 64:219–225. doi:10.1016/j.biop
enhanced control over motor excitability in Tourette syndrome. sych.2008.01.019
Curr Biol 24:2343–2347. doi:10.1016/j.cub.2014.08.038 Grados MA, Mathews CA (2009) Clinical phenomenology and
Eapen V, Robertson MM (2015) Are there distinct subtypes in phenotype variability in Tourette syndrome. J Psychosom Res
Tourette syndrome? Pure-Tourette syndrome versus Tourette 67:491–496. doi:10.1016/j.jpsychores.2009.07.011
syndrome-plus, and simple versus complex tics. Neuropsychiatr Granziera C, Pollo C, Russmann H et al (2008) Sub-acute delayed
Dis Treat 11:1431–1436. doi:10.2147/NDT.S72284 failure of subthalamic DBS in Parkinson’s disease: the role of
Eddy CM, Rickards HE, Cavanna AE (2011) Treatment strategies for micro-lesion effect. Parkinsonism Relat Disord 14:109–113.
tics in Tourette syndrome. Ther Adv Neurol Disord 4:25–45. doi:10.1016/j.parkreldis.2007.06.013
doi:10.1177/1756285610390261 Graybiel AM (2000) The basal ganglia. Curr Biol 10:R509–R511
Ercan-Sencicek AG, Stillman AA, Ghosh AK et al (2010) L-histidine Graybiel AM (2005) The basal ganglia: learning new tricks and
decarboxylase and Tourette’s syndrome. N Engl J Med loving it. Curr Opin Neurobiol 15:638–644. doi:10.1016/j.conb.
362:1901–1908. doi:10.1056/NEJMoa0907006 2005.10.006
Fahn S, Jankovic J, Hallett M (2011) Tics and Tourette syndrome. In: Haber SN (2008) Functional anatomy and physiology of the basal
Fahn S, Jankovic J, Hallett M (eds) Principles and practice of ganglia: non-motor functions. In: Tarsy D, Vitek JL, Starr PA,
movement disorders. Elsevier, Atlanta, pp 350–379 Okun MS (eds) Current clinical neurology: deep brain stimula-
Faraone SV, Sergeant J, Gillberg C, Biederman J (2003) The tion in neurological and psychiatric disorders. Okun Humana
worldwide prevalence of ADHD: is it an American condition? Press, Totowa, pp 33–62
World Psychiatry 2:104–113 Haber SN, Calzavara R (2009) The cortico-basal ganglia integrative
Felling RJ, Singer HS (2011) Neurobiology of tourette syndrome: network: the role of the thalamus. Brain Res Bull 78:69–74.
current status and need for further investigation. J Neurosci doi:10.1016/j.brainresbull.2008.09.013
31:12387–12395. doi:10.1523/JNEUROSCI.0150-11.2011 Hallett M (2001) Neurophysiology of tics. In: Cohen DJ, Jankovic J,
Flaherty AW, Graybiel AM (1991) Corticostriatal transformations in Goetz CG (eds) Tourette syndrome. Advances in neurology.
the primate somatosensory system. Projections from physiolog- Lippincott Williams & Wilkins, Philadelphia, pp 237–244
ically mapped body-part representations. J Neurophysiol Hallett M (2015) Tourette syndrome: update. Brain Dev 37:651–655.
66:1249–1263 doi:10.1016/j.braindev.2014.11.005
123
26 Brain Topogr (2017) 30:3–29
Hammond C, Bergman H, Brown P (2007) Pathological synchro- Kadesjo B, Gillberg C (2000) Tourette’s disorder: epidemiology and
nization in Parkinson’s disease: networks, models and treat- comorbidity in primary school children. J Am Acad Child
ments. Trends Neurosci 30:357–364. doi:10.1016/j.tins.2007.05. Adolesc Psychiatry 39:548–555. doi:10.1097/00004583-
004 200005000-00007
Hampson M, Tokoglu F, King RA, Constable RT, Leckman JF (2009) Kalanithi PS, Zheng W, Kataoka Y et al (2005) Altered parvalbumin-
Brain areas coactivating with motor cortex during chronic motor positive neuron distribution in basal ganglia of individuals with
tics and intentional movements. Biol Psychiatry 65:594–599. Tourette syndrome. Proc Natl Acad Sci USA 102:13307–13312.
doi:10.1016/j.biopsych.2008.11.012 doi:10.1073/pnas.0502624102
Hanna PA, Janjua FN, Contant CF, Jankovic J (1999) Bilineal Karagiannidis I, Dehning S, Sandor P et al (2013) Support of the
transmission in Tourette syndrome. Neurology 53:813–818 histaminergic hypothesis in Tourette syndrome: association of
Hariz MI, Robertson MM (2010) Gilles de la Tourette syndrome and the histamine decarboxylase gene in a large sample of families.
deep brain stimulation. Eur J Neurosci 32:1128–1134. doi:10. J Med Genet 50:760–764. doi:10.1136/jmedgenet-2013-101637
1111/j.1460-9568.2010.07415.x Kataoka Y, Kalanithi PS, Grantz H, Schwartz ML, Saper C, Leckman
Hartmann A, Worbe Y (2013) Pharmacological treatment of Gilles de JF, Vaccarino FM (2010) Decreased number of parvalbumin and
la Tourette syndrome. Neurosci Biobehav Rev 37:1157–1161. cholinergic interneurons in the striatum of individuals with
doi:10.1016/j.neubiorev.2012.10.014 Tourette syndrome. J Comp Neurol 518:277–291. doi:10.1002/
Hashemiyoon R (2013) Plasticity, neuronal synchrony and multi- cne.22206
stability in the human thalamus. In: Proceedings of the twenty Kornhuber HH, Deecke L (1965) Changes in the brain potential in
second annual computational neuroscience meeting, Paris, voluntary movements and passive movements in man: readiness
France. doi: 10.13140/2.1.4707.4249 potential and reafferent potentials. Pflugers Arch 284:1–17
Hashemiyoon R, Tomescu M, Coito A et al (2016) Effective Kurlan R, Como PG, Miller B et al (2002) The behavioral spectrum of
connectivity of subcortical-cortical networks revealed by simul- tic disorders: a community-based study. Neurology 59:414–420
taneous scalp and depth EEG recordings in humans. Clin Kwak CH, Hanna PA, Jankovic J (2000) Botulinum toxin in the
Neurophysiol 127:e289 treatment of tics. Arch Neurol 57:1190–1193
Hassler R, Dieckmann G (1970) Stereotaxic treatment of tics and Kwak C, Vuong KD, Jankovic J (2003) Migraine headache in patients
inarticulate cries or coprolalia considered as motor obsessional with Tourette syndrome. Arch Neurol 60:1595–1598. doi:10.
phenomena in Gilles de la Tourette’s disease. Rev Neurol 1001/archneur.60.11.1595
123:89–100 Lai CH, Wu YT (2015) The patterns of fractional amplitude of low-
Hazrati LN, Parent A (1992a) Convergence of subthalamic and frequency fluctuations in depression patients: the dissociation
striatal efferents at pallidal level in primates: an anterograde between temporal regions and fronto-parietal regions. J Affect
double-labeling study with biocytin and PHA-L. Brain Res Disord 175:441–445. doi:10.1016/j.jad.2015.01.054
569:336–340 Leckman JF (2002) Tourette’s syndrome. Lancet 360:1577–1586.
Hazrati LN, Parent A (1992b) Differential patterns of arborization of doi:10.1016/S0140-6736(02)11526-1
striatal and subthalamic fibers in the two pallidal segments in Leckman JF (2003) Phenomenology of tics and natural history of tic
primates. Brain Res 598:311–315 disorders. Brain Dev 25(Suppl 1):S24–S28
Hyde TM, Aaronson BA, Randolph C, Rickler KC, Weinberger DR Leckman JF, Walker DE, Cohen DJ (1993) Premonitory urges in
(1992) Relationship of birth weight to the phenotypic expression Tourette’s syndrome. Am J Psychiatry 150:98–102. doi:10.1176/
of Gilles de la Tourette’s syndrome in monozygotic twins. ajp.150.1.98
Neurology 42:652–658 Leckman JF, Peterson BS, Anderson GM, Arnsten AF, Pauls DL,
Hyde TM, Stacey ME, Coppola R, Handel SF, Rickler KC, Cohen DJ (1997) Pathogenesis of Tourette’s syndrome. J Child
Weinberger DR (1995) Cerebral morphometric abnormalities Psychol Psychiatry 38:119–142
in Tourette’s syndrome: a quantitative MRI study of monozy- Leckman JF, Vaccarino FM, Kalanithi PS, Rothenberger A (2006)
gotic twins. Neurology 45:1176–1182 Annotation: tourette syndrome: a relentless drumbeat—driven by
Insel TR, Cuthbert BN (2015) Medicine. Brain disorders? Precisely. misguided brain oscillations. J Child Psychol Psychiatry
Science 348:499–500. doi:10.1126/science.aab2358 47:537–550. doi:10.1111/j.1469-7610.2006.01620.x
Israelashvili M, Loewenstern Y, Bar-Gad I (2015) Abnormal neuronal Leckman JF, Bloch MH, Smith ME, Larabi D, Hampson M (2010)
activity in Tourette syndrome and its modulation using deep brain Neurobiological substrates of Tourette’s disorder. J Child Ado-
stimulation. J Neurophysiol 114:6–20. doi:10.1152/jn.00277.2015 lesc Psychopharmacol 20:237–247. doi:10.1089/cap.2009.0118
Jahanshahi M, Obeso I, Rothwell JC, Obeso JA (2015) A fronto- Leisman G, Braun-Benjamin O, Melillo R (2014) Cognitive-motor
striato-subthalamic-pallidal network for goal-directed and habit- interactions of the basal ganglia in development. Front Syst
ual inhibition. Nat Rev Neurosci 16:719–732. doi:10.1038/ Neurosci 8:16. doi:10.3389/fnsys.2014.00016
nrn4038 Lenglet C, Abosch A, Yacoub E, De Martino F, Sapiro G, Harel N
Jankovic J (1997) Tourette syndrome. Phenomenology and classifi- (2012) Comprehensive in vivo mapping of the human basal
cation of tics. Neurol Clin 15:267–275 ganglia and thalamic connectome in individuals using 7T MRI.
Jankovic J (2001) Tourette’s syndrome. N Engl J Med PLoS ONE 7:e29153. doi:10.1371/journal.pone.0029153
345:1184–1192. doi:10.1056/NEJMra010032 Lennington JB, Coppola G, Kataoka-Sasaki Y et al (2016) Transcrip-
Jankovic J, Stone L (1991) Dystonic tics in patients with Tourette’s tome analysis of the human striatum in Tourette syndrome. Biol
syndrome. Mov Disord 6:248–252. doi:10.1002/mds.870060309 Psychiatry 79:372–382. doi:10.1016/j.biopsych.2014.07.018
Jeffries KJ, Schooler C, Schoenbach C, Herscovitch P, Chase TN, Libet B (1985) Unconscious cerebral initiative and the role of
Braun AR (2002) The functional neuroanatomy of Tourette’s conscious will in voluntary action. Behav Brain Sci 8:529–566
syndrome: an FDG PET study III: functional coupling of Liu Y, Miao W, Wang J et al (2013) Structural abnormalities in early
regional cerebral metabolic rates. Neuropsychopharmacology Tourette syndrome children: a combined voxel-based morphom-
27:92–104. doi:10.1016/S0893-133X(01)00428-6 etry and tract-based spatial statistics study. PLoS ONE 8:e76105.
Joel D, Weiner I (1994) The organization of the basal ganglia– doi:10.1371/journal.pone.0076105
thalamocortical circuits: open interconnected rather than closed Llinas R, Ribary U (1993) Coherent 40-Hz oscillation characterizes
segregated. Neuroscience 63:363–379 dream state in humans. Proc Natl Acad Sci USA 90:2078–2081
123
Brain Topogr (2017) 30:3–29 27
Llinas RR, Ribary U, Jeanmonod D, Kronberg E, Mitra PP (1999) Müller-Vahl KR (2013) Surgical treatment of Tourette syndrome.
Thalamocortical dysrhythmia: a neurological and neuropsychi- Neurosci Biobehav Rev 37:1178–1185. doi:10.1016/j.neubiorev.
atric syndrome characterized by magnetoencephalography. Proc 2012.09.012
Natl Acad Sci USA 96:15222–15227 Nambu A (2007) Globus pallidus internal segment. Prog Brain Res
Maia TV (2009) Reinforcement learning, conditioning, and the brain: 160:135–150. doi:10.1016/S0079-6123(06)60008-3
successes and challenges. Cogn Affect Behav Neurosci Nambu A (2008) Seven problems on the basal ganglia. Curr Opin
9:343–364. doi:10.3758/CABN.9.4.343 Neurobiol 18:595–604. doi:10.1016/j.conb.2008.11.001
Maia TV, Frank MJ (2011) From reinforcement learning models to Nambu A (2015) Functional circuitry of the basal ganglia. In: Itakura
psychiatric and neurological disorders. Nat Neurosci T (ed) DBS for neurological disorders. Springer, New York,
14:154–162. doi:10.1038/nn.2723 pp 1–11
Maling N, Hashemiyoon R, Foote KD, Okun MS, Sanchez JC (2012) Nambu A, Tokuno H, Takada M (2002) Functional significance of the
Increased thalamic gamma band activity correlates with symp- cortico–subthalamo–pallidal ‘hyperdirect’ pathway. Neurosci
tom relief following deep brain stimulation in humans with Res 43:111–117
Tourette’s syndrome. PLoS ONE 7:e44215. doi:10.1371/journal. Obeso JA, Rothwell JC, Marsden CD (1981) Simple tics in Gilles de
pone.0044215 la Tourette’s syndrome are not prefaced by a normal premove-
Marceglia S, Servello D, Foffani G et al (2010) Thalamic single-unit ment EEG potential. J Neurol Neurosurg Psychiatry 44:735–738
and local field potential activity in Tourette syndrome. Mov O’Connor K, Brisebois H, Brault M, Robillard S, Loiselle J (2003)
Disord 25:300–308. doi:10.1002/mds.22982 Behavioral activity associated with onset in chronic tic and habit
Marras C, Andrews D, Sime E, Lang AE (2001) Botulinum toxin for disorder. Behav Res Ther 41:241–249
simple motor tics: a randomized, double-blind, controlled Papa SM, Artieda J, Obeso JA (1991) Cortical activity preceding self-
clinical trial. Neurology 56:605–610 initiated and externally triggered voluntary movement. Mov
Marsh R, Alexander GM, Packard MG, Zhu H, Wingard JC, Disord 6:217–224. doi:10.1002/mds.870060305
Quackenbush G, Peterson BS (2004) Habit learning in Tourette Parent M, Parent A (2005) Single-axon tracing and three-dimensional
syndrome: a translational neuroscience approach to a develop- reconstruction of centre median-parafascicular thalamic neurons
mental psychopathology. Arch Gen Psychiatry 61:1259–1268. in primates. J Comp Neurol 481:127–144. doi:10.1002/cne.20348
doi:10.1001/archpsyc.61.12.1259 Pauls DL, Leckman JF (1986) The inheritance of Gilles de la
Marsh R, Zhu H, Wang Z, Skudlarski P, Peterson BS (2007) A Tourette’s syndrome and associated behaviors. Evidence for
developmental fMRI study of self-regulatory control in Tour- autosomal dominant transmission. N Engl J Med 315:993–997.
ette’s syndrome. Am J Psychiatry 164:955–966. doi:10.1176/ajp. doi:10.1056/NEJM198610163151604
2007.164.6.955 Peterson BS, Leckman JF (1998) The temporal dynamics of tics in
Matsumoto N, Minamimoto T, Graybiel AM, Kimura M (2001) Gilles de la Tourette syndrome. Biol Psychiatry 44:1337–1348
Neurons in the thalamic CM-Pf complex supply striatal neurons Peterson BS, Staib L, Scahill L et al (2001) Regional brain and
with information about behaviorally significant sensory events. ventricular volumes in Tourette syndrome. Arch Gen Psychiatry
J Neurophysiol 85:960–976 58:427–440
McCairn KW, Nagai Y, Hori Y et al (2016) A primary role for Peterson BS, Thomas P, Kane MJ et al (2003) Basal Ganglia volumes
nucleus accumbens and related limbic network in vocal tics. in patients with Gilles de la Tourette syndrome. Arch Gen
Neuron 89:300–307. doi:10.1016/j.neuron.2015.12.025 Psychiatry 60:415–424. doi:10.1001/archpsyc.60.4.415
McCormick DA (1999) Are thalamocortical rhythms the Rosetta Piacentini J, Himle MB, Chang S, Baruch DE, Buzzella BA,
Stone of a subset of neurological disorders? Nat Med Pearlman A, Woods DW (2006) Reactivity of tic observation
5:1349–1351. doi:10.1038/70911 procedures to situation and setting. J Abnorm Child Psychol
McIntyre CC, Savasta M, Kerkerian-Le Goff L, Vitek JL (2004) 34:649–658. doi:10.1007/s10802-006-9048-5
Uncovering the mechanism(s) of action of deep brain stimula- Piacentini J, Woods DW, Scahill L et al (2010) Behavior therapy for
tion: activation, inhibition, or both. Clin Neurophysiol children with Tourette disorder: a randomized controlled trial.
115:1239–1248. doi:10.1016/j.clinph.2003.12.024 JAMA 303:1929–1937. doi:10.1001/jama.2010.607
McNaught KS, Mink JW (2011) Advances in understanding and Pittenger C, Bloch MH, Williams K (2011) Glutamate abnormalities
treatment of Tourette syndrome. Nat Rev Neurol 7:667–676. in obsessive compulsive disorder: neurobiology, pathophysiol-
doi:10.1038/nrneurol.2011.167 ogy, and treatment. Pharmacol Ther 132:314–332. doi:10.1016/j.
Meidinger AL, Miltenberger RG, Himle M, Omvig M, Trainor C, pharmthera.2011.09.006
Crosby R (2005) An investigation of tic suppression and the Plessen KJ, Wentzel-Larsen T, Hugdahl K et al (2004) Altered
rebound effect in Tourette’s disorder. Behav Modif 29:716–745. interhemispheric connectivity in individuals with Tourette’s
doi:10.1177/0145445505279262 disorder. Am J Psychiatry 161:2028–2037. doi:10.1176/appi.ajp.
Melillo R, Leisman G (2009) Neurobehavioral disorders of child- 161.11.2028
hood: an evolutionary perspective. Springer, Dordrecht Plessen KJ, Bansal R, Peterson BS (2009) Imaging evidence for
Michel CM, Murray MM (2012) Towards the utilization of EEG as a anatomical disturbances and neuroplastic compensation in
brain imaging tool. Neuroimage 61:371–385. doi:10.1016/j. persons with Tourette syndrome. J Psychosom Res
neuroimage.2011.12.039 67:559–573. doi:10.1016/j.jpsychores.2009.07.005
Mink JW (2001) Basal ganglia dysfunction in Tourette’s syndrome: a Porta M, Brambilla A, Cavanna AE, Servello D, Sassi M, Rickards H,
new hypothesis. Pediatr Neurol 25:190–198 Robertson MM (2009a) Thalamic deep brain stimulation for
Mohammadi MR, Ghanizadeh A, Rahgozar M et al (2004) Prevalence treatment-refractory Tourette syndrome: two-year outcome.
of obsessive–compulsive disorder in Iran. BMC Psychiatry 4:2. Neurology 73:1375–1380. doi:10.1212/WNL.
doi:10.1186/1471-244X-4-2 0b013e3181bd809b
Moustafa AA, Bar-Gad I, Korngreen A, Bergman H (2014) Porta M, Servello D, Sassi M, Brambilla A, Defendi S, Priori A,
Basal ganglia: physiological, behavioral, and computational Robertson M (2009b) Issues related to deep brain stimulation for
studies. Front Syst Neurosci 8:150. doi:10.3389/fnsys.2014. treatment-refractory Tourette’s syndrome. Eur Neurol
00150 62:264–273. doi:10.1159/000235595
123
28 Brain Topogr (2017) 30:3–29
Pourfar M, Tang C, Lin T, Dhawan V, Kaplitt MG, Eidelberg D Servello D, Zekaj E, Saleh C, Lange N, Porta M (2016) Deep brain
(2009) Assessing the microlesion effect of subthalamic deep stimulation in Gilles de la Tourette syndrome: what does the
brain stimulation surgery with FDG PET. J Neurosurg future hold? A cohort of 48 patients. Neurosurgery 78:91–100.
110:1278–1282. doi:10.3171/2008.12.JNS08991 doi:10.1227/NEU.0000000000001004
Price RA, Kidd KK, Cohen DJ, Pauls DL, Leckman JF (1985) A twin Shibasaki H, Hallett M (2006) What is the Bereitschaftspotential?
study of Tourette syndrome. Arch Gen Psychiatry 42:815–820 Clin Neurophysiol 117:2341–2356. doi:10.1016/j.clinph.2006.
Priori A, Giannicola G, Rosa M, Marceglia S, Servello D, Sassi M, 04.025
Porta M (2013) Deep brain electrophysiological recordings Shprecher DR, Gannon K, Agarwal N, Shi X, Anderson JS (2014)
provide clues to the pathophysiology of Tourette syndrome. Elucidating the nature and mechanism of tic improvement in
Neurosci Biobehav Rev 37:1063–1068. doi:10.1016/j.neubiorev. tourette syndrome: a pilot study. Tremor Other Hyperkinet Mov
2013.01.011 4:217. doi:10.7916/D8TH8JQQ
Proenca CC, Gao KP, Shmelkov SV, Rafii S, Lee FS (2011) Slitrks as Singer HS (2005) Tourette’s syndrome: from behaviour to biology.
emerging candidate genes involved in neuropsychiatric disorders. Lancet Neurol 4:149–159. doi:10.1016/S1474-4422(05)01012-4
Trends Neurosci 34:143–153. doi:10.1016/j.tins.2011.01.001 Singer HS (2010) Treatment of tics and tourette syndrome. Curr Treat
Rajagopala S, Serib S, Cavanna AE (2013) Premonitory urges and Options Neurol 12:539–561. doi:10.1007/s11940-010-0095-4
sensorimotor processing in Tourette syndrome. Behav Neurol Singer HS, Reiss AL, Brown JE et al (1993) Volumetric MRI changes
27:65–73. doi:10.3233/BEN-120308 in basal ganglia of children with Tourette’s syndrome. Neurol-
Rivlin-Etzion M, Marmor O, Heimer G, Raz A, Nini A, Bergman H ogy 43:950–956
(2006) Basal ganglia oscillations and pathophysiology of Smith Y, Galvan A, Ellender TJ et al (2014) The thalamostriatal
movement disorders. Curr Opin Neurobiol 16:629–637. doi:10. system in normal and diseased states. Front Syst Neurosci 8:5.
1016/j.conb.2006.10.002 doi:10.3389/fnsys.2014.00005
Rizzo R, Curatolo P, Gulisano M, Virzi M, Arpino C, Robertson MM Sowell ER, Kan E, Yoshii J et al (2008) Thinning of sensorimotor
(2007) Disentangling the effects of Tourette syndrome and cortices in children with Tourette syndrome. Nat Neurosci
attention deficit hyperactivity disorder on cognitive and behav- 11:637–639. doi:10.1038/nn.2121
ioral phenotypes. Brain Dev 29:413–420. doi:10.1016/j.brain Steriade M, McCormick DA, Sejnowski TJ (1993) Thalamocortical
dev.2006.12.003 oscillations in the sleeping and aroused brain. Science
Robertson MM (2000) Tourette syndrome, associated conditions and 262:679–685
the complexities of treatment. Brain 123(Pt 3):425–462 Steriade M, Contreras D, Amzica F, Timofeev I (1996) Synchroniza-
Robertson MM (2008) The prevalence and epidemiology of Gilles de tion of fast (30–40 Hz) spontaneous oscillations in intrathalamic
la Tourette syndrome. Part 1: the epidemiological and preva- and thalamocortical networks. J Neurosci 16:2788–2808
lence studies. J Psychosom Res 65:461–472. doi:10.1016/j. Stern E, Silbersweig DA, Chee KY et al (2000) A functional
jpsychores.2008.03.006 neuroanatomy of tics in Tourette syndrome. Arch Gen Psychi-
Robertson MM, Orth M (2006) Behavioral and affective disorders in atry 57:741–748
Tourette syndrome. Adv Neurol 99:39–60 Swain JE, Scahill L, Lombroso PJ, King RA, Leckman JF (2007)
Roessner V, Becker A, Banaschewski T, Freeman RD, Rothenberger Tourette syndrome and tic disorders: a decade of progress. J Am
A, Tourette Syndrome International Database C (2007) Devel- Acad Child Adolesc Psychiatry 46:947–968. doi:10.1097/chi.
opmental psychopathology of children and adolescents with 0b013e318068fbcc
Tourette syndrome—impact of ADHD. Eur Child Adolesc Temel Y, Visser-Vandewalle V (2004) Surgery in Tourette syndrome.
Psychiatry 16(Suppl 1):24–35. doi:10.1007/s00787-007-1004-6 Mov Disord 19:3–14. doi:10.1002/mds.10649
Roessner V, Plessen K, Rothenberger A et al (2011) European clinical Thomalla G, Siebner HR, Jonas M et al (2009) Structural changes in
guidelines for Tourette syndrome and other tic disorders. Part II: the somatosensory system correlate with tic severity in Gilles de
pharmacological treatment. Eur Child Adolesc Psychiatry la Tourette syndrome. Brain 132:765–777. doi:10.1093/brain/
20:173–196. doi:10.1007/s00787-011-0163-7 awn339
Salgado JV, Sandner G (2013) A critical overview of animal models Thomalla G, Jonas M, Baumer T et al (2014) Costs of control:
of psychiatric disorders: challenges and perspectives. Rev Bras decreased motor cortex engagement during a Go/NoGo task in
Psiquiatr 35(Suppl 2):S77–S81. doi:10.1590/1516-4446-2013- Tourette’s syndrome. Brain 137:122–136. doi:10.1093/brain/
1156 awt288
Sassi M, Porta M, Servello D (2011) Deep brain stimulation therapy Tinaz S, Belluscio BA, Malone P, van der Veen JW, Hallett M,
for treatment-refractory Tourette’s syndrome: a review. Acta Horovitz SG (2014) Role of the sensorimotor cortex in Tourette
Neurochir 153:639–645. doi:10.1007/s00701-010-0803-6 syndrome using multimodal imaging. Hum Brain Mapp
Scharf JM, Yu D, Mathews CA et al (2013) Genome-wide association 35:5834–5846. doi:10.1002/hbm.22588
study of Tourette’s syndrome. Mol Psychiatry 18:721–728. Tinaz S, Malone P, Hallett M, Horovitz SG (2015) Role of the right
doi:10.1038/mp.2012.69 dorsal anterior insula in the urge to tic in Tourette syndrome.
Schrock LE, Mink JW, Woods DW et al (2014) Tourette syndrome Mov Disord 30:1190–1197. doi:10.1002/mds.26230
deep brain stimulation: a review and updated recommendations. Tobe RH, Bansal R, Xu D, Hao X, Liu J, Sanchez J, Peterson BS
Mov Disord. doi:10.1002/mds.26094 (2010) Cerebellar morphology in Tourette syndrome and obses-
Schultz W (2004) Neural coding of basic reward terms of animal sive–compulsive disorder. Ann Neurol 67:479–487. doi:10.1002/
learning theory, game theory, microeconomics and behavioural ana.21918
ecology. Curr Opin Neurobiol 14:139–147. doi:10.1016/j.conb. Tykocki T, Nauman P, Koziara H, Mandat T (2013) Microlesion
2004.03.017 effect as a predictor of the effectiveness of subthalamic deep
Servello D, Sassi M, Brambilla A, Porta M, Haq I, Foote KD, Okun brain stimulation for Parkinson’s disease. Stereotact Funct
MS (2009) De novo and rescue DBS leads for refractory Neurosurg 91:12–17. doi:10.1159/000342161
Tourette syndrome patients with severe comorbid OCD: a Uhlhaas PJ, Singer W (2006) Neural synchrony in brain disorders:
multiple case report. J Neurol 256:1533–1539. doi:10.1007/ relevance for cognitive dysfunctions and pathophysiology.
s00415-009-5159-6 Neuron 52:155–168. doi:10.1016/j.neuron.2006.09.020
123
Brain Topogr (2017) 30:3–29 29
van de Griendt JM, Verdellen CW, van Dijk MK, Verbraak MJ Neuropsychopharmacology 33:1239–1251. doi:10.1038/sj.npp.
(2013) Behavioural treatment of tics: habit reversal and exposure 1301528
with response prevention. Neurosci Biobehav Rev Woods DW, Watson TS, Wolfe E, Twohig MP, Friman PC (2001)
37:1172–1177. doi:10.1016/j.neubiorev.2012.10.007 Analyzing the influence of tic-related talk on vocal and motor
van der Salm SM, Tijssen MA, Koelman JH, van Rootselaar AF tics in children with Tourette’s syndrome. J Appl Behav Anal
(2012) The bereitschaftspotential in jerky movement disorders. 34:353–356. doi:10.1901/jaba.2001.34-353
J Neurol Neurosurg Psychiatry 83:1162–1167. doi:10.1136/jnnp- Woods DW, Piacentini J, Himle MB, Chang S (2005) Premonitory
2012-303081 Urge for Tics Scale (PUTS): initial psychometric results and
Vandewalle V, van der Linden C, Groenewegen HJ, Caemaert J examination of the premonitory urge phenomenon in youths with
(1999) Stereotactic treatment of Gilles de la Tourette syndrome Tic disorders. J Dev Behav Pediatr 26:397–403
by high frequency stimulation of thalamus. Lancet 353:724 Worbe Y, Malherbe C, Hartmann A et al (2012) Functional
Verdellen C, van de Griendt J, Hartmann A, Murphy T (2011) immaturity of cortico-basal ganglia networks in Gilles de la
European clinical guidelines for Tourette syndrome and other tic Tourette syndrome. Brain 135:1937–1946. doi:10.1093/brain/
disorders. Part III: behavioural and psychosocial interventions. aws056
Eur Child Adolesc Psychiatry 20:197–207. doi:10.1007/s00787- Worbe Y, Marrakchi-Kacem L, Lecomte S et al (2015) Altered
011-0167-3 structural connectivity of cortico-striato-pallido-thalamic net-
Volkmann J, Daniels C, Witt K (2010) Neuropsychiatric effects of works in Gilles de la Tourette syndrome. Brain 138:472–482.
subthalamic neurostimulation in Parkinson disease. Nat Rev doi:10.1093/brain/awu311
Neurol 6:487–498. doi:10.1038/nrneurol.2010.111 Yu D, Mathews CA, Scharf JM et al (2015) Cross-disorder genome-
Watson TS, Dufrene B, Weaver A, Butler T, Meeks C (2005) Brief wide analyses suggest a complex genetic relationship between
antecedent assessment and treatment of tics in the general Tourette’s syndrome and OCD. Am J Psychiatry 172:82–93.
education classroom: a preliminary investigation. Behav Modif doi:10.1176/appi.ajp.2014.13101306
29:839–857. doi:10.1177/0145445505279252 Zhuang P, Hallett M, Zhang X, Li J, Zhang Y, Li Y (2009) Neuronal
Welter ML, Mallet L, Houeto JL et al (2008) Internal pallidal and activity in the globus pallidus internus in patients with tics.
thalamic stimulation in patients with Tourette syndrome. Arch J Neurol Neurosurg Psychiatry 80:1075–1081. doi:10.1136/jnnp.
Neurol 65:952–957. doi:10.1001/archneur.65.7.952 2008.161869
Wichmann T, DeLong MR (1996) Functional and pathophysiological Zohar AH, Ratzoni G, Pauls DL et al (1992) An epidemiological
models of the basal ganglia. Curr Opin Neurobiol 6:751–758 study of obsessive–compulsive disorder and related disorders in
Wong DF, Kuwabara H, Schretlen DJ et al (2006) Increased Israeli adolescents. J Am Acad Child Adolesc Psychiatry
occupancy of dopamine receptors in human striatum during 31:1057–1061. doi:10.1097/00004583-199211000-00010
cue-elicited cocaine craving. Neuropsychopharmacology Zou QH, Zhu CZ, Yang Y et al (2008) An improved approach to
31:2716–2727. doi:10.1038/sj.npp.1301194 detection of amplitude of low-frequency fluctuation (ALFF) for
Wong DF, Brasic JR, Singer HS et al (2008) Mechanisms of resting-state fMRI: fractional ALFF. J Neurosci Methods
dopaminergic and serotonergic neurotransmission in Tourette 172:137–141. doi:10.1016/j.jneumeth.2008.04.012
syndrome: clues from an in vivo neurochemistry study with PET.
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