Contemporary Perspectives on Neurobiology and Treatment of Tic Disorders: A Narrative Review

Abstract

Tic disorders are neurodevelopmental conditions characterized by involuntary movements and vocalizations. Recent technological advancements and deeper clinical insights have driven progress in both the neurobiology and treatment paradigms of these disorders. This narrative review provides a comprehensive synthesis of contemporary perspectives, bridging upstream pathophysiological mechanisms with downstream therapeutic modalities. From a pathophysiological perspective, the classic model of cortico-striato-thalamo-cortical circuit dysfunction has significantly expanded into a system-level network. Emerging evidence highlights the critical involvement of cerebellar pathways in tic generation, abnormal insular and somatosensory processing underlying premonitory urges, and intricate neuroendocrine cascades that modulate stress and prepubertal symptom exacerbation. By mirroring these complex biological mechanisms, contemporary treatment strategies are moving toward tailored, mechanism-based interventions. Evidence-based behavioral therapies, led by comprehensive behavioral interventions for tics, remain the first-line options. Pharmacotherapies are reserved for patients with significant functional impairment, whereas novel targeted agents, such as ecopipam, and innovative neuromodulation modalities, including adaptive deep brain stimulation, offer promising avenues for circuit-specific modulation. Thus, integrating advanced neurobiological frameworks with expanding therapeutic alternatives underscores the definitive shift toward precision medicine in tic management.

INTRODUCTION

Tic disorders are neurodevelopmental disorders that are characterized by involuntary movements and vocalizations. According to the Fifth Edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the diagnosis of tic disorders is categorized based on the type and duration of the presenting symptoms, including Tourette syndrome (TS), persistent motor or vocal tic disorder, and provisional tic disorder [1]. Although TS garners the majority of clinical and academic attention, symptom severity and functional impairment are often comparable to those of other persistent tic disorders [2]. Despite the lack of comparative neurobiological data, clinical observations support the conceptualization of tic disorders in a single spectrum rather than as discrete categories [2,3]. Thus, the neurobiology and therapeutic interventions for tic disorders should be conceptualized uniformly, regardless of current diagnostic classifications.

Over the past decade, advancements in technological modalities and deeper insights into symptomatology have driven continuous progress in the neurobiology and treatment of tic disorders. In particular, regarding the neurobiology of tics, numerous studies have been conducted to elucidate various clinical features that are not explicitly defined in the DSM-5, such as premonitory urge, fluctuating symptoms, prepubertal exacerbation, and stress-induced exacerbation [4,5]. This review aims to identify these recent developments, focusing on the most current insights.

This narrative review aimed to provide a contemporary perspective on tic disorders. A comprehensive literature search was performed on PubMed using combinations of the keywords “tic disorders,” “Tourette syndrome,” “neurobiology,” and “treatment” to identify relevant English-language articles published for the last 15 years. Although strict inclusion and exclusion criteria were not formally applied, the author carefully screened, selected, and synthesized the retrieved literature based on thematic relevance. In addition, cross-references and related articles were manually searched and integrated to ensure a thorough, robust, and comprehensive review.

CONTEMPORARY NEUROBIOLOGY OF TIC DISORDERS

Beyond the classic cortico-striato-thalamo-cortical circuit

The cortico-striato-thalamo-cortical (CSTC) circuit, which regulates complex behaviors, is associated with TS pathophysiology [6]. Affected by imbalance among various neurotransmitters such as dopamine and glutamate and γ-aminobutyric acid (GABA), disruption of CSTC circuit leads to involuntary expression of tics [7]. Striatal GABAergic network dysfunctions and the resulting surge in dopamine levels in the basal ganglia can impair the thalamocortical pathway linked to the primary motor cortex, thereby compromising the selective inhibition required to regulate specific motor movements [8]. The traditional CSTC model of TS effectively explains unintentional tic phenomena and has been used to support neuromodulation mechanisms such as deep brain stimulation (DBS) [9]. Furthermore, because parallel CSTC loops operate differently based on their precise anatomical topography, this model effectively accounts for the cognitive and emotional dimensions of tic disorders [10].

Recently, the cerebellum has been regarded as an important region for tic generation. In addition to connectivity in the CSTC circuit, connectivity between the cortex and cerebellum is altered in patients with TS [11]. Structural alterations identified using structural MRI and diffusion tensor imaging further support these findings. Specifically, neuroimaging reveals reduced gray matter volume in the cerebellar lobules that subserve higher-order cognitive functions and sensorimotor processing [12], as well as higher fractional anisotropy in the cerebellar peduncles [13]. Treatment response to DBS revealed that tic reduction was associated with network-level changes, suggesting the basal ganglia-cerebellar-thalamo-cortical network mechanisms [14]. According to a computational model based on reported research, the cerebellum in tic generation works directly with the basal ganglia and indirectly with the cortex [15]. These findings highlight the fact that the cerebellum is an essential component of the tic network, thereby broadening our pathophysiological framework from that of conventional models. Despite the current uncertainties, the proposed functional roles of the cerebellum in tic production include gating tic release, sensorimotor timing, error prediction, and compensatory regulatory control [15,16]. Beyond exhibiting passive neural activation, emerging perspectives suggest that the cerebellum may actively modulate the excitability of the striatum and supplementary motor area (SMA), potentially lowering the threshold for tic generation; however, definitive empirical evidence to substantiate this proactive regulatory mechanism remains insufficient [17,18].

Although alterations in the foundational CSTC circuit account for the execution of tics, they do not fully capture the upstream sensory experiences that drive them. To understand tic symptoms comprehensively, it is essential to bridge this classic motor framework with the neurobiology of the premonitory urge, a subjective sensory phenomenon whose underlying neurobiology offers crucial insights into the altered gating of sensorimotor processing.

Premonitory urge and related neurobiology

Premonitory urges are uncomfortable somatic sensations that precede and predict tic symptoms and are typically resolved after tic release. More than 60% of children with tic disorders report experiencing these urges, with awareness becoming particularly prominent around the age of 10 years [4]. Premonitory urges represent a distinct pathophysiology of tic disorders, separate from core motor abnormalities, and stem from the failure of neurological sensorimotor gating, which filters into the child’s focal awareness and ultimately manifests as a major source of behavioral disruption and emotional burden [19].

The primary and secondary somatosensory cortices (S1 and S2, respectively) have been structurally and functionally implicated in the generation of premonitory urges [20,21]. Mirroring the clinical manifestation of sensory urges preceding tic symptoms, neuroimaging studies have demonstrated that the S1 and S2 are activated before tic onset [22]. Moreover, S1 and S2 are closely associated with insular activity in TS, and structural and functional alterations in the insula have been reported in TS [23]. Given its role in integrating somatosensory, visceral, and emotional information, the insula appears to modulate premonitory urges by integrating sensory information with emotional characteristics such as aversiveness [24]. Because premonitory urges inherently involve interoceptive processing, the insula represents a pivotal node for understanding the sensory pathology of tic disorders [25]. In this process, the anterior cingulate cortex and SMA are involved in premonitory urge generation [26].

Most importantly, the neurobiological mechanisms underlying premonitory urges were hypothesized to be intimately linked to tic symptom generation in the CSTC model. First, the insular connection between the SMA and cingulate motor area projects to the primary motor cortex and descending motor pathways, directly affecting tic generation [27]. Second, the striatum showed abnormally enhanced structural connectivity with the sensory cortex, implying a relationship between premonitory urges and tic symptoms [28]. Third, with the phasic dopamine signals in the CSTC circuit, the termination of premonitory urges immediately after tic expression leads to a positive prediction error, resulting in a reduction in the aversiveness of the premonitory urge. This phenomenon reinforces tic symptoms in the CSTC loop, which is known as the tic learning process [29].

Understanding the sensory-motor integration involved in premonitory urges deepens our understanding of tic generation but simultaneously reveals a broader regulatory layer. A comprehensive model of tic pathophysiology must also consider the neurobiological pathways through which shifts in systemic triggering factors aggravate these symptoms.

Preadolescent developmental tic exacerbation and its neurobiology

Previous studies have indicated that TS symptoms typically peak in late childhood and improve during adolescence [5]. Although the mechanisms underlying this symptom trajectory remain to be fully elucidated, exploring neurodevelopmental aspects and endocrinological factors, despite the currently limited empirical evidence for the latter, may provide valuable insights into these longitudinal changes.

The male predominance, chronological age at onset, and characteristic exacerbation periods of tic disorders have provided a strong rationale for exploring their neuroendocrinological substrates. The administration of exogenous androgens was reported to worsen tics in men with TS, whereas drugs counteracting the action of testosterone showed a ticreducing effect, suggesting a role for gonadal hormones in tic disorders [30]. Bortolato et al. [31] have proposed that enhanced 5α-reductase during adrenarche drives inappropriate androgen synthesis via “backdoor” pathway for androgen synthesis, which may induce tic symptoms. Likewise, 5α-reductase inhibitors exerted marked anti-dopaminergic and tic-suppressing properties. Although sex hormones are implicated in tic pathogenesis, designating testosterone as the primary driver remains problematic, as it fails to account for the postpubertal reduction in symptoms that coincides with rising testosterone levels [32].

However, the limitations of testosterone as a definitive hormonal marker do not preclude the broader involvement of other neuroactive steroids in tic disorders. Thus, the current study has shifted its focus toward dehydroepiandrosterone (DHEA) and its sulfated form, dehydroepiandrosterone sulfate (DHEAS) [32]. Plasma DHEAS levels exhibited a concomitant increase in testosterone levels in patients with TS [33]. More importantly, the adrenarche-induced surge in DHEAS aligns with the typical median age of tic onset at approximately six years, and its continuous increase leading up to puberty provides a compelling explanation for the worsening of symptoms during the prepubertal years [32]. In a previous study, flutamide, a drug that attenuates the synthesis of DHEA(S) in the adrenal gland, reduced tic severity [34]. Despite how DHEAS induce tic symptom in the brain is not clear yet, both DHEAS and DHEA are known to exert potent endogenous antagonistic effects on GABA-A receptors, which may trigger disinhibition of movement control [35]. Similar to testosterone, DHEAS cannot explain the reduction in TS symptoms after puberty. Complex interactions and changes in sex-related hormones during puberty and maturation of inhibitory control, followed by the frontal lobe maturation, should be considered to explain this phenomenon [36].

Stress-related tic exacerbation and its neurobiology

Tic symptoms are highly responsive to environmental factors, particularly acute and chronic stress [37]. Several mechanisms have been proposed to explain how stress drives tic exacerbation, and these pathways are likely to coexist and mutually reinforce each other.

Stress-induced tic exacerbation is reportedly associated with the hypothalamic-pituitary-adrenal (HPA) axis and cortisol secretion. The relationship between the HPA axis and TS begins with a study showing increased corticospinal fluid corticotropin-releasing factor tone in patients with TS, which may amplify the downstream stress response [38]. Although acute exposure to stressors is directly linked to immediate cortisol responses [39], elevated hair cortisol concentrations have been observed before the actual expression of tics in patients with TS [40]. Although the diurnal rhythm and baseline axis activity were preserved in patients with TS, the acute response of the HPA axis showed enhanced activity after exposure to external stressors [41]. Upon exposure to stressors, the paraventricular nucleus of the hypothalamus secretes the corticotropin-releasing hormone, which subsequently elevates adrenocorticotropic hormone (ACTH) levels. This surge in ACTH levels drives a corresponding increase in cortisol levels, accompanied by a concurrent increase in DHEA(S) levels [42]. Although DHEA(S) is recognized for its protective role in counteracting the adverse effects of excessive cortisol activity [43], it simultaneously acts as a potent GABA-A receptor antagonist, as previously mentioned above, thereby potentially precipitating tic symptoms. Along with DHEA(S), allopregnanolone, which is increased in response to external stressors, is known to disrupt sensorimotor gating, inducing tic symptoms that affect GABA-A receptors in the frontal lobe [32]. Although the explicit mechanisms through which allopregnanolone influences tic symptoms remain to be fully elucidated, the therapeutic efficacy of finasteride, which suppresses allopregnanolone synthesis by reducing tics, supports the pathophysiological role of this neurosteroid [44].

However, not only neurosteroids explain the association between tics and stress. Neurotransmitters, particularly noradrenaline and dopamine, as well as immunologic factors, tend to play an important role in increasing vulnerability to external stress in patients with TS, although further studies are required to unveil the exact mechanisms [45]. In a preclinical study, chronic stress was suggested to directly alter the stress-related plasticity of neuronal excitation and inhibition in the dorsomedial striatum, resulting in hyperexcitationand disinhibition-inducing tic symptoms [46]. Imbalance in the autonomic nervous system should also be considered. According to a one-year follow-up study, persistent dysfunction in autonomic function showed distinct results in heart rate variability (HRV), a physiological measure of the variation in time between each heartbeat that reflects autonomic regulation in patients with TS [47]. Given that HRV is a valuable tool for assessing physiological stress reactivity and adaptability, previous findings have suggested that chronic stress may trigger an imbalance between sympathetic and parasympathetic activities, thereby exacerbating tic symptoms. As studies relating to tic disorders and the autonomic nervous system are insufficient, further research associating the autonomic nervous system with tic symptoms may help comprehensively understand the phenomenon.

Thus, these contemporary insights into the neurobiology of tic disorders do not replace the classic paradigm of CSTC circuit dysfunction; rather, they significantly expand upon it. By integrating novel neurobiological dimensions, such as neuroactive steroid dynamics, neuroimmune cascades, and HPA-axis stress hyperreactivity, the current study provides a more holistic orchestration in the CSTC framework. Nevertheless, because these emerging hypotheses require rigorous validation through further empirical studies, caution is warranted in their clinical interpretations. Ultimately, sophisticated mapping of these expanded biological mechanisms is not merely an academic endeavor but also a clinical imperative that paves the way for more targeted, effective, and personalized therapeutic interventions for tic disorders.

CONTEMPORARY TREATMENT OF TIC DISORDERS

Behavioral therapies

Habit-reversal training (HRT), exposure and response prevention (ERP), and comprehensive behavioral intervention for tics (CBIT) are evidence-based behavioral treatments widely used to treat tic disorders. Among these, CBIT is currently considered the first-line treatment in treatment guidelines [48,49]. Behavioral therapies applying HRT with ERP showed comparable result in tic reduction with pharmacotherapy [50].

The CBIT comprises two major domains: HRT and functional interventions. Compared with psychoeducation with supportive therapy, CBIT significantly reduced tic symptoms in both children and adults [51,52]. ERP was also repeatedly reported to be effective treatment; a meta-analysis estimated ERP to have a small-to-medium effect size in TS or chronic tic disorders [53-55]. The advantage lies not only in its clinical efficacy but also in its potential for long-term adherence [53,56]. Moreover, emerging evidence suggests that digital or videoconference-based delivery of CBIT and ERP yields treatment outcomes equivalