Review

Tourette syndrome: clinical features, pathophysiology,

and treatment
Kara A Johnson, Yulia Worbe, Kelly D Foote, Christopher R Butson, Aysegul Gunduz, Michael S Okun

Tourette syndrome is a chronic neurodevelopmental disorder characterised by motor and phonic tics that can Lancet Neurol 2023; 22: 147–58
substantially diminish the quality of life of affected individuals. Evaluating and treating Tourette syndrome is complex, Published Online
in part due to the heterogeneity of symptoms and comorbidities between individuals. The underlying pathophysiology October 28, 2022
https://doi.org/10.1016/
of Tourette syndrome is not fully understood, but recent research in the past 5 years has brought new insights into the
S1474-4422(22)00303-9
genetic variations and the alterations in neurophysiology and brain networks contributing to its pathogenesis.
Norman Fixel Institute for
Treatment options for Tourette syndrome are expanding with novel pharmacological therapies and increased use of Neurological Diseases
deep brain stimulation for patients with symptoms that are refractory to pharmacological or behavioural treatments. (K A Johnson PhD,
Potential predictors of patient responses to therapies for Tourette syndrome, such as specific networks modulated Prof K D Foote MD,
Prof C R Butson PhD,
during deep brain stimulation, can guide clinical decisions. Multicentre data sharing initiatives have enabled several
A Gunduz PhD,
advances in our understanding of the genetics and pathophysiology of Tourette syndrome and will be crucial for Prof M S Okun MD) and
future large-scale research and in refining effective treatments. Department of Neurology
(K A Johnson, Prof C R Butson,
Introduction Clinical features and diagnosis Prof M S Okun) and Department
of Neurosurgery
Tourette syndrome, named after and described by Motor and phonic tics (Prof K D Foote, Prof C R Butson)
Georges Gilles de la Tourette in 1885,1 is a childhood- Motor and phonic tics, the hallmark symptoms of Tourette and J Crayton Pruitt Family
onset neurodevelopmental disorder characterised by syndrome, vary widely between individuals in type, Department of Biomedical
Engineering (Prof C R Butson,
involuntary movements (motor tics) and vocalisations severity, frequency, and complexity (figure 1). Tics are
A Gunduz), University of
(phonic tics). An estimated 0·3–0·9% of school-aged generally categorised into simple and complex, and they Florida, Gainesville, FL, USA;
children (4–18 years)2 and 0·002–0·08% of adults3 have can include virtually any combination of move­ments or Sorbonne University, ICM,
a diagnosis of Tourette syndrome, although few vocalisations. Simple motor tics are brief repetitive Inserm, CNRS, Department of
Neurophysiology, Hôpital
adult epidemiological studies have been done globally. movements that involve a single muscle group or body Saint Antoine (DMU 6), AP-HP,
Tourette syndrome occurs more frequently in males, part (eg, blinking and snapping fingers), whereas complex Paris, France (Y Worbe, MD)
with a male-to-female ratio of 4:1, and males tend to motor tics are distinct coordinated patterns of movements Correspondence to:
have more severe symptoms than females.4 Tourette involving multiple muscle groups (eg, facial grimace with Dr Kara A Johnson, Department
syndrome is often accompanied by comorbid a head tilt and a shoulder shrug, and spinning around of Neurology, Norman Fixel
Institute for Neurological
behavioural disorders, including most prominently while walking). Simple phonic tics are non-word
Diseases, University of Florida,
obsessive-compulsive behaviour and attention deficit vocalisations (eg, sniffing, single syllables, or noises), and Gainesville, FL 32608, USA
disorders. complex phonic tics include phrases or combinations of kara.johnson@neurology.ufl.
Diagnosis and treatment of and research into Tourette sounds. Obscene or socially inappropriate gestures or edu
syndrome and its associated comorbidities is complex. vocalisations (copro­pheno­mena) occur in approximately
Symptoms and comorbidities severities are highly 28·1% of individuals with Tourette syndrome.5 The severity
heterogeneous, and fluctuate over time. Although the of tics has been documented to worsen under stress,
pathophysiology of Tourette syndrome is not fully fatigue, or excitement, and to improve when the individual
understood, various genetic and neurophysiological is engaged in mental or physical activity, or during focused
factors are likely to contribute. Established treatments attention.6,7 Tics can be involuntary or semi-voluntary
for Tourette syndrome include behavioural therapies (ie, voluntary responses to urges or sensory phenomena),
and medications, and emerging treatments include non- and in some cases, the distinction between the two can be
invasive neuro­modulation and deep brain stimulation. challenging even for an experienced clinician.8 Premonitory
Many gaps in knowledge about Tourette syndrome urges often precede tics, although an observational study
remain, including the factors contributing to the of 21 adults with Tourette syndrome suggested that tics
variability in clinical manifestations and how to best have a consistent temporal association with premonitory
treat tics and comorbidities. In this Review, we provide urges in only 57–66% of individuals, depending on the
an overview of the latest evidence on the clinical features, method used to measure the urges.9 Tics can sometimes
diagnosis, genetics, pathophysiology, and treatment of be partly or completely suppressed, although the ability to
Tourette syndrome. In particular, recent progress in the suppress tics varies between individuals.10 Furthermore,
past 5 years has been made in refining the patho­ according to a retrospective study of 201 patients with
physiological models and genetics of Tourette syndrome, Tourette syndrome, 17% of individuals with Tourette
and in the further development of pharma­ cological, syndrome experience self-injurious tics.11 In extreme cases,
behavioural, and neuromodulation inter­ ventions. We self-injurious tics can lead to injury necessitating
also highlight key questions and topics for future hospitalisation, loss of bodily function, or permanent
research. disfigurement.12

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 Review

is the most commonly used tool. Given the variability and

A B
fluctuations in symptoms, guidelines16 recommend using
multiple methods for measuring symptom severity,
including direct observation in environments within and
outside the clinic, historical information from the
individual and their family, and video-based assessment.
Diagnosis and evaluation of Tourette syndrome can be
challenging due to its clinical heterogeneity, the
suppressibility of tics, and symptom fluctuations over
time and under different conditions. Diagnosis can be
delayed up to 3–11 years after symptom onset,
and an estimated 73% of patients receive an initial
misdiagnosis, although this estimate is based on patient
C D self-report, which shows the low awareness and knowledge
in the general community and among health professionals
of how to recognise Tourette syndrome.17,18 Early diagnostic
markers, such as imaging, blood, or CSF biomarkers,
have not yet been identified to enable diagnosis before
symptoms emerge. However, some evidence suggests
individuals with particular characteristics are at risk of
developing tics. For example, a study by a multicentre
consortium suggests that children with conduct problems,
autism spectrum disorder symptoms, compulsions, and
emotional problems might be more at risk of developing
tics.19 Increasing awareness about Tourette syndrome and
Figure 1: Variability of Tourette syndrome and associated comorbidities its risk factors could enable caregivers and health-care
(A) Child with common simple motor and phonic tics (eg, shrugging shoulders
providers to recognise tics and establish treatment early.
and winking). (B) Adolescent with a combination of complex motor tics
(eg, pulling hair) and complex phonic tics (eg, saying “don’t trip”), and emerging Accurate diagnosis of Tourette syndrome can be
behavioural features including attention deficit hyperactivity disorder (ADHD) challenging due to the presence of other behavioural
depicted as swirling thoughts. (C) Although tics become less severe after disorders20,21 and difficulty in differentiating between tics
adolescence in most cases, complex motor tics, phonic tics, and behavioural
and functional tic-like behaviours.22 During the
features can persist into adulthood in some individuals. This adult example
experiences complex motor tics (eg, hand gestures, followed by snapping COVID-19 pandemic, there has been a worldwide
fingers and scatching their head) and phonic tics (eg, humming repetitively). increase in adolescents and young adults presenting with
(D) Psychiatric and behavioural comorbidities can be the primary symptoms functional tic-like behaviours linked to watching videos
(with or without tics) in some individuals and can include obsessive-compulsive
on social media of individuals executing movements and
disorder (eg, checking behaviours, as depicted in the thought cloud) or mood
disorders (eg, depression or anxiety, depicted as darkness in the thought cloud). vocalisations meant to depict symptoms of Tourette
Although individuals of various ages are depicted, tics and comorbidities do not syndrome.23,24 Functional tic-like behaviours differ from
follow a single time course; the natural history of Tourette syndrome and the Tourette syndrome by an abrupt and later onset of
severities and types of symptoms differ widely among patients of various ages.
symptoms, an absence of symptom fluctuations, a higher
prevalence in females than males, and more complex
Diagnosis and evaluation motor and vocal tics.23,24 Early and accurate diagnosis and
Tourette syndrome is diagnosed through clinical treatment of Tourette syndrome is crucial because
assessment using the individual’s history. The American symptoms can interfere with social integration and
Psychiatric Diagnostic and Statistical Manual of Mental cognitive and intellectual development, and treatment
Disorders (DSM-5) specifies that to diagnose Tourette can mitigate symptoms and reduce challenges in daily
syndrome, tics must have begun before the age of life for the affected individual and caregivers.
18 years and the individual must have had tics for at least
1 year, including at least two motor tics and one phonic Time course of symptoms
tic. DSM-5 differentiates between provisional tic The time course of Tourette syndrome is variable. Tics
disorders, persistent (chronic) tic disorders, and Tourette typically start in individuals aged 3–8 years, often
syndrome; however, defining these disorders as a beginning with simple motor tics (figure 1) followed by
spectrum (listed from least to most severe) has been phonic tics. The peak severity of tics is commonly in
proposed.13,14 Family history of tics or Tourette syndrome individuals aged 8–12 years (mean [SD] of 10 [2·4] years).25
can also aid in diagnosis, but it is not a requirement. A single centre study5 of 1032 individuals has reported that
Several rating scales can be used for evaluation of premonitory urges and the ability to suppress tics can also
symptoms in individuals with Tourette syndrome of any be present from around tic onset. The severity of tics and
age group,15 but the Yale Global Tic Severity Scale (YGTSS) most associated psychiatric disorders typically improve

