3.1.1. Definition and phenomenology

Symptom network analysis was applied to examine symptom structure in 715 patients with tic disorders from the Beijing Children’s Hospital. ¹ Tic symptoms were linked to premonitory urge symptoms and attention deficit hyperactivity disorder (ADHD) symptoms, and depressive symptoms, anxiety symptoms and neuroticism were found to be central nodes in the network. These findings suggest potential key targets for intervention.

The phenomenology of tics in adults with tic disorders was examined in a cross-sectional study of 227 adults from the Calgary and Paris Adult Tic Registry. ² The male-to-female ratio was 1.8:1, indicating that male predominance in adulthood is less pronounced than in childhood. No significant sex differences were observed in tic severity or tic phenomenology. Generalized anxiety disorder and ADHD were the most common comorbidities, reported in 49.5% and 35.8% of this cohort, respectively. The same group, but this time using not an adult but a pediatric cohort with TS and persistent motor or vocal tic disorders (PMTD/PVTD) examined the currently used diagnostic criteria for both, i.e., whether the separation of TS and PMTD/PVTD makes actual sense. ³ Specifically, 341 children and adolescents with primary chronic tic disorders were included (90.0% with TS, 7.0% with PMTD, 1.8% with PVTD). There were no differences in sex ratio, tic severity and impairment between the two groups. However, participants with PMTD/PVTD had a later age at tic onset than those with TS (p = 0.01) and had less psychiatric comorbidity (p = 0.01), specifically ADHD and obsessive-compulsive disorder (OCD). Finally, there were no differences in tic severity or impairment. Given that the major difference between TS and PMTD/PVTD lies in psychiatric comorbidities, which are not part of the diagnostic criteria, the authors suggest creating a single category for primary persistent tic disorders. Also, since tic onset in adolescence is uncommon, they question whether the age limit in the diagnostic criteria might not be more relevant as a supportive criterion.

A study from Baylor School of Medicine compared the clinical and demographic features of consecutive patients with TS who exhibited simple and complex phonic tics. ⁴ In total, quite a high number of patients (23.5%) had complex phonic tics, while 17.4% had verbalizations. No statistically significant differences were observed between TS patients with simple versus complex phonic tics with respect to sex, age at onset, age at presentation, or comorbid ADHD or OCD. Patients with complex phonic tics more frequently had trunk tics, complex motor tics, copropraxia, a wider variety of phonic tics, and greater tic severity. The multivariate regression analysis showed an independent association between trunk tics and complex phonic tics. The authors concluded that complex phonic tics seem to be part of a more widely distributed, severe, and complex presentation of TS, likely representing a continuum within the spectrum of motor and phonic tics.

In a comparative study of children with tic disorders and primary stereotypic movement disorder, children with stereotypies exhibited greater motor impairment and significantly higher levels of neurological soft signs, particularly in the sequencing of complex motor acts. ⁵ Neurological soft signs—reflecting subtle deficits in motor coordination, sensorimotor integration, and motor planning—were more pronounced in the stereotypy group, alongside poorer fine and gross motor performance, balance, and coordination. These findings support distinct neurodevelopmental mechanisms underlying tic disorders and stereotypic movements and highlight the importance of comprehensive motor and neurological assessment in differential diagnosis.

In acoustic analyses of adults with TS, linguistic tics differed from normal speech by exhibiting higher pitch, lower harmonicity, and altered phonation patterns consistent with a more falsetto-like voice quality. ⁶ These findings suggest that tic-related vocalizations are physiologically distinct from voluntary speech and may reflect specific laryngeal control mechanisms that help differentiate tics from intentional communication.

A study from China investigated risk factors for recurrence in children with chronic tic disorders following pharmacological treatment. ⁷ In a cohort of 124 pediatric patients, outcomes were assessed after one year of medication and six months following treatment discontinuation. Comparative and multivariate analyses identified Mycoplasma pneumoniae IgM positivity and the presence of vocal tics as significant independent risk factors for relapse, while older age and treatment with aripiprazole were associated with a reduced risk of recurrence.

In a large pediatric cohort, approximately 7% of patients with TS met criteria for treatment-refractory tics based on a recent expert consensus definition. ⁸ Refractory cases were associated with greater tic severity and higher IQ, and with a trend toward more frequent family history of TS.

3.1.2. Assessment and quantification of tics and comorbidities

Loewenstern and colleagues ⁹ examined whether a custom-developed smartphone application that recorded selfie videos of 12 children and adolescents aged 7–18 years with facial tics could be used to distinguish between “tic” and “non-tic” movements using facial landmarks analyzed by deep neural networks. Training the models on all videos achieved an accuracy of 95%, suggesting that this approach may become a valuable tool for clinicians.

Using automated video analysis, adults with TS showed significantly increased blink rates, driven primarily by a higher frequency of atypical blinks. ¹⁰ These atypical blink patterns enabled accurate differentiation from controls and were consistent within individuals but heterogeneous across patients, highlighting their potential as a quantitative marker of tic-related motor abnormalities.

The Chinese version of the Parent Tic Questionnaire (PTQ) demonstrated good reliability and validity in assessing tic severity in children with tic disorders, with satisfactory internal consistency, test–retest reliability, and convergent validity with clinician-rated measures. Variability in item difficulty suggests cultural differences in tic perception, highlighting the need for further adaptation to improve assessment accuracy across contexts. ¹¹ This study was complemented by a similar one by Li et al. ¹² A total of 414 participants aged 2–16 years were evaluated using the PTQ alongside established clinician- and parent-reported instruments. The results demonstrated good internal consistency across PTQ subscales and strong correlations with the Yale Global Tic Severity Scale (YGTSS), supporting its convergent validity. A cutoff score of 14 was identified as optimal for distinguishing between mild and moderate tic severity. Overall, the Chinese PTQ showed robust psychometric properties, providing a reliable and practical tool for parent-based assessment of tic severity and facilitating broader, more accessible evaluation in clinical and research settings.

The study on the Autism–Tics, ADHD and other Comorbidities (A-TAC) inventory provides important evidence for its usefulness as a screening tool in population-based samples, while also highlighting its limitations for clinical applications. ¹³ Drawing on participants from the Child and Adolescent Twin Study in Sweden, the researchers evaluated the instrument against comprehensive clinical assessments in 263 children. The findings demonstrated that the A-TAC has strong predictive validity for most neurodevelopmental disorders, with high accuracy values, although it performed less effectively for developmental coordination disorder. Notably, the study also revealed a high rate of comorbidity, with over 40% of children meeting criteria for more than one neurodevelopmental disorder, underscoring the complexity of these conditions. Overall, the results support the use of the A-TAC as an effective screening measure in both research and public health contexts, but emphasize that it cannot substitute for detailed clinical evaluations or be used as the sole basis for determining access to specialized care.

A study from Canada evaluated the diagnostic accuracy of commonly used psychiatric screening instruments in adults with TS, a population characterized by high rates of comorbid attention-deficit hyperactivity disorder, obsessive-compulsive disorder, anxiety, and depression. ¹⁴ Thirty-six adults with TS completed standardized screening tools (GAD-7, PHQ-9, PHQ-2, ASRS v1.1, and OCI) alongside a structured psychiatric interview. The results indicated that optimal cutoff points for this population differ from those established in the general population, with higher thresholds generally required for accurate detection. The ASRS v1.1 demonstrated the strongest diagnostic performance, followed by the GAD-7 and OCI, whereas the PHQ-9 and PHQ-2 showed comparatively weaker accuracy. Overall, the findings suggest that standard screening cutoffs may not be directly applicable to adults with TS, highlighting the need for population-specific adjustments to improve the identification of comorbid psychiatric conditions.

A interesting and highly relevant question concerns the accurate assessment of treatment outcomes in patients with TS. McGuire and colleagues determined the minimal clinically important difference on the Yale Global Tic Severity Scale (YGTSS) Total Tic Score (YGTSS-TTS) and YGTSS Impairment Scale (YGTSS-I), using the Clinical Global Impression of TS Severity (CGI-TS-S) and Improvement (CGI-TS-I) as anchors, in 133 pediatric patients participating in two of the ecopipam trials. ¹⁵ They found that a 25% reduction in YGTSS scores was a generally appropriate minimum threshold to define clinically meaningful improvement in this population. This squares with clinical experience as well as the primary endpoint choice in many pharmacological trials to date.

3.1.3. Epidemiology

Yilmaz and colleagues ¹⁶ performed a literature search covering the period 2000–2025 to examine incidence and prevalence of TS. The prevalence was estimated to be approximately 1% in children and adolescents, particularly among boys, with a male-to-female ratio of about 4:1, and around 0.01% in adults. The latter number would suggest a 99% remission rate which, based on clinical experience and small follow-up studies, seems highly unlikely. Rather, it underscores the need for more and better epidemiological studies in adults with chronic tics.

The prevalence of TS and its comorbidities in children was also examined using data from 79,236 children aged 3–17 years from the 2021 National Survey of Children’s Health. ¹⁷ The key question was “ Has a doctor or other healthcare provider ever told you that this child has Tourette Syndrome?” Defined thus, the prevalence of TS was 0.3%, with higher rates observed in adolescents and males. Neurodevelopmental and psychiatric disorders were more common among children with TS compared to those without TS, with ADHD present in 49%, autism spectrum disorder (ASD) in 21%, anxiety in 60%, and depression in 25% (compared to 10.2%, 3.2%, 11.3%, and 5% among children without TS, respectively). Prematurity and low birth weight were associated with higher rates of TS and its comorbidities.

Sex differences in outcomes in TS and Persistent Motor or Vocal tic disorders (PMVT) were analyzed using the Tourette Association of America International Consortium for Genetics (TAAICG) dataset in 2403 participants. ¹⁸ Akin to autism, female vs. male participants with TS are less likely to be formally diagnosed, have a later age at diagnosis, and longer time to diagnosis. This suggests that females are an underrecognized and underserved community when it comes to chronic tics, and much progress still needs to be made.

3.1.4. Prognosis and natural history

The relationship between early developmental milestones and tic severity was examined in the EMTICS study. ¹⁹ Developmental milestones were retrospectively evaluated in 383 participants (aged 3–16 years) and showed significant correlations, but small effect sizes, with age at walking and first words (r = 0.11 and r = 0.12, respectively). These milestones were also associated with several psychopathological comorbidities, including ADHD, OCD, oppositional defiant disorder, and suspected ASD. These findings can be used for early detection of individuals at risk.

A Swedish population-based study included all singleton births after 22 weeks of gestation between 2001 and 2021 to investigate the association between maternal tic disorders and pregnancy, delivery, and neonatal outcomes. ²⁰ In total, 581 pregnancies in women with tic disorders were compared with 5,777 matched unexposed pregnancies. Maternal tic disorders were associated with significantly increased risks of gestational diabetes and both elective and emergency cesarean sections, but no increased risk of adverse neonatal outcomes was observed. The authors suggest that enhanced maternal care for women with tic disorders is warranted.

A total of 50,018 patients with tic disorders and four matched controls per patient from the nationwide database in Taiwan were included to examine mortality rates. ²¹ Patients with tic disorders had a higher likelihood of death from unnatural causes and suicide compared to controls, even after adjustment for demographics, clinical characteristics, and psychiatric comorbidities. These findings suggest that healthcare professionals should closely monitor patients with tic disorders for both physical and mental health.

3.1.5. Transient effects of environment on tic severity

Voluntary tic suppression reduces tic frequency, but so does social context. However, Wellen and colleagues ²² demonstrated that merely being in the presence of a clinician, whether discussing tics or other psychiatric symptoms, without instruction to suppress tics, reduced tic frequency substantially more (87% reduction) than did intentional tic suppression (62% reduction). The authors discuss potential implications for clinical and research assessment of this “social automatic tic suppression.” For instance, this study highlights important limitations in traditional clinical assessment of TS and other tic disorders, demonstrating how strongly tic expression is influenced by social context; the presence of a clinician may unintentionally facilitate tic suppression, potentially leading to underestimation of symptom severity during standard clinical evaluations. Additionally, while tic frequency decreased across treatment in both contexts, the reduction was significantly greater when participants were alone, suggesting that video tic counts while the person is alone may prove more sensitive than traditional clinician ratings for controlled trials. Overall, the study supports the value of objective, video-based assessment methods as a complement to clinical observation, as they can capture tic behaviors that may otherwise go undetected and provide a more accurate representation of symptom severity and treatment effects.

A study from Australia used a qualitative descriptive method to understand the sensory experiences that reduce or exacerbate tics from the perspectives of young people with tic disorders and their caregiver(s). ²³ Three themes were identified: sensory experiences associated with tics; environmental contexts that reduce or exacerbate tics; and occupational participation as a method of focus and distraction. The following auditory factors were listed as the ones that exacerbate tics: unexpected noises, eating, sounds of swallowing and breathing. While lack of movement made tics worse, moving the body around, stretching and fidgeting were listed by participants as factors that make tics better. Diverse experiences related to touching were mentioned as alleviating tics. Watching TV or looking at screens was mainly associated with tic worsening. Examples of activities that alleviate tics included sports, craft, playing the piano or singing. Calm environments such as a bedroom were the best environmental setting, while loud and crowded environments, unsurprisingly, made tics worse.

In a case–control study of children with tic disorders, screen time was significantly higher compared to controls and was positively associated with tic severity. Greater daily screen exposure predicted higher YGTSS scores, while age of first screen exposure was not related to symptom severity. These findings suggest that prolonged screen time may contribute to increased tic severity, highlighting the importance of monitoring screen use in children with TS. ²⁴

Regarding hormonal influences on tic expression, an online survey was completed by 112 female adults with TS to study the potential relationships between the menstrual cycle and neuropsychiatric and physical symptoms. ²⁵ 26% of respondents endorsed tic changes in relation to their menstrual cycles, with higher current tic severity and impairment as well as co-occurring cycle-related mood and anxiety changes. However, notable study limitations concern the lack of information about hormonal influences such as contraceptives and menopause.

In total, 66 children with tic disorders and 72 healthy controls were included to examine the role of environmental factors in tic severity and quality of life. ²⁶ Significant differences were observed between the two groups with respect to physical activity, academic achievement, peer relationships, and parent–child reading. These four environmental factors were found to moderate the relationship between tic severity and quality of life and should be considered in treatment strategies.

3.1.6. Sensory phenomena and premonitory urge

Clinical correlates of premonitory urges in children were investigated by Yu and colleagues. ²⁷ In line with previous research, the following predictors of premonitory urges were identified: age, severity of motor tics, severity of vocal tics, and impairment of quality of life.

In a systematic review from China ²⁸ the measurement properties of premonitory urge patient-reported outcome measures (PROMs) in patients with tic disorder were assessed. A total of 18 studies were included, involving four PROMs: Premonitory Urge for Tics Scale (PUTS), University of São Paulo’s Sensory Phenomena Scale (USP-SPS), Individualized Premonitory Urge for Tics Scale (I-PUTS), and the Rumination and Awareness Scale for tic-associated sensations (RASTS). The PUTS was recommended for assessing premonitory urge in tic disorder, which aligns with the “European Clinical Guidelines for Tourette Syndrome and other Tic disorder-version 2.0. Part I: assessment”. To assess premonitory urge and sensory modulation disorder, the USP-SPS was identified as the most appropriate, while the RASTS was suitable for evaluating premonitory urge and tic-related cognitions. However, USP-SPS and RASTS were deemed to need further validation due to limited evidence, and their use was recommended in specific clinical or research settings.

3.1.7. Functional tic-like behaviors

A study from England ²⁹ investigated the prognosis of 43 adolescents with functional tic-like behaviors (FTLB) at a mean of 2.6 years after onset. Patient demographics support the European Society for the Study of Tourette Syndrome diagnostic criteria for FTLB, with a 100% female sex bias, adolescent onset and high levels of co-occurring disorders. The most common comorbidities were anxiety and other types of functional neurological disorder (FND). In line with previous reports, FTLB had good prognosis, with two thirds improving or recovered. In another long-term follow-up study of 30 patients with mass social media–induced FTLB, most showed improvement or remission over an average of 2.2 years. ³⁰ Better outcomes were associated with younger age, male sex, fewer psychiatric comorbidities, absence of depression, early diagnosis, and discontinuation of secondary gain, while psychotherapy and medication showed limited impact on prognosis.

In a qualitative study of adolescents with FTLB and their parents, participants reported experiences of stigma, disbelief, and difficulties accessing care, alongside significant impacts on identity, relationships, and family functioning. ³¹ Findings highlight the need for improved psychoeducation, individualized support, and greater public and professional awareness to reduce stigma and improve care.

In patients with TS, co-occurring functional tic-like behaviors (FTLB) were associated with more complex and severe symptom profiles, including increased coprolalia, self-injurious behaviors, tic attacks, anxiety, and other functional neurological symptoms. ³² The authors highlight key clinical features that help differentiate functional overlay from primary tics and underscore the importance of accurate diagnosis to guide appropriate treatment.

3.1.8. Comorbidities

Vigil-Pérez and colleagues ³³ examined the presence of repetitive and restrictive behaviors and sensory phenomena in children and adolescents aged 6–17 years diagnosed with OCD (n = 23), TS (n = 19), or ASD (n = 21). No differences were found in the prevalence of repetitive and restrictive behaviors between the diagnostic groups, except for the routine subscale, which was more prevalent in the OCD group. At least one type of sensory phenomenon was present in 90% of the participants.

A scoping review was conducted to examine the use of assessment tools for non-motor symptoms in pediatric movement disorders, including tic disorders. ³⁴ The review identified substantial gaps in the evaluation of non-motor symptoms in these patient populations, particularly with respect to pain, sleep, and gastrointestinal symptoms. Development of disease-specific tools for the assessment of non-motor symptoms is needed.

Questionnaires were distributed to parents of children with TS to explore the presence of communication difficulties. ³⁵ In total, 38% showed signs suggestive of communication challenges, and 10% were reported to have a language disorder diagnosis. Communication difficulties were correlated with psychosocial functioning. Healthcare professionals should consider referral to a speech-language pathologist when communication challenges are suspected.

The association between TS and sleep disorders was assessed using data from a nationwide database in Taiwan. ³⁶ A total of 13,646 patients with new-onset TS from 2002–2015 were included, each matched with four controls. Patients with TS were found to have a higher risk of sleep disorders, particularly those with comorbid ADHD and anxiety.

Another longitudinal study investigated predictors of sleep disturbance in individuals with TS from childhood into early adulthood. ³⁷ A cohort of 80 participants who had previously completed a randomized controlled trial of behavioral therapy for tics in childhood were reassessed approximately 11 years later. The findings demonstrated that greater tic-related impairment following initial treatment significantly predicted poorer sleep outcomes in early adulthood. In addition, cross-sectional analyses at follow-up identified older age, higher anxiety severity, and greater ADHD symptom severity as significant contributors to sleep disturbance. These results suggest that residual functional impairment from tics, along with comorbid psychiatric symptoms, plays a key role in long-term sleep difficulties in individuals with TS.

A study from Denmark also explored the topic of sleep disturbances in adolescents with different medical conditions, including tics. ³⁸ A total of 157 children with medical conditions and 117 healthy controls completed the validated Sleep Screening Questionnaire–Children and Adolescents (SSQ-CA). The findings revealed a high prevalence of sleep disturbances in both groups, with a greater proportion among those with medical conditions, although the difference was not statistically significant. However, children with medical conditions reported significantly poorer sleep quality, more frequent nocturnal awakenings, and increased use of electronic devices before bedtime. These results highlight sleep disturbances as a common and underrecognized issue in pediatric populations with chronic conditions, underscoring the importance of routine screening and targeting modifiable factors, such as pre-sleep screen use, in clinical management. The study did not provide subgroup analysis specifically for tic disorders, so conclusions for tic disorders must be interpreted cautiously.

A cluster analysis study between tics and ADHD was conducted by Jiang and colleagues. ³⁹ They showed that in TS comorbid with ADHD there were two identifiable clusters: the severe TS group and the severe ADHD group. The severe TS group had more pronounced tic symptoms, but their age, ADHD symptoms, and functional impairment were all significantly lower than those of the severe ADHD group. Interestingly, compared to samples with ADHD alone, the distribution of age and impairment among individuals did not change with the addition of tic symptoms, but was mainly related to ADHD symptoms.

In a network analysis of drug-naïve children and adolescents with tic disorders, premonitory urges were closely linked to tic severity and obsessive-compulsive symptoms (OCS), with obsessive thoughts emerging as a key bridging symptom. While premonitory urges were indirectly associated with reduced quality of life, obsessive-compulsive symptoms showed a direct impact, highlighting their central role and the importance of targeting OCS in clinical interventions. ⁴⁰

Pain in tic disorders is frequent and important comorbidity. In a study by Małek ⁴¹ of 76 adults with TS, 73.7% reported tic-related pain; almost all of them declared pain located in more than one part of the body. The affective pain domain was the highest scored by both men and women. Coping self-statements was the most common coping strategy chosen by men, whereas catastrophizing was more common in women. Respondents rated internal factors as the most important in pain management and external factors, particularly medical professionals, as the least important. Another study on pain examined a large cohort using two Medicaid databases with a total of 47 242 individuals with tic disorders. ⁴² Taken together, around 20% had chronic pain, especially headaches (migraines), which is much higher, up to 7.5 times higher, than in the general population.

In youth with chronic tic disorders, sensory dysregulation—particularly increased sensory sensitivity and avoidance—was associated with greater tic severity and stronger premonitory urges. ⁴³ It was also linked to higher severity of co-occurring conditions, including anxiety, ADHD, and obsessive-compulsive symptoms.

3.2.1. Genetics and epigenetics

In 2025 two large-scale whole exome studies (WES) of TS/chronic tic disorders (CTD) were published. In the first study, Wang and colleagues ⁴⁴ analyzed 1,550 chronic tics disorders (CTD) trios (625 of them had both OCD and CTD) and 1,493 OCD trios and identified 10 high confidence CTD (hcCTD) and 6 probable CTD (pCTD) genes. Of the ten hcCTD genes, two (CELSR3, WWC1) were identified only in the CTD analyses, three (SETD1A, QRICH1, DNAH9) in the separate analyses of both OCD and CTD trios and five (NIPBL, ARHGAP5, PKD1, ULK1, DST) in the omnibus analyses of the two cohorts. In the second study, Zhan and colleagues ⁴⁵ analyzed WES data from 1,466 TS and 6,714 autism spectrum disorder (ASD) trios. They observed a significant exome-wide enrichment of protein-truncating de novo mutations in TS probands, especially within genes intolerant to loss-of-function variation (pLI ≥ 0.9). When they integrated both de novo and rare inherited coding variants, they identified three novel candidate TS risk genes (PPP5C, EXOC1, GXYLT1).

Another study investigating the rare variants in TS/CTD was performed by Halvorsen and colleagues. ⁴⁶ For this study, they generated copy number variant (CNV) calls from microarray data from 5,725 TS/CTD cases and 10,982 matched controls. With their analyses they observed a higher burden of ultra-rare deletions overlapping loss-of-function intolerant genes in cases, as well as that cases were more likely to carry known neurodevelopmental CNVs than controls. From their genome-wide CNV scan they replicated the previously known NRXN1 deletion and identified a novel genome-wide-significant CNV locus covering duplications at 17q12 affecting the ACACA gene.

Grotzinger and colleagues conducted a comprehensive cross-disorder psychiatric genomics analysis spanning 14 disorders in over one million cases, identifying five latent genomic factors that captured the majority of shared genetic variance across disorders. ⁴⁷ TS, using the summary statistics from Yu et al., ⁴⁸ loaded mostly on the Compulsive Disorders factor along with anorexia nervosa and OCD, and more weakly on the Neurodevelopmental factor alongside ASD and ADHD. Interestingly, TS showed the most genetically distinct profile of all 14 disorders, with 87% of its genetic variance left unexplained by the five factors (the highest residual variance observed). Multivariate GWAS in each factor revealed 6 genome-wide significant loci, with one not present in the univariate GWASs for the Compulsive Disorders factor, and 3 genome-wide significant loci for the Neurodevelopmental factor. Additionally they performed case-case GWAS and they observed five significant loci between TS and schizophrenia, two between TS and bipolar disorder and 1 locus between TS and each of anorexia nervosa, alcohol use disorder and autism. Overall, more than 99% of the significant case-case GWAS hits were observed between traits belonging to different factors.

Another study using the TS summary statistics from Yu and colleagues ⁴⁸ was performed by Fanelli and colleagues ⁴⁹ aiming to investigate the genetic overlap using LAVA local genetic correlation analyses, between three insulin resistant-related (IR) conditions (obesity, Type 2 Diabetes (T2DM), and metabolic syndrome (MetS)), as well as nine psychiatric disorders including TS. Although TS did not have any significant global genetic correlation with the three IR traits, they uncovered one positive local genetic correlation between TS and MetS and two positive and two negative local genetic correlations between TS and T2DM. Follow-up geneset enrichment analyses of the local genetic correlated loci between TS and T2DM revealed significance for embryonic placenta development and an immune related pathway (immunoregulatory interactions between a lymphoid and a non-lymphoid cell) .

3.2.2. Environmental risk factors

National population databases in Taiwan were used to investigate whether maternal autoimmune diseases are associated with an increased risk of tic disorders in offspring, as maternal autoimmune conditions have been linked to several neurodevelopmental disorders through maternal immune activation. ⁵⁰ Indeed, maternal autoimmune diseases were found to be associated with tic disorders in offspring. The pathogenic mechanisms underlying this association warrant further investigation.

3.3.1. Autopsy studies

The Vaccarino lab reported an analysis of single-nucleus RNA and open-chromatin DNA from caudate and putamen in 6 TS and 6 matched control post-mortem brains. ⁵¹ Most clearly, the number of interneurons was decreased by half in TS brains without significant difference in any other cell type; this finding would be consistent with striatal hyperactivity in vivo. The remaining results showed decreased oxidative metabolic genes in medium spiny neurons, correlating with activation of microglia.

3.3.2. Neurophysiology

In recent years, much research has been conducted within the theory of event coding framework, which posits increased binding between perception ( i.e., premonitory urges) and action ( i.e., tics) in TS. ^{52, 53} In 2025, two studies added empirical support to that conceptual framework. First, Hao and colleagues assessed theta, alpha, and beta oscillatory activity among individuals with TS and controls during a stimulus-response event file task. ⁵⁴ Behaviorally, they found no between-group differences regarding binding of perceptual and motor processes. At the neural level, both groups shared similar activity patterns across frequency bands in several regions critical for sensorimotor integration. However, findings revealed a temporal disconnect of oscillatory activity between different processing stages of sensorimotor integration in individuals with TS, which was particularly evident for beta-band activity in the supplementary motor area and prefrontal cortex. Second, Prochnow and colleagues assessed the modulation of these same frequency bands during a motor inhibition task designed to manipulate perception-action binding. ⁵⁵ In this study, the authors found that adults with TS had worse inhibitory performance when perceptual features Go and NoGo stimuli overlapped, which is consistent with overly strong perception-action links in TS. In those trials, individuals with TS showed stronger and more extended theta band modulation as well as weaker and more restricted alpha band modulation. Both studies highlight the relevance of assessing theta, alpha, and beta oscillatory activity in the context of the theory of event coding framework.

Another study contributed to characterizing the neurophysiological correlates of perception-action binding. Schüller and colleagues investigated sensorimotor predictive processes in adults with TS during a cued Posner task. ⁵⁶ Behaviorally, adults with TS showed reduced modulation of reaction times by cue predictability. This may be attributable to increased binding of stimulus-response features in TS which could interfere with appropriate updating of behavior based on cue information. Amplitude of the P3b, which reflects cue predictability, was reduced among adults with TS. This finding suggests impaired updating of stimulus-response associations in TS.

Two studies also provided mechanistic insight into the symptomatology of TS, through the use of evoked potentials. One study of transcranial magnetic stimulation evoked potentials found a delayed P180 latency following stimulation of the primary motor cortex among adults with TS, relative to control participants. ⁵⁷ Delayed P180 latency following stimulation of the dorsolateral prefrontal cortex was also correlated with increased tic severity. These results were interpreted as disruptions in GABA transmission, potentially mediating symptom severity. Another study investigated somatosensory evoked potentials among adults with TS. ⁵⁸ A larger P100 was found in the TS group, relative to the control group, which suggests hyper-responsivity to tactile stimuli. Additionally, trial-by-trial variability of somatosensory evoked potentials was larger in adults with TS than in controls, which was interpreted as increased neural noise. This unstable recruitment of sensorimotor populations at rest may however normalize following median nerve stimulation.

Another aspect of the TS symptomatology that has received attention recently is tic suppression. A recent study investigated changes in event-related EEG power associated with blink and tic suppression among children with TS and typically developing children. ⁵⁹ In both groups, blink and tic suppression was associated with increases in theta power in several frontal and parietal regions. However, beta power over sensorimotor areas increased during suppression in typically developing children but increased in children with TS. This latter finding highlighted the potential role of sensorimotor areas as a neural marker of tic suppression abilities.

