Editorial on the Research Topic
The Neurobiology and Genetics of Gilles de la Tourette Syndrome: New Avenues Through
Large-Scale Collaborative Projects
Gilles de la Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder
with an estimated prevalence of 0.3–0.9% (1, 2). Although the occurrence of multiple
motor and vocal tics is key to the diagnosis, the clinical phenotype is extremely
heterogeneous with only 10–13.5% of pure TS cases (i.e., tics only), and the vast
majority of patients presenting with additional psychiatric comorbidities (3–5). For
instance, TS is commonly associated with comorbid attention-deficit hyperactivity
disorder (ADHD, in about 60% of patients), obsessive-compulsive disorder (OCD, in
30–50% of patients) and to a lesser extent depression, anxiety, autism spectrum disorder
(ASD), and others (3, 6–8). There is no cure for TS and treatment aims to only alleviate
symptoms. Our search for novel therapies that may significantly improve patient quality
of life is hampered by our limited understanding of the pathophysiology of the disorder.
A complex and still unclarified genetic background further modified by non-genetic
factors, such as infections, autoimmunity, neural, and psychosocial stressors, is
implicated in TS pathogenesis (1, 9). Parallel, interacting cortico-striato-thalamo-cortical
(CSTC) circuits, linking specific regions in the frontal cortex to subcortical structures
(including the basal ganglia and thalamus) are thought to be involved together with
abnormalities in the dopamine, glutamate, serotonin, histamine, and acetylcholine
systems (1).
For a very long time, efforts to elucidate the etiology and pathophysiology of TS
have been fragmented and hampered by low statistical power. Finally, after decades
of active research aiming to identify the etiology and pathophysiology of TS, we are
on the verge of a new era, promising exciting and rapid discoveries in the field.
Investigators from around the world, representing multiple disciplines and scientific
approaches, are joining their efforts in large-scale initiatives and multiple resources
are being consolidated and coming together to serve the study of TS, including large
well-characterized patient cohorts, specialized epidemiological databases, and novel
analytical tools that allow integrated systems biology approaches. These are supported
both by European Union and US National funding agencies, as well as patient support
and advocacy groups such as the Tourette Association of America and Tourette’s Action
UK. This Research Topic was motivated by large-scale initiatives, such as the Marie
Curie Initial Training Network TS-EUROTRAIN (Forde et al.), the rapid growth of the
European Society for the Study of Tourette Syndrome (10, Mathews and Stern et al.),
and an important milestone in TS international research collaboration, the First World
Congress on Tourette Syndrome and Tic Disorders (Mathews and Stern et al.). We reached
out to the whole of the TS research community in order to put together a special issue
that showcases current large-scale efforts in the field, while covering both clinical
and etiological aspects of TS and providing an excellent overview about current knowledge
and areas of research in this complex neurodevelopmental disorder.
TS represents a model complex disorder with great clinical heterogeneity pointing
to an equally complex and heterogeneous etiological basis. Thus, understanding the
clinical spectrum of the disorder is the first step toward improved patient management
but also uncovering the pathophysiology of the disorder. In this issue, new insights
into clinical characteristics of TS are presented by Sambrani et al., who analyzed
clinical data in 1,032 patients with TS from a single center. The results give clinically
relevant new information about tics, premonitory urges, and comorbidities. Tics are
typically preceded by premonitory urges, but until today the relation between tics
and urges is not understood. Therefore, it is important to have reliable assessments
for both tics and premonitory urges. Brandt et al. investigated the validity of the
“Premonitory Urge for Tic Disorders Scale” (PUTS) and suggest to develop different
subscales of the PUTS, since there is evidence for more than one dimension of urges
in patients with TS. Ruhrman et al. specifically focus on “non-motor aspects” of TS,
including tic-related cognitions, the influence of environmental factors on tics and
sensory modulation disorder. Recent studies and clinical experience suggest that stress
often worsens tics. Buse et al. report results from an experimental study investigating
the effect of stress on tics in children with TS and interestingly found that stress
resulted in a situational decrease of tic frequency. Eapen et al. summarized available
data on quality of life in patients with TS and highlight the social impact of the
disease on both an individual’s and family’s life. An under-recognized symptom that
may impair in particular children’s health related quality of life is described by
Zanaboni Dina et al. They point out that handwriting is one of the most impaired school
activities in children with TS and report about a case with severe “handwriting tics.”
Robinson et al. describe the phenomenon of “tic attacks” in patients with TS and discuss
the etiology of this clearly underreported symptom. They suggest that “tic attacks”
resemble a combination of tics and functional movements and give recommendations for
the treatment of “tic attacks.”