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 Review

with age.26 However, a prospective longitudinal follow-up males and females.33,34 Although the DSM-5 diagnostic
study of 314 individuals with Tourette syndrome27 has criteria differentiate between Tourette syndrome and
suggested that only 17% of patients will experience chronic tic disorders, studies suggest both disorders
complete remission after the age of 16 years, and 60% will result from a similar genetic background.34,35
still experience some persistent mild to moderate tics. Up Among familial factors, parental and especially
to 23% of affected individuals will have persistent and, in maternal psychiatric diagnoses have been associated
some cases, severe tics into adulthood (figure 1).27 with a diagnosis of Tourette syndrome in offspring.36
Predictors of the time course of Tourette syndrome have Indeed, large studies on neurological and psychiatric
not been well established and few longitudinal large disorders showed a high genetic correlation among
cohort studies have been done. Childhood tic severity28 psychiatric disorders, suggesting important overlap in
(but not age at tic onset5), a family history of Tourette common gene variants that might explain why
syndrome, presence of comorbidities, teasing in childhood individuals with psychiatric disorders, particularly
perhaps due to symptoms, and psychosocial stress might those with Tourette syndrome, have an increased risk
predict tic severity into early adulthood.28,29 Identification of developing OCD and major depressive episodes.37,38
of predictors of who will experience severe symptoms into One study using whole exome sequencing of 511 Tourette
adulthood will be crucial to enable the development of syndrome trios (affected children and both biological
effective treatment plans and ensure that these individuals parents) showed that in approximately 12% of individuals
receive the support they need as adults. with Tourette syndrome, de novo damaging gene variants
contributed to the risk of the disorder and there was no
Comorbidities difference across sexes.39 A study of 222 trios of children
Tourette syndrome commonly occurs with other with OCD and their parents showed these de novo variants
psychiatric and behavioural disorders, including obsessive- account for 22% of cases of OCD.40 However, not one of
compulsive behaviour or obsessive-compulsive disorder the genes implicated in Tourette syndrome has met the
(OCD), attention-deficit hyperactivity disorder (ADHD), threshold for high-confidence association for both
autism spectrum disorder, anxiety, depression, sleep Tourette syndrome and OCD, which suggests that specific
disorders, and self-injurious behaviour.5 A cross-sectional neuronal pathways for these disorders exist.40 The cause of
study in 1374 individuals suggests that isolated Tourette Tourette syndrome is monogenetic in less than 2%
syndrome is the exception, not the rule: up to 88% of of individuals; the genes that cause monogenetic
individuals with Tourette syndrome are diagnosed with at Tourette syndrome include genes implicated in neuronal
least one additional psychiatric disorder during their and dendrite development, axonal guidance, cellular
lifetime and 58% are diagnosed with two or more membrane stability (eg, SLITRK 1–6, CELSR3, CNTN6,
comorbidities (figure 1).30 The most common comorbidities and NRXN1),34 neurotransmitters such as opioids
are ADHD and OCD, with an estimated 72% of individuals (OPRK1),41 and histamine (histidine decarboxylase (HDC)
with Tourette syndrome diagnosed with either disorder.30 genes).42 Because the population with Tourette syndrome
Although timelines vary among individuals, ADHD related to monogenetic causes is small, generalisation of
might have the earliest onset (median age 5 [IQR 3–6] findings from these individuals to the whole Tourette
years), followed by OCD (7 [5–9] years), anxiety disorders syndrome population is difficult.
(7 [4–10] years), and mood disorders (13 [10–18] years).30 Although genetic and familial factors probably affect
Additionally, consistent with other psychiatric disorders, brain pathway development and the manifestation of
individuals with Tourette syndrome and comorbidities Tourette syndrome, the exact mechanisms of these
have increased risk of mortality by natural or unnatural interactions are unclear. However, whole exome studies
causes (such as suicide) when compared with individuals have implicated some cellular processes in Tourette
with Tourette syndrome without comorbidities, although syndrome pathophysiology, including genes regulating
the contributing factors are unclear.31 Assessments for cell polarity and migration,39,43 cell adhesion molecules
comorbid behavioural and psychiatric symptoms in implicated in trans-synaptic signalling, ion channel
children with Tourette syndrome should begin early and signalling through GABA and glutamate neuro­ trans­
be repeated at regular intervals, as comorbidities generally mitters, glial-derived neuroimmunity,44 and synaptic
have a greater detrimental effect on quality of life than tic membrane stability.45 A meta-analysis of genome-wide cell
severity.32 and tissue-based enrichment analyses in a database of
714 healthy adult donors with samples collected from
Genetics 53 distinct human tissues (from the brain and elsewhere)
Tic disorders are considered to be among the most revealed that modulation of expression of numerous genes
heritable neuropsychiatric disorders. Two large through non-coding variants might be a key mechanism in
population-based and genome-wide association studies Tourette syndrome pathogenesis, with the brain regions
(approximately 4800 individuals in each) have estimated most affected by genes implicated in Tourette syndrome
that genetic variants explain 77·0–92·4% of the being the dorsolateral prefrontal cortex, followed by frontal
heritability of Tourette syndrome, with similar risk in cortex, striatum, and cerebellum.34

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New advancements in our understanding of neuro­ the execution of learned actions (ie, tics), via changes of
immunity are of particular interest for Tourette syndrome plasticity in the direct and indirect cortico-basal ganglia
because neurodevelopmental deficits might result both pathways, has gained some traction.61 Tics as a habitual
from external factors, such as maternal inflammation and learned action also might explain premonitory urges:
leading to fetal neuroinflammation,46,47 and from termination of premonitory urges by execution of tics
perturbation of genetic neuroimmunological pathways might trigger a positive prediction error and phasic
as a result of genetic variants.44 Some peripheral markers, dopamine release, thus reinforcing the learning of tics.64
such as myeloid type 1 and 2 cells, implicated in the The current model of premonitory urges (figure 2)
pathogenesis of autoimmune disorders, also support the proposes that abnormal interoceptive and exteroceptive
alteration of the immune-brain crosstalk in Tourette processing might generate premonitory urges, leading to
syndrome, suggesting that immunomodulation might action initiation and subsequent tic execution via the
be a promising avenue for treatment.48 cortico-basal ganglia sensorimotor network.65
Neurophysiological studies in humans can identify
Pathophysiology markers of tics during surgery to implant deep brain
Convergent evidence drawn from both genetics and stimulation devices,66 during externalised lead studies,67 or
neuroimaging strongly supports that Tourette syndrome is via neurostimulators capable of recording neural
a neurodevelopmental disorder. Neuroimaging studies activity.68–70 All of these studies point to increased activity in
have revealed a difference in functional brain connectivity low-frequency power (1–10 Hz) in the centromedian
(ie, a statistically significant measure of brain activity thalamic region in individuals with Tourette syndrome
See Online for appendix derived from functional imaging in the at-rest condition) that might be associated with tics (appendix). Other studies
when comparing adults who have Tourette syndrome with also have revealed the presence of low-frequency activity in
children who have Tourette syndrome.49 Additionally, the anterior pallidum in Tourette syndrome.67,71–73 How this
developmental trajectories seemed to differ in individuals low-frequency activity translates into tics is unclear, but
with Tourette syndrome, in which the functional brain low-frequency power in the anterior pallidum might be
connectivity of children with Tourette syndrome appeared associated with premonitory urges.74
older, and the functional brain connectivity of adults with Additional alternative hypotheses related to Tourette
Tourette syndrome appeared younger, when compared syndrome pathogenesis include Tourette syndrome being
with age-matched controls.49 This difference might result a disorder of social behavioural networks.75 This hypothesis
from variances in cellular and axonal pruning, potentially could explain the common predominant eye, face, and
influenced by genetic and environmental factors.50 head distribution of tics. Face perception in Tourette
Collectively, genetic and environmental factors are likely to syndrome was shown to elicit abnormally high activity
result in widespread neuronal network dysfunction and compared with healthy controls in the insular cortex and
the potential emergence of symptoms related to Tourette the neural network implicated in tic generation, including
syndrome (figure 2).53,54 motor cortical regions and the putamen.76 Another
On a network level, tics might be a product of inhibitory important clue was provided in a study of sensory
dysfunction within the sensorimotor cortico-basal ganglia perception–action binding, showing increased strength of
network,55 namely from alterations of striatal inhibitory binding between perception and action in Tourette
microcircuitry (figure 2)51–56 and problems with automatic syndrome compared with healthy controls, which was
inhibition of actions.57 This inability to delay an action has also correlated with severity of tics. Analysis of EEG
been correlated with the severity of tics.58 In contrast, signals during an event file coding task to measure
volitional inhibition, measured by proactive inhibition perception-action binding showed that this effect was
(inhibition of action in preparation) or reactive inhibition associated with activity in the inferior parietal cortex,
(inhibition of already initiated action), is largely unaltered suggesting that tics could be an elicited response to
in people with Tourette syndrome,59 and has been related internal or even external stimuli.77
to the individual’s capacity to inhibit their tics.60
However, the disinhibition model does not explain Treatments
some fundamental features of tic disorders, such as the Treatments approved for Tourette syndrome include
waxing and waning character and the premonitory urges. behavioural therapies, and pharmacological therapies, or
An alternative hypothesis is that tics could represent a combination of the two. Research is ongoing to develop
exaggerated and persistent motor habits that are and refine new effective treatments for Tourette
reinforced by aberrant increased phasic dopamine syndrome, including non-invasive neuromodulation
release.61 In support of this idea, dopamine-associated modalities and deep brain stimulation, although neither
reward-guided learning, also known as reinforcement are currently approved for clinical use. In this section,
learning, seems to be enhanced in Tourette syndrome.62 we present the latest evidence and summarise guidelines
Individuals with Tourette syndrome tend to rely on habits for Tourette syndrome therapies, from first-line therapies
when in the non-medicated state.63 Therefore, the to therapies reserved for select patients with severe,
hypothesis that aberrant tonic dopamine release increases treatment-refractory symptoms.

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Behavioural therapies
A
Comprehensive Behavioural Intervention for Tics (CBIT) Associative: Sensorimotor:
Comorbidities (ADHD) Tics
is rated as effective in tic reduction in both children and
adults with Tourette syndrome according to guidelines Prefrontal
from the American Academy of Neurology (AAN)78,79 and cortex
the European Society for the Study of Tourette Syndrome
(ESSTS).80 Notably, CBIT is the only therapy in the AAN
guidelines with high confidence in its efficacy (panel).
CBIT is recommended as an initial treatment option
Supplementary
before the initiation of pharmacotherapy or other non- motor area and
pharmacological interventions. Overall, CBIT has been Dorsal sensorimotor cortex
reported to reduce the number and severity of tics by
26–31% as measured by the YGTSS across studies. One
Striatum
randomised control trial in 110 patients (aged 8–17 years)
suggested that it was as effective as pharmacological Ventral
OFC
treatment.82 Limbic:
Comorbidities (OCD)
Habit reversal training is one of the main components
of CBIT. Habit reversal training aims to increase a person’s B
Basal ganglia: cellular distribution Striatal microcircuitry organisation
awareness of premonitory urges and tics. Another Tourette syndrome Control
40 Tourette syndrome
component of CBIT focuses on competing response Control
training, which is used in an effort to suppress tics.83,84 If 30 GABA GABA
Percentage (%)

CBIT is unavailable, exposure and response prevention, Pav+ Pav+

which suppresses tics gradually over time,85 can be tried to 20 GABA GABA
increase the tolerance to premonitory urges and to MSN MSN
potentially reduce tics.78 Alternating between habit reversal 10
Ach+ Ach+
training and exposure and response prevention might be
0
valuable, although there is only one randomised trial in Putamen Caudate GPe GPi
54 adolescents (aged 9–17 years).86 Group therapy has also C
been suggested as a practical and cost effective alternative Exteroceptive Action initiation
sensitivity
for children and adolescents.87 Videoconference88 and
telemedicine approaches89 might be similarly effective to
Abnormal processing of
in-person behavioural therapies and will likely improve sensory information SM
access for patients and their caregivers. Acc
Although behavioural therapies are effective for many Ins

individuals with Tourette syndrome, some patients might Tic execution

not benefit from them. Thus, several studies have focused
Interoceptive
on identifying predictors and moderators of good response sensitivity
to behavioural therapy. In an analysis of data from clinical
trials assessing the efficacy of CBIT and psychoeducation Figure 2: Models of Tourette syndrome pathophysiology
(A) Cortico-basal ganglia networks and Tourette syndrome clinical characteristics. Distinct cortico-basal ganglia
and supportive therapy (PST), ADHD, OCD, and anxiety networks are related to tics (sensorimotor network [orange]) and comorbidities (associative and limbic networks
did not significantly moderate the tic severity reduction [grey]) in Tourette syndrome. (B) Neuropathological underpinnings of Tourette syndrome: stereological cellular
obtained with CBIT; however, anxiety disorders and count in post-mortem tissue revealed different cellular distributions in the basal ganglia of individuals with Tourette
premonitory urge severity were associated with less syndrome (3 patients, mean [SEM] age 42·0 [11·9] years) compared with controls (5 healthy controls, mean [SEM]
age 60·0 [9·7] years; left panel), with fewer inhibitory GABAergic cells (red circle) and cholinergic cells (green
reduction in tic severity across CBIT or PST.90 This analysis hexagon) within the striatum in Tourette syndrome (5 patients, mean [SEM] age 43·0 [3·6] years) compared with
also revealed that tic suppressing medication might 5 controls mean [SEM] age 61·8 [4·3] years (right panel). (C) Model of relationship between premonitory urges and
moderate CBIT effectiveness, and CBIT might be more tics: abnormal interoceptive information processing (insular cortex; blue area) and exteroceptive processing
effective for individuals who are medication naive (sensorimotor cortex; pink areas) results in genesis of premonitory urges (insular cortex), leading to action initiation
(via anterior cingulate cortex; green area) and subsequent tic execution (via cortico-basal ganglia sensorimotor
compared to those who have tried medication.90 However, network (as shown in A). Acc=anterior cingulate cortex. Ach+=cholinergic interneurons of the striatum.
questions remain about the optimal age to implement ADHD=attention deficit hyperactivity disorder. GABA Pav+=GABAergic parvalbumin-positive interneurons of the
CBIT and differences in effects among individuals using striatum. GPi=globus pallidus internus. GPe=globus pallidus externus. Ins=insular cortex. MSN=medium spiny
different medications. Further research is needed to neurons. OCD=obsessive-compulsive disorder. OFC=orbitofrontal cortex. SM=sensorimotor cortex. B (left) has been
adapted from Kalanithi and colleagues51 and B (right) from Kataoka and colleagues.52
disentangle the factors contributing to the clinical
response to behavioural therapy for Tourette syndrome. or are unavailable, and for those with severe tics that
require more urgent treatment. Several pharmacological
Pharmacological treatments treatments have been evaluated to reduce tics, including
Pharmacological treatments are suggested for individuals α2-agonists, typical and atypical antipsychotics, and
for whom behavioural therapies have not been effective anticonvulsants.

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The evidence for efficacy and adverse effects of benefit based on the AAN guidelines and latest evidence.78,79
pharmacological treatments was recently reviewed by the The survey administered to 59 Tourette syndrome
AAN and by the ESSTS in the past 3 years.78,79,81 According specialists as part of the ESSTS guidelines indicated that
to the AAN, no pharmacological treatments warranted medication preferences did not substantially differ for
high confidence in their efficacy for tic reduction, probably adults versus children and adolescents. Aripiprazole was
due to the relative paucity of rigorous clinical trials. the most common choice for all age groups; however,
However, the ESSTS suggested a hierarchy for selecting haloperidol was more commonly considered in adults
medications based on evidence and a survey among than in children, and tiapride was more often considered
Tourette syndrome specialists. We have combined the in children and adolescents than in adults.81
complementary reports from both organisations to Although pharmacological treatments can be highly
summarise a suggested order for pharmacological successful for managing symptoms, many patients might
treatments and their respective amount of evidence for not experience therapeutic effects or might have adverse
tics and for individuals with comorbid ADHD or OCD effects. Thus, several new pharmacological compounds
(panel).81 We highlight the pharmacological agents are being examined for use in Tourette syndrome.
deemed beneficial with moderate or low confidence for Ecopipam, a dopamine D1-receptor antagonist, was tested
in a double-blind randomised trial on 40 patients with
Tourette syndrome (aged 7–17 years) and showed
Panel: Overview of therapies for Tourette syndrome significant improvement of total tic scores with an overall
safe profile with regards to adverse effects and dropout
Behavioural therapies:
rate.91 Further double-blind randomised studies are needed
• Comprehensive behavioural intervention for tics and
to assess the effect of ecopipam on tics and Tourette
habit reversal training*
syndrome. Neither the AAN78,79 or the ESSTS81 addressed
• Exposure and response prevention†
this compound in their guidelines. Valbenazine, a vesicular
Pharmacological therapies: monoamine transporter inhibitor, was tested in several
First-line clinical trials for paediatric and adult Tourette syndrome. A
• Atypical antipsychotics (ie, aripiprazole‡, tiapride‡, randomised study in both children and adults did not
and risperidone‡) show a benefit over placebo treatment,92 despite previous
Second-line encouraging open-label trials and reports. One open-label
• Typical antipsychotics (ie, haloperidol‡ and pimozide§) trial revealed a positive effect of another vesicular
• Anticonvulsants (ie, topiramate§) monoamine transporter inhibitor, deutetrabenazine, on
• Antidepressants (ie, desipramine§) tics in adolescents (aged 12–18 years);93 however, a placebo-
• Chinese medicine (ie, Ningdong granule‡ and 5-Ling controlled randomised study did not show benefit.94
granule‡) The positive effect of cannabinoids for Tourette
• Neurotoxins (ie, Botulinum toxin injections‡ [focal tics]) syndrome in adults has been shown in open label trials.95,96
One retrospective data analysis of cannabis compounds
Neuromodulation therapies (for patients with severe,
revealed a self-reported improvement of tics and an overall
treatment-refractory symptoms):
positive adverse-effect profile.95 However, several
• Deep brain stimulation targeted to the pallidum† or the
systematic reviews and meta-analyses have not revealed
thalamus†
robust effects on tic suppression.97–99 The double-blinded
• Transcranial magnetic stimulation† targeted to the
CANNA-TICS trial investigated the capacity of nabiximols,
supplementary motor area, primary motor area, or
drugs combining a standardised dose of tetrahydro­
prefrontal cortex
cannabinol and cannabidiol compounds, as a possible
Therapies that could have therapeutic effects on tics and approach to reduce tic frequency and severity in adults.100
comorbidities: Preliminary results from this study reported during the
• Tourette syndrome plus obsessive-compulsive disorder: 2021 ESSTS conference showed an absence of effect
cognitive behavioural therapy (eg, exposure and response compared with placebo, but the final results are awaited.
prevention) or selective serotonin reuptake inhibitors¶ Accordingly, the AAN78,79 and the ESSTS81 guidelines
• Tourette syndrome plus attention deficit hyperactivity categorised the treatment with cannabis compounds as
disorder: clonidine‡ and guanfacine§ experimental that might be given to patients with otherwise
treatment-resistant Tourette syndrome.
The above therapy types are presented in order of suggested use according to guidelines
from the American Academy of Neurology (AAN)78,79 and the European Society for the
Study of Tourette Syndrome (ESSTS).80,81 First-line and second-line designations for Non-invasive neuromodulation
pharmacological therapies were assigned according to the ESSTS guidelines.80 Evidence
levels were determined according to a modified form of the Grading of Recommendations
Several clinical trials have investigated non-invasive brain
Assessment, Development, and Evaluation process according to the AAN comprehensive stimulation of motor cortical areas (motor cortex and
review.69 *Evidence level is high. †Insufficient evidence of efficacy. ‡Evidence level is supplementary motor area), including transcranial direct
moderate. §Evidence level is low. ¶Not evaluated as part of the AAN comprehensive
review, but discussed as potentially effective in the ESSTS guidelines.
current stimulation or repetitive transcranial magnetic
stimulation, in both adults and children with Tourette