A few studies used EEG to assess functional connectivity in TS. Schmidgen and colleagues assessed functional connectivity in children with TS during a cued reaction time task. ⁶⁰ They found reduced theta-band functional connectivity in children with TS during the processing of the cue stimulus, which they interpreted as a compensatory mechanism used to weaken perception-action binding. Morand-Beaulieu and colleagues used functional connectivity analyses to investigate the electrophysiological correlates behind the frequent co-occurrence of TS and ADHD in youth. ⁶¹ Findings from that study revealed that TS and ADHD were associated with different networks of reduced functional connectivity spanning several frequency bands. This suggests that effects of TS and ADHD on functional connectivity are mostly additive. Complementing these task-based findings, Morand-Beaulieu and colleagues ⁶¹ examined resting-state functional connectivity using EEG in children with TS, ADHD, comorbid TS + ADHD, and healthy controls. The results revealed distinct connectivity patterns associated with each condition. In TS, reduced functional connectivity was primarily observed in the theta band between sensorimotor regions (particularly the postcentral gyrus) and occipital areas such as the lingual and pericalcarine cortices. In contrast, ADHD was mainly associated with decreased connectivity involving sensorimotor and prefrontal regions across delta, theta, and alpha bands. Importantly, the effects of TS and ADHD appeared largely additive rather than interactive at the neural level.

Another study developed and evaluated a machine learning–based framework for the diagnosis and severity assessment of tic disorders (TD) using electroencephalogram (EEG) data. ⁶² The sample included 90 children with TD and 88 healthy controls. A two-stage progressive diagnostic approach was implemented, incorporating a novel individual-based feature-weighted integration method and a SHAP-driven feature selection and weighting strategy to enhance model performance and interpretability. Using 13 selected features, a Logistic Regression model achieved high diagnostic accuracy (94.2%), with strong sensitivity (92.4%) and specificity (96.1%), while a Decision Tree model demonstrated moderate accuracy (81.5%) in predicting tic severity. These results were further supported by validation on a hold-out dataset. Key predictive features included EEG-derived mean frequency measures in specific brain regions, as well as age. Overall, the findings highlight the potential of EEG-based machine learning approaches as effective and interpretable tools for individualized diagnosis and severity assessment in TD, with promising implications for clinical decision support.

In a case–control study, individuals with tic disorders showed altered autonomic nervous system functioning, reflected by differences in heart rate variability, particularly reduced low-frequency power. ⁶³ HRV measures were also associated with quality of life, suggesting a link between autonomic regulation, tic symptoms, and psychosocial well-being.

3.3.3. Neuroimaging studies

Several recent neuroimaging studies have provided new insights into the structural substrates of Tourette syndrome (TS), particularly regarding iron metabolism, brain clearance systems, and large-scale anatomical networks.

Two studies specifically investigated the long-standing iron hypothesis in TS. Gkotsoulias and colleagues ⁶⁴ combined 7 T MRI-derived measures of brain iron content with PET imaging of dopamine D ₁ receptor availability, two modalities that have rarely been investigated in TS, to study 25 adults with TS and 40 control participants. They reported decreased iron-related MRI markers across several basal ganglia structures, with the substantia nigra, subthalamic nucleus, red nucleus and pallidum showing consistent differences from controls across metrics. D ₁ receptor availability was reduced in the striatum, including both the putamen and caudate nucleus. Importantly, D ₁ receptor availability, but not iron measures, was significantly correlated with tic severity as assessed by the YGTSS. This study provides important support for the longstanding iron hypothesis in TS and contributes to a more integrated understanding of its neurobiological underpinnings. Complementing these findings, Lin et al. ⁶⁵ investigated brain iron concentration in TS using 3 T MRI-based quantitative susceptibility mapping (QSM). Unlike previous findings, whole-brain voxel-based morphometry analysis revealed iron-related alterations primarily in the bilateral putamen (increased QSM values) and the right anterior cingulate cortex (decreased QSM values). The study included 50 children with TS and 50 controls, providing valuable insights into the role of iron in TS pathophysiology.

A structural MRI study of 34 children with TS, but no comorbidities, and 34 controls found that machine learning classifiers with the highest diagnostic accuracy identified medial orbitofrontal cortex, thalamus, hippocampus and amygdala, mostly in the right hemisphere. ⁶⁶

Other work has explored structural mechanisms. Huang and colleagues ⁶⁷ investigated glymphatic system dysfunction in TS, a brain clearance system that has rarely been examined in this condition. They assessed perivascular space burden and the diffusion tensor imaging analysis along the perivascular space index as indirect markers of glymphatic function. Compared with controls, children with TS showed increased perivascular space volume and reduced DTI index, suggesting impaired glymphatic clearance. This work represents one of the first neuroimaging studies addressing glymphatic function in TS and provides preliminary evidence that glymphatic alterations may contribute to its pathophysiology. Also, in another study investigating the glymphatic system, children with TS showed reduced glymphatic system function, as measured by the analysis along the perivascular space (ALPS) index, compared to controls. ⁶⁸ Lower glymphatic activity was strongly associated with greater tic severity and poorer quality of life, with motor tics partially mediating this relationship.

At a broader network level, a large transdiagnostic analysis by Yu and colleagues ⁶⁹ examined the relationship between white matter tracts and a broad range of psychiatric disorders. A major strength of the work lies in its transdiagnostic approach, integrating multiple conditions within a single analytical framework. Regarding TS specifically, the findings primarily highlighted the potential involvement of the fornix/stria terminalis pathway in its pathophysiology.

Finally, a dual VBM–fMRI meta-analysis by Yang and colleagues, ⁷⁰ integrating 29 studies, providing a comprehensive overview of structural alterations in TS. They mostly identified grey matter volume reduction in cortical areas (anterior cingulate and postcentral gyri) and an increase in deep areas (cortico-spinal projections, striatum, cerebellum). For the fMRI part, they reported under-activation for motor areas (namely the SMA) and hyper-activation for frontal compensatory regions (superior frontal and superior temporal gyri).

Functional studies published in 2025 further refined our understanding of the neural dynamics underlying tic generation and motor control in TS.

Developmental aspects of functional networks were explored by Heinen and colleagues ⁷¹ in drug-naïve children and adolescents with TS. Using a combination of fMRI and an inhibitory control behavioral task, they aimed to characterize the developmental trajectory of motor networks. Their results indicated that patients with TS follow a different developmental pattern compared with healthy controls. While healthy participants showed increasing involvement of parietal and premotor regions with age, individuals with TS exhibited greater recruitment of sensorimotor areas. More specifically, higher activation of the right M1/S1 was observed in TS patients during a right-hand movement task. Dynamic causal modeling further revealed increased connectivity between the intraparietal sulci of the two hemispheres, as well as from the intraparietal sulcus to the premotor cortex. Taken together, these findings suggest an atypical developmental trajectory of motor networks in TS, likely reflecting compensatory mechanisms.

The Nottingham group followed up on their finding that rhythmic median nerve stimulation (MNS) at 10 Hz can reduce tics with a functional magnetic resonance spectroscopy (MRS) study. ⁷² Both rhythmic and arrhythmic MNS decreased GABA, and initially increased glutamate followed by a decrease over time. They speculate that adaptation to stimulation may suppress tics by decreasing glutamate release.

Neuropsychology

Morand-Beaulieu and colleagues provided an clear and updated review of the neurocognitive profile of both youth and adult patients with TS. ⁷³ While intellectual functions remain largely intact, patients often face challenges in attention, executive functions, and social cognition. A critical finding was that these difficulties are frequently driven by co-occurring conditions like ADHD and OCD rather than TS alone. The authors emphasized that comprehensive neurocognitive assessments may offer key insights for tailoring educational accommodations and predicting treatment outcomes to improve daily functioning.