Still on the clinical front, the optimal treatment strategy for TS patients must take
into consideration tic severity as well as determine which co-existing symptoms are
the most prominent, disabling and causing the patient the most difficulty (1). Behavioral
interventions are currently considered the first-line treatment for tics (11–14).
However, the limited number of trained therapists, inconveniences such as travel distance,
and willingness to engage can serve as barriers. Here, Jakubovski et al. alternatively
suggest a sophisticated internet-delivered treatment program for comprehensive behavioral
intervention for tics (CBIT) and describe the protocol of a large randomized controlled
trial (ONLINE-TICS). Morand-Beaulieu et al. used a modified CBIT program, called the
cognitive–psychophysiological (CoPs) model, to treat patients with both TS and body-focused
repetitive behaviors (BFRB). They found that CoPs improves both types of symptoms
and suggest that CoPs therapy modifies attentional processes as demonstrated by altered
event-related potentials (ERP). Leclerc et al. suggest “Facotik therapy” as an alternative
treatment for tics: Facotik was adapted from the adult cognitive and psychophysiological
program for tics. The authors present data suggesting that Facotik therapy may be
effective in tic reduction in children with TS due to a modification of cognitive–behavioral
and physiological processes.
Pharmacological interventions are typical second-line options whereas experimental
approaches include deep brain stimulation (DBS) for severe and treatment refractory
cases (1). In an open-label uncontrolled study, Gerasch et al. were able to demonstrate
that aripiprazole improves not only tics but also OCD and possibly other comorbidities,
including depression, anxiety, and ADHD, but has no influence on premonitory urges.
Surgical treatment with DBS has been suggested as a promising therapy in otherwise
treatment-resistant patients with TS. Pedroarena-Leal and Ruge summarized all available
data on both invasive and non-invasive stimulation techniques for TS and, in addition,
discuss novel applications for neurostimulation techniques based on a symptom-guided
approach. Since the database on DBS in TS is still weak, it was very important to
build up a DBS database to further increase our knowledge about efficacy and safety
of DBS in TS. Deeb et al. give an excellent overview on this international DBS registry
and explain how it works. Haense et al. used single photon emission computed tomography
(SPECT) and 99mTc-ECD to investigate the effects of DBS in both globus pallidus internus
(GPi) and centromedian-parafascicular/ventralis oralis internus nuclei of the thalamus
(CM/Voi) and sham stimulation on cerebral blood flow. They found altered brain perfusion
in the frontal cortex and the cerebellum that can be reversed by both GPi and CM/Voi
DBS. Finally, Jimenez-Shahed et al. recorded intraoperative local field potentials
(LFPs) from the postero-ventrolateral GPi in unmedicated Parkinson’s disease (PD)
patients and patients with TS (both at rest, during voluntary movements, and during
tic activity). From their data, it is suggested that beta-high frequency oscillations
(HFO) cross-frequency coupling (CFC) in the GPi might be specific to involuntary movements
in general.
Neuroimaging studies may uncover clues to the complex pathways and brain circuits
underlying TS, although to-date studies are limited by small sample size. In a subset
of papers in this issue, results from neuropsychological and neuroimaging studies
are reported. Eichele et al. used a task measuring performance monitoring and found
that children with TS may employ additional attentional resources as a compensatory
mechanism to maintain equal behavioral performance. In two other papers, data from
neuroimaging studies are reported in patients with common comorbidities in TS, OCD,
and ADHD. Fan et al. used diffusion tensor imaging (DTI) and investigated both patients
with OCD, unaffected siblings, and healthy controls and found white matter alterations
in the left cingulum bundle in OCD, which were partly also seen in unaffected siblings.
In patients suffering from ADHD, Forde et al. found no changes in cortical gyrification
or intrinsic curvature compared to healthy controls. It is worth noting that large-scale
neuroimaging studies for neuropsychiatric disorders are now starting to emerge [see,
for instance, Ref. (15, 16)]. However, we are only just entering the era of such large-scale
neuroimaging studies in TS and efforts such as the newly established ENIGMA-TS working
group will undoubtedly prove pivotal to increasing our understanding of the neurophysiology
of TS and the link between brain circuits and genetic background (http://enigma.ini.usc.edu/ongoing/enigma-ts/).
Indeed, several twin and family studies have demonstrated that TS is one of the most
heritable, non-Mendelian neuropsychiatric disorders with the population-based heritability
estimate estimated at 0.77 (17–19). However, to date no definitive TS-associated risk
gene of major effect has been identified [Georgitsi et al.; (9)] although recent large-scale
studies have provided evidence for the first robust genetic associations to the disorder
(20, 21). These landmark discoveries were made possible thanks to international collaboration.
Here, Georgitsi et al. offer a comparative report of active large-scale efforts aiming
to understand the genetic etiology of TS, including the Tourette Syndrome Association
International Consortium for Genetics (TSAICG), TIC Genetics targets rare, the European
Multicentre Tics in Children Study (EMTICS), and TS-EUROTRAIN, a Marie Curie Initial
Training Network. Each of these initiatives represents a range of different approaches
to the study of disorders with complex inheritance; from genome-wide association studies
targeting common variants to exome sequencing for rare variants and integration with
neurophysiological and gene-expression findings. Importantly, these complementary
large-scale efforts are joining forces to uncover the full range of genetic variation
and environmental risk factors for TS, holding great promise for identifying definitive
TS susceptibility genes. In this issue, we also present studies that follow-up on
promising leads for TS genetics [Alexander et al.; Padmanabhuni et al.] and include
a critical review of the functional evaluation of genes that have been previously
found to be disrupted in TS patients (Sun et al.). The gap between gene identification
and underlying biology still remains to be bridged.
The high comorbidity rates with other neurodevelopmental disorders, such as OCD, ADHD,
and ASD, lend support to the hypothesis of a shared etiological basis and suggest
that genes underlying TS susceptibility actually have a role across neurodevelopmental
phenotypes (22). Thus, TS can be considered a model disorder that can help shed light
into the etiology of other neurodevelopmental disorders as well. Indeed, family studies
indicate that, within TS families, OC symptoms and tics are etiologically related
(23), while ADHD symptoms have also been shown to be etiologically related although
in a more complex manner (24). Cross-disorder analysis may indeed provide clues to
such shared etiological basis. In this issue, Tsetsos et al. present the first meta-analysis
of GWAS for TS and ADHD and offer support for a shared etiological basis. In a large-scale
study, including participants in the Netherlands Twin Register, Zilhão et al. find
substantial genetic correlations between hoarding, OC symptoms, and tics.
Consistent with observations of other neurodevelopmental disorders, increasing evidence
links neural and immune interactions to the pathogenesis of TS (1). For instance,
streptococcal infection has been implicated as an environmental trigger leading to
TS onset (25). Here, Spinello et al. critically discuss the available evidence in
preclinical models in support of the link between TS and pediatric autoimmune neuropsychiatric
disorders associated with streptococcus infections (PANDAS), as well as the limitations
of these studies. Intriguingly, a case report included in this collection also suggests
a relationship between S. aureus colonization and tic improvement (Eftimiadi et al.).
The link between immunity and TS pathophysiology still remains to be fully explored.
Epigenetic mechanisms may mediate the effect of environmental triggers on genetic
background, thus leading to the onset of TS. Pagliaroli et al. provide a summary of
the recent findings in genetic background of TS, followed by an overview on different
epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding
RNAs in the regulation of gene expression. Epigenetic studies in other neurological
and psychiatric disorders are discussed along with the TS-related epigenetic findings
available in the literature to date. Moreover, they offer evidence that some general
epigenetic mechanisms seen in other neuropsychiatric disorders may also play a role
in the pathogenesis of TS.
Animal models of tics could help elucidate the complex interplay between genetic,
environmental, and neuroimmunological risk factors, and facilitate the development
of improved therapies. However, still considerable debate exists over the validation
of TS animal models. Here two comprehensive reviews (Nespoli et al.; Yael et al.)
present all existing TS models highlighting recent advances as well as the need to
overcome shortcomings. Importantly, Yael et al. call for a standardization process
in the study of TS animal models as the next logical step. They suggest that a generation
of standard examination criteria will improve the utility of these models and enable
their consolidation into a general framework. This should lead to a better understanding
of these models and their relationship to TS, thereby improving the research of the
mechanism underlying this disorder and aiding the development of new treatments.
Thanks to international collaboration, we are on the verge of a new era promising
exciting discoveries on the neurobiology of TS. For instance, large well-characterized
cohorts of TS patients have become available, and US and European TS genetics consortia
have harmonized phenotypic assessments and established pre-publication data sharing
and joint meta-analyses [Georgitsi et al.; (26)]. As a result, already the first definitive
TS risk genes have been identified although they still encompass a small portion of
the overall TS susceptibility risk (20, 21). The next step will now be to shift from
linear thinking to more complex, integrated and multi-dimensional approaches (Lessov-Schlaggar
et al.). TS is not a unitary condition and as such patients also respond to treatment
in different ways. This highlights the importance of thinking across diagnostic categories
when attempting to understand the neurobiology of these phenotypes (27–29). The development
of quantitative TS phenotypes and analyzing across a spectrum rather than on ends
of a distribution may hold the promise to unravel the etiology of TS and be the starting
point to personalized medicine in TS.
Author Contributions
PP coordinated the Research Topic and wrote the manuscript. KM-V coordinated the Research
Topic and wrote the manuscript.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.