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syndrome. The underlying rationale for transcranial direct activity (measured by EEG) of the motor cortex, and
current stimulation or repetitive transcranial magnetic reduced tic frequency and intensity.104 There was a long-
stimulation is to modulate pathological neural activity in lasting post-stimulation effect in some individuals;
brain networks implicated in Tourette syndrome to however, much larger cohorts will be required to verify
improve symptoms. Overall, these techniques were these results. Additionally, there has been a single
considered safe. In clinical studies, the results have been randomised sham-controlled study investigating real-
conflicting with some studies reporting improvement of time functional MRI neurofeedback to improve tics.105
tics and associated OCD whereas others have reported no This study directed visual modulation of the activity of
benefit.101–103 The inconsistencies might be attributable to the supplementary motor area as a treatment for tics in
the differences in stimulation protocols and the possible adolescents (21 patients aged 11–19 years). There was a
influence of comorbidities, such as ADHD, on cortical clinically meaningful effect of this intervention on tics
excitability. The current AAN guidelines and the European when compared with the sham-controlled study, but it is
guidelines for treatment of Tourette syndrome do not unclear whether the therapy will be practical or sustained.
recommend non-invasive brain stimulation for the
treatment of tics. Deep brain stimulation
In addition to non-invasive brain stimulation, there Deep brain stimulation is a promising neurosurgical
is increasing interest in other non-invasive neuro­ treatment for carefully selected individuals with severe,
modulation modalities for Tourette syndrome to improve treatment-refractory Tourette syndrome.106 It is not
tics. One study showed that, in 20 adolescents and adults approved by the US Food and Drug Administration or
with Tourette syndrome, rhythmic peripheral somato­ regulatory agencies in other countries. However, over
sensory stimulation of the median nerve modified the 300 patients worldwide have been treated with deep brain

A B
GPe A Left
amGPi Voi
pvGPi
GPi L R
CM
P
P A

Left Right
Right

Pf

P A A P
Thalamus
A P

C (left) (right)

GPe Voi
GPi

CM
Pf
Sensorimotor Sensorimotor

Limbic and Limbic and

Associative Associative

Correlation (R) of structural connectivity with % improvement in tics

≤–0·5 –0·3 –0·1 0·1 0·3 ≥0·5

Figure 3: Neurosurgical targets for deep brain stimulation in Tourette syndrome and structural networks associated with tic improvement
Adapted with permission from Johnson and colleagues.109,118 Active contact locations (represented by spheres) varied across patients with Tourette syndrome implanted
with deep brain stimulation in (A) the pallidum (30 patients; yellow represents contacts targeted to amGPi and green pvGPi) and (B) the centromedian regions of the
thalamus (33 patients; red contacts targeted to centromedian regions of the thalamus). (C) With pallidal deep brain stimulation (of either the amGPi or pvGPi), higher
structural connectivity from the site of stimulation to limbic and associative networks was positively correlated with a reduction in tic severity (left). With thalamic deep
brain stimulation, higher structural connectivity from the site of stimulation to sensorimotor networks was positively correlated with a reduction in tic severity (right).
CM=centromedian nucleus. GPe=globus pallidus externus. GPi=globus pallidus internus. Pf=parafascicular nucleus. Voi=ventro-oralis internus.

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 Review

stimulation according to the Tourette Association of to tics in Tourette syndrome,69 has shown promising
For more on the International America International Tourette Syndrome Deep Brain results. A case study reported a 48% improvement in tic
Tourette Syndrome Deep Brain Stimulation Registry and Database. Overall, the safety severity as measured by the YGTSS and a 63% improve­
Stimulation Registry and
Database see https://tourette
profile of deep brain stimulation for Tourette syndrome is ment in projected battery life compared with continuous
deepbrainstimulation favourable when executed by an experienced multi­ stimulation.68 Further studies are needed to determine the
registry.ese.ufhealth.org disciplinary team.107 Improvements in tics and comor­ long-term efficacy of closed-loop stimulation for Tourette
bidities have been shown in numerous open-label and syndrome treatment.
retrospective studies, which make up most of the evidence
to date. Multicentre retrospective studies and meta- Conclusions and future directions
analyses have reported mean improvements of Research over the past 5 years has substantially
45·1–52·7% in tic severity in retrospective studies, the contributed to our understanding of the clinical
largest of which included 185 patients.107–110 Outcomes presentation, genetics, and pathophysiology of Tourette
across the few randomised controlled trials, which have syndrome, which has enabled progress towards
been done only in adults, have been mixed and difficult to development of new therapies and improvement of
generalise due to small sample sizes and differences in existing therapies for tics and associated comorbidities.
study design.111–114 The mixed results across trials highlight New insights into the typical time course and predictors
the challenges of implementing randomised trials in the of tics and comorbidities might improve the ability of
Tourette syndrome population and the importance of clinicians to diagnose Tourette syndrome and to
stringent patient selection and of allowing time for determine effective treatment plans. Multicentre
stimulation parameter optimisation in a fluctuating consortia have transformed genetic research for Tourette
disease. syndrome and have identified gene variants potentially
The most common brain targets for deep brain associated with increased risk, which could be relevant
stimulation in Tourette syndrome are the centromedian for diagnosis or developing novel therapeutic targets.
thalamic region and the anteromedial or posteroventral Although experts generally agree that deficits in inhibition
regions of the pallidum (panel). Previous multicentre of behaviour underlie Tourette syndrome, new models
studies and meta-analyses have shown similar tic improve­ propose that it might encompass over-learned behaviours
ment with thalamic versus pallidal deep brain or deficits in social behavioural brain networks. These
stimulation.107–109 However, one meta-analysis revealed models might help to explain both tics and the behavioural
greater improvement in tics and obsessive-compulsive symptoms of Tourette syndrome and could lead to new
behaviour with pallidal deep brain stimulation,115 and the targets for pharmacological or neuromodulation
AAN guidelines reported moderate confidence that pallidal therapies. Behavioural therapies such as CBIT can be
deep brain stimulation reduces tic severity (panel).79 There highly effective in improving tics, and access is continuing
is no clear consensus on which target is most effective for to expand with online and telehealth options. Finally, new
improving tics; however, similar to more commonly predictors of response to deep brain stimulation and
treated disorders like Parkinson’s disease, individual novel investigational tools are rapidly improving our
symptom profiles and comorbidities might be important understanding of the neurophysiology underlying
factors when selecting the optimal surgical target for a Tourette syndrome, which might guide neurosurgical
given patient with Tourette syndrome. For example, a targeting and stimulation programming to improve the
retrospective study of 55 patients from a single centre efficacy of deep brain stimulation therapy for treatment-
found anteromedial pallidum stimulation led to greater refractory symptoms.
improvement in OCD symptoms than did thalamic Despite progress in our understanding of Tourette
stimulation.116 Other studies suggest that the structural syndrome, several unsolved challenges affect both
networks modulated by deep brain stimulation that are research and clinical domains. To address these
associated with tic improvement might differ across challenges, aggregating data across centres will be crucial,
surgical targets. Tic improvement with deep brain especially for research studies requiring large patient
stimulation targeted to either the anteromedial or cohorts (eg, neuroimaging or genetics) and those with a
posteroventral pallidum was associated with modulation small candidate population (eg, neuromodulation).
of limbic and associative structural networks, and Several research organisations and multicentre consortia
improvement with thalamic stimulation was associated have been established to pool data, resources, and multi­
with sensorimotor networks (figure 3).117–121 Larger disciplinary expertise across Tourette syndrome research
multicentre studies are necessary to develop specific domains.122 Examples of active consortia include the
predictors to optimise patient-tailored brain target ESSTS,123 several inter­national organisations focused on
selection. large genetics studies,124 and the International Tourette
Another promising area of research is the use of Syndrome Deep Brain Stimulation Registry and
neurophysiology to guide deep brain stimulation. Closed- Database125 and the Neuroimaging Consortium,126 both of
loop deep brain stimulation controlled by low-frequency which are supported by the Tourette Association of
thalamic activity, a potential marker that has been linked America. Multicentre research initiatives and open access

154 www.thelancet.com/neurology Vol 22 February 2023

 Review

Declaration of interests
Search strategy and selection criteria KAJ reports receiving fellowship funding from the National Science
Foundation and travel grant awards from the International Congress of
We searched PubMed for articles published between Parkinson’s Disease and Movement Disorders. AG has received grant
Jan 1, 2016, and July 1, 2022, and checked reference lists in funding from the National Institutes of Health (NIH; R01NS096008) and
relevant articles. Search terms used were “Tourette syndrome”, the National Science Foundation (NSF PECASE 1553482); support from
the Tourette Association of America; device donations from Medtronic
or “tics”, in combination with “comorbidities”, under an NIH contract; and serves as a board member of the Brain
“pathophysiology”, or “treatment” without language Computer Interfaces Society. KDF reports receiving research support and
restrictions. We chose original research articles and select review fellowship support from Medtronic and Boston Scientific and research
papers on the basis of originality and relevance to this Review. support from Functional Neuromodulation. CRB has received support
from the NIH (UH3 NS119844) and has served as a consultant for
NeuraModix. MSO serves as a medical advisor for the Parkinson’s
Foundation; has received research grants from NIH, Parkinson’s
datasets will be essential to advance knowledge and to Foundation, the Michael J Fox Foundation, the Parkinson Alliance,
refine treatments. Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette
Future research should aim to further our under­ Syndrome Association, and the UF Foundation; has received support for
research by NIH (R01 NR014852, R01NS096008, UH3NS119844, and
standing of the pathophysiology of Tourette syndrome U01NS119562); and is principal investigator of the NIH R25NS108939
and translate this knowledge to refine therapies. Objective Training Grant. All other authors declare no competing interests.
measures of tic severity are needed to track symptoms Acknowledgments
longitudinally and in naturalistic environ­ments to better We would like to thank Erica Rodriguez for the figure illustrations.
capture patient-specific fluctuations and supplement References
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