Regarding social cognition, Eddy ⁷⁴ emphasized the critical role of the basal ganglia and dopaminergic modulation in interpersonal reactivity and perception of social intent. In TS, this manifest as a specific ‘hyper-responsiveness’ to social stimuli, where patients may show a heightened tendency to attribute purposeful goals or intentions to ambiguous movements. These alterations suggest that the neurobiological circuits traditionally associated with motor control also fundamentally shape how individuals with TS navigate and interpret their social environment.

3.3.4. Pharmacological studies informing pathophysiology

Abkur and colleagues ⁷⁵ reported on 10 patients with a tic disorder who later developed Parkinson disease. As with smaller earlier reports, ⁷⁶ development of parkinsonian signs indicating nigrostriatal cell loss did not improve tics, nor did treatment with dopaminomimetic therapies worsen tics. These results show that dopamine and tics are not linked via a trivial “more bad, less good” mechanism.

3.3.5. Animal models

It was reported almost a decade ago that unilateral disinhibition of the nucleus accumbens (NAc) by the gamma-aminobutyric acid A antagonist (bicuculline) is able to generate vocal tics in monkeys. ⁷⁷ Now, Sagalajev and colleagues replicate this approach in rats by eliciting nonsensical vocalizations after bicuculline injections into the NAc. ⁷⁸ Furthermore, they implanted an ipsilateral stimulation electrode targeting the border between the central medial (CM) and ventrolateral (VL) thalamic nuclei which was effective in reducing hyperkinesia akin to motor tics observed after bicuculline injections into the caudate-putamen (CPu), but not on vocalizations. Whether the latter truly correspond to vocal tics is, of course, hard to ascertain.

Another group collected electrophysiological and behavioral data from adult rats after unilateral picrotoxin infused into the anterior dorsal striatum. ⁷⁹ The rats developed stereotypic “tic-like” movements and locomotor hyperactivity while awake. Under anesthesia, an increase in burst-pattern firing was observed in striatal neurons. Interestingly, prepulse inhibition (PPI) to acoustic startle did not differ after picrotoxin. The authors speculate that dorsal striatal disinhibition may produce both tics and non-tic motoric hyperactivity, but independent of any deficits in PPI.

Also, innovation is expanding beyond conventional stimulation paradigms. Preclinical work by Kim and colleagues demonstrated that low-intensity focused ultrasound can reduce tic-like behaviors and electrophysiological abnormalities in a bicuculline-induced mouse model, supporting its translational potential as a noninvasive, circuit-level intervention. ⁸⁰ Notably, this approach combines the advantage of being less invasive than deep brain stimulation while offering superior spatial resolution compared with transcranial magnetic stimulation and the ability to target deep brain structures. Complementary experimental data further validate striatal disinhibition models capable of reproducing both motor and vocal tic–like phenomena, providing an important platform for future therapeutic development.

3.4.1. Psychological interventions

Treatment guidelines from the American Academy of Neurology (AAN) ⁸¹ and the European Society for the Study of Tourette Syndrome (ESSTS) ⁸² recommend behavior therapy (BT) as the first-line intervention for TS/CTD. Among the available BT modalities, Habit Reversal Training (HRT) and its extended protocol, Comprehensive Behavioral Intervention for Tics (CBIT), have the strongest empirical support. Another BT modality, Exposure and Response Prevention (ERP), has less support to date but is particularly favored by many European clinicians and researchers.

Assessing ways to deliver BT remotely to increase access has been a key focus in recent years, a trend that continued in 2025. In the first study evaluating CBIT delivered remotely in a group format, Inoue and colleagues ⁸³ conducted a randomized controlled trial (RCT) in Japan in which 40 children and adolescents with TS/CTD were randomized to CBIT delivered via videoconference (9 sessions over 10 weeks) or a waitlist control. Results showed significantly greater improvement in tic severity (YGTSS-TTS) in the CBIT group compared with the waitlist at a 1-month follow-up, supporting both the efficacy and feasibility of this treatment format.

Another study of remote treatment was published by Jöhnk and colleagues, ⁸⁴ in which BT was delivered through a mobile app to increase flexibility compared with earlier desktop-based digital programs. The intervention, based on a manual combining HRT and ERP, consisted mainly of pre-recorded videos with therapist contact via chat. In this pilot RCT from Denmark, 30 children and adolescents with TS/CTD were randomized to the app-based treatment or videoconference-delivered BT, with similar treatment content across conditions. Both formats were feasible and acceptable to families, and within-group reductions in tic severity (YGTSS-TTS) were observed in both groups. A fully powered RCT is needed to evaluate the efficacy of the app-based format.

Building on previous Swedish studies of internet-delivered BT for children and adolescents, ⁸⁵ a study protocol for an RCT evaluating therapist-guided internet-delivered BT for adults with TS/CTD was published in 2025. ⁸⁶ The intervention is primarily based on ERP but also includes elements of HRT. In this ongoing trial, Sannemalm and colleagues aim to recruit 110 adults who will be randomized to internet-delivered BT or an internet-delivered psychoeducation comparator. The primary outcome is tic severity (YGTSS-TTS) assessed at post-treatment (week 11). Data collection is expected to be completed in 2026.

Additionally, two meta-analyses of internet-delivered BT for TS/CTD, including partly overlapping studies and datasets, were published in 2025 by research groups based in China and the Republic of Korea. Xu and colleagues ⁸⁷ identified nine eligible trials, whereas Jo and colleagues ⁸⁸ identified eight studies, of which five were included in their quantitative meta-analysis. Despite minor differences in inclusion criteria and analytical approaches, both meta-analyses reported statistically significant reductions in tic severity following internet-delivered BT, although the magnitude of the effect varied somewhat between the reviews. Overall, both studies emphasize the need for larger RCTs of internet-delivered BT, particularly with longer follow-up periods to evaluate the durability of treatment effects.

Recently, variations of BT and related interventions have also been investigated. In a retrospective study from China, Liu and colleagues ⁸⁹ examined 122 children with TS/CTD to compare HRT alone with HRT combined with adjunctive music therapy. The intervention consisted of preference-based instrumental music delivered as a structured breathing and muscle relaxation exercise. After one therapist-led clinic session, caregivers administered 30-minute sessions at home each evening for 8 weeks. Both groups showed significant reductions in tic severity (YGTSS-TTS), with significantly greater improvement in the HRT + music therapy group compared to HRT alone. However, the retrospective, non-randomized design warrants cautious interpretation of the findings.

In another study from China, Liping and colleagues ⁹⁰ randomized 135 children with TS/CTD to a mindfulness-based intervention in addition to standard pharmacological care (clonidine or aripiprazole depending on symptom severity) or to pharmacological care alone. The intervention was a 12-week mindfulness program integrating breathing exercises, body awareness, and structured movement, delivered through brief instructor-led sessions and daily home practice. The mindfulness + standard care group showed greater reductions in tic severity (YGTSS-TTS) than standard care alone. The intervention group also showed greater improvements in mindfulness, anxiety, and quality of life. Overall, the findings support mindfulness-based interventions as a potential adjunctive treatment for TS/CTD.

In a study conducted in Taiwan, Lee and colleagues ⁹¹ randomized 79 adolescents with TS to receive four 60-minute board game sessions in addition to standard care (typically 50 mg pyridoxine daily), or standard care alone. The board game addressed topics such as information about TS, living with the condition, family and social interactions, and school experiences. Results showed no significant differences in tic severity (YGTSS-TTS) between groups, but the intervention group demonstrated improvements in positive mental health, social adjustment, and depression. Overall, the findings suggest that gamified psychoeducation may benefit psychosocial outcomes in adolescents with TS, although further research is needed to determine whether such approaches can also influence tic severity.

Lastly, another gamified treatment approach was evaluated by Vermilion and colleagues ⁹² in the United States. Perhaps better characterized as a biofeedback intervention than a psychological treatment, 11 children with TS and co-occurring rage attacks received a video game-based biofeedback therapy specifically targeting rage attacks. The intervention involved playing a video game while wearing a heart rate monitor, such that increases in heart rate led to increased game difficulty. Participants were encouraged to use relaxation strategies to reduce their heart rate, thereby learning skills for regulating physiological arousal associated with rage attacks. This preliminary evaluation demonstrated feasibility and engagement, as well as preliminary reductions in rage severity, supporting the need for larger controlled studies.

3.4.2. Pharmacological treatment

An exploratory study aiming to identify the most promising targets for drug-discovery in tic-related research has been published by the researchers from Changchun University in China. ⁹³ The authors used cis-expression quantitative trait loci (cis-eQTLs) of druggable genes obtained from the eQTLGen Consortium and genome-wide association study (GWAS) data for TS from the Psychiatric Genomics Consortium as the outcome to simulate the effects of pharmacological interventions on TS via Mendelian randomization (MR). LAMA5 was the most promising potential drug target for mitigating TS risk.

A research group from the International Parkinson and Movement Disorders Society published a systematic review of complementary/integrative medicine for treating tics. ⁹⁴ This is important, as in one study, two thirds of TS patients were using complementary medicine treatments. ⁹⁵ Most studies reviewed showed high risk of bias; fMRI-based neurofeedback and three traditional Chinese medicine (TCM) concoctions were exceptions. Overall, the authors concluded that this class of treatments is at present “limited in methodological quality and widespread applicability”.

Speaking of TCM, another RCT assessed Shaomazhijing granules, a mixture of 11 herbs, in 603 youth with TS, using a parallel group design to compare it to the dopamine antagonist tiapride and to placebo. ⁹⁶ Both active drugs had an effect size on YGTSS-TTS about twice that of placebo ( p < .001 for each), and the TCM mixture had fewer side effects. Identifying which of the multiple compounds in the mixture is sufficient to provide benefit would be of great interest.

The impact of long-term montelukast (a leukotriene receptor antagonist and anti-asthmatic medication) use for development of neurodevelopmental disorders, including tics, was evaluated by Lei and colleagues. ⁹⁷ Overall, montelukast use did not increase the risk of neuropsychiatric disorders. Nevertheless, in children aged 6–15 years, prolonged use of longer than 63 days was associated with a significantly elevated risk of tics, with a 2.6-fold increase observed in girls and a 1.8-fold increase in boys.

Mohamed and colleagues compared high- and low-dose vitamin D supplementation on tic severity. High-dose vitamin D ₃ supplementation was more effective than low-dose supplementation in reducing tic severity and increasing serum 25(OH) D levels in children with tics. ⁹⁸

In a retrospective cohort of pediatric patients with motor tic disorders, botulinum neurotoxin (BoNT) injections were associated with clinical improvement in 64% of cases, with no significant predictors of response based on tic characteristics or comorbidities. These findings suggest that BoNT is a safe and potentially effective treatment option for children with motor tics, including complex presentations. ⁹⁹

In a pilot randomized, double-blind crossover trial in adolescents with TS, medicinal cannabis was feasible and acceptable, with high protocol adherence and no serious adverse events. Preliminary signals suggested potential clinical improvement in some participants, though the small sample size limits conclusions. ¹⁰⁰ Also, in an open-label trial of adolescents with TS, medicinal cannabis was feasible, well tolerated, and associated with significant improvements in tic severity, behavioral symptoms, and quality of life. No serious adverse events were reported, supporting the need for larger randomized controlled trials to confirm efficacy and safety. ¹⁰¹

While we await the results from the phase III ecopipam study, Gilbert and colleagues released 12-month follow-up data (open-label extension) on the safety profile of ecopipam, a D1 receptor antagonist, in a cohort of 80 children and adolescents. ¹⁰² The drug was overall well tolerated, showing in particular a safe metabolic profile while maintaining efficacy (TS symptom severity and quality of life) over the follow up period. The most common adverse events were nasopharyngitis (14.0%) and anxiety (9.1%).

3.4.3. Neurosurgery

Recent literature increasingly conceptualizes TS as a network disorder, with converging electrophysiological data highlighting the central role of thalamo-basal ganglia circuits in tic generation. Lowor and colleagues showed that tic generation is associated with increased low-frequency activity (<20 Hz) within both the centromedian (CM) thalamus and the anterior globus pallidus internus (aGPi), with thalamic activity consistently preceding pallidal signals. ¹⁰³ Specifically, six patients with severe, treatment-refractory TS were implanted with four leads targeting the centromedian thalamus (CM) and the anterior globus pallidus internus (aGPi). Then, in 9 monthly visits, recordings were obtained from all leads to determine brain activity during a tic. The results revealed a clear increase in low-frequency oscillatory power during tics in both structures. In addition, coherence analyses showed enhanced pallido-thalamic synchrony in the 1-10 Hz band during tic expression. Extending this perspective, Wehmeyer et al. identified an alpha-band thalamo-frontal connectivity signature (8–12 Hz) in TS patients treated with DBS, with stronger connectivity correlating with lower tic and urge severity. ¹⁰⁴ Notably, connectivity decreased immediately prior to tic onset, reinforcing the hypothesis that dynamic network states—not simply regional activity—underlie tic expression. Together, these studies support the emergence of connectivity-informed biomarkers that could guide adaptive stimulation strategies. Also, these findings provide rare human electrophysiological evidence that tic generation involves abnormal low-frequency synchronization within a pallido-thalamic network, highlighting the coordinated role of CM and aGPi in the pathophysiology of TS.

This shift toward network-level modulation is reflected in emerging surgical approaches. Multifocal DBS has been proposed to simultaneously target complementary circuits within the cortico-striato-thalamo-cortical loop. Strelko and colleagues reported clinical improvement following dual bilateral stimulation of the CM and nucleus accumbens in a patient with refractory TS and self-injurious behaviors, suggesting that thalamic targets may primarily reduce tic generation while limbic structures address behavioral comorbidities. ¹⁰⁵ Clinical reports further refine the indications for DBS. Tsuji and colleagues described two patients with violent cervical tics at high risk of spinal cord injury who experienced marked and sustained benefit from bilateral CM stimulation, preventing injury progression in one case and likely averting its onset in the other. ¹⁰⁶ These findings argue for earlier DBS consideration in drug-refractory patients with potentially severe motor complications.

Beyond tic reduction, broader outcome dimensions are gaining attention. Cassimjee and colleagues emphasized that postoperative adaptation may involve complex processes of identity reconstruction, altered agency, and social adjustment. ¹⁰⁷ Despite motor improvement, some patients may struggle to adapt to life after symptom reduction, highlighting the need for thorough preoperative counseling and sustained psychosocial support within a person-centered care framework.

As DBS is increasingly offered to young patients, specific clinical scenarios are emerging. Mehanna and colleagues reported stable tic severity and no adverse outcomes across the limited number of pregnancies documented in women with TS treated by DBS. ¹⁰⁸

Meta-analytic data help contextualize neuromodulation strategies. Aloufi and colleagues confirmed consistent benefits of DBS but found no significant tic reduction with rTMS in randomized trials, with improvements in non-randomized studies likely reflecting methodological bias or placebo effects. ¹⁰⁹

3.4.4. Non-invasive modulation

Three recent studies reported findings related to noninvasive brain stimulation over the supplementary motor area. Mahjoub and colleagues performed a randomized, double-blind, sham-controlled trial of bilateral cathodal transcranial direct current stimulation. ¹¹⁰ They did not find a significant effect of stimulation on the total tic severity but reported larger improvements in motor tic severity in the active group, relative to the sham group. Another study used functional magnetic resonance imaging to identify targets for repetitive transcranial magnetic stimulation, according to functional connectivity between the supplementary motor area and the globus pallidus internus. ¹¹¹ A small proportion of individuals undergoing stimulation of the left supplementary motor area achieved a clinically significant improvement of tics. Changes in functional connectivity between the globus pallidus internus and the stimulation target were significantly associated with clinical improvement. Finally, ¹¹² found that a single session of low-frequency repetitive transcranial magnetic stimulation applied to the supplementary motor area in youth with TS led to reductions in tic frequency during free-to-tic intervals or during reward-contingent voluntary tic suppression. They also found that stimulation of the supplementary motor area reduced the perceived severity of premonitory urges during the voluntary suppression of tics. Together, findings from these studies reiterate the relevance of the supplementary motor area as a target for neuromodulation in TS.

3.5.1. Lived experience

Surveys were distributed to patients, caregivers, and health care professionals to investigate their views on TS labeling. ¹¹³ Among the 421 responses from 26 countries, including 174 patients, 160 caregivers, and 89 health care professionals, it was found that patients and caregivers favored the diagnostic term “Tourette syndrome” whereas the healthcare professionals showed a preference for “Tourette spectrum”.

A systematic review examined illness perceptions among patients with tic disorders and parents. ¹¹⁴ Evidence highlighted negative consequences of tic disorders for education, social relationships, and employment opportunities. In addition, feelings of self-consciousness, perceived abnormality, and anxiety related to tic disorders were found. These factors could be addressed through targeted interventions.

A web-based survey of 39 users of online support communities explored empowerment processes and outcomes. ¹¹⁵ Online support communities were found to support mental well-being through peer validation and recognition, as well as by expanding knowledge via the exchange of information and experiences. However, participation was also associated with reduced trust in healthcare professionals.

3.5.2. Access to care

Escobar and colleagues ¹¹⁶ distributed an online survey to health care professionals treating patients with primary tic disorders in Latin America and found limited awareness of tics and available treatment possibilities, as well as limited referral pathways, concluding that more effective pathways for tic disorder in Latin America are needed.

Another study examined the organization and quality of tic service provision for children and young people (CYP) in England, alongside healthcare professionals’ (HCPs) experiences in delivering care. ¹¹⁷ Using data from freedom of information requests to service commissioners and providers, as well as a national survey of 184 HCPs, the study found that only a small proportion of services (19.4%) offered a comprehensive pathway encompassing referral, assessment, and treatment, with most concentrated in London. Across professional groups, services were widely perceived as fragmented, under-resourced, and poorly structured. HCPs also reported significant gaps in training and limited access to evidence-based interventions. Overall, the findings highlight substantial inequities and systemic shortcomings in tic service provision, underscoring the urgent need for standardized care pathways, improved resource allocation, and enhanced professional training to support effective management of tics in CYP.

The lived experience of accessing healthcare for individuals with tic disorders in the UK was explored using qualitative focus group research. ¹¹⁸ The results highlighted a lack of prioritization for tic disorders and challenges across the healthcare pathway, including obtaining a diagnosis and receiving treatment, often leading individuals to rely on self-help strategies to manage their symptoms.

In a thematic analysis from France of parents of children with TS, families described a complex diagnostic and therapeutic journey marked by distress, uncertainty, and delays in care. ¹¹⁹ Recurrent themes included symptom recognition, impact of diagnosis, and challenges navigating healthcare systems, highlighting the need for improved support and earlier, more efficient diagnostic pathways.

Health care expenditure estimates for American children with tic disorders were examined in comparison with children without tic disorders by Wanga and colleagues. ¹²⁰ Mean per-person expenditures were higher for children with tic disorders, who also had more frequent healthcare encounters. The higher prevalence of comorbidities in children with tic disorders accounted for most of the differences in expenditures between the groups.

A systematic review and meta-analysis from Yale University examined racial, ethnic, and sex representation in randomized controlled trials (RCTs) of medications for Tourette’s syndrome (TS) in the United States. ¹²¹ Across 40 trials including 1717 participants, reporting of demographic data was inconsistent, with only 55% and 30% of studies reporting race and ethnicity, respectively, although reporting improved over time. Analysis using participation-to-prevalence ratios revealed significant underrepresentation of Asian, Black, Hispanic, and female individuals in TS clinical trials. While Hispanic representation showed some improvement over time, disparities persisted across most groups. These findings highlight substantial inequities in clinical trial representation, which may limit the generalizability of evidence and reflect broader disparities in diagnosis, access to care, and research participation. It also underscores the need for more inclusive recruitment strategies to ensure equitable and representative evidence in TS treatment research.

3.5.3. Healthcare professionals

Another aspect, this time focused on the healthcare professionals, was explored by a group from the United States. ¹²² Here, different providers that can have contact with patients with tics were taken into consideration (altogether 1058 child-serving providers including 403 family practitioners, 232 internists, 251 pediatricians, and 172 nurse practitioners or physician assistants). Less than two-thirds of providers (62.4%) considered evaluation of tics as their role, less than half (40.8%) considered diagnosis of tic disorders their role, and around one-fourth considered treatment of patients with tic disorders to be their role (27.3%). Lack of knowledge of tics/TS and lack of comfort evaluating patients for tics and tic disorders were the most often reported barriers to identification and diagnosis for most provider types, and across practice metro status categories. Online training was the most preferred source of information about tics and tic disorders overall, and for each provider type.

Care delivery strategies in pediatric depression, anxiety, OCD and TS were explored in the scoping review by Pringsheim and colleagues. ¹²³ The majority of research studies published in the past 15 years sought to establish if alternative delivery systems for psychological therapies (i.e., by telephone, videoconference, online with minimal therapist involvement) are superior to waitlist or attention controls, or similar in efficacy to face-to-face delivery across these four conditions.

An interesting bibliometric analysis was published by the group from China. ¹²⁴ Based on the Web of Science Core Collection, a topic-based search strategy yielded 4,011 records (1960–2024). As expected, TS research exhibited a phased growth pattern. As for research domains, the interdisciplinary nature of TS was mirrored by the following research domains: psychiatry, psychology, neurosciences and neurology. While the United States remained the primary contributor, European countries - particularly the United Kingdom, Germany, and Denmark - demonstrated superior international collaboration. There was also an important shift in research topics with initial focus on genetics and neuroimaging and more recent change towards patient-centered topics (quality of life and precision interventions).

Finally, an interesting article from Brazil and France highlights Georges Guinon as an early contributor to the clinical understanding of tic disorders within the Salpêtrière school led by Jean-Martin Charcot. ¹²⁵ Guinon described patients with complex motor and vocal tics and helped characterize the condition later known as Tourette syndrome, emphasizing its neurological nature. However, his contributions were overshadowed by Georges Gilles de la Tourette, whose more comprehensive and widely cited 1885 publication led to the disorder bearing his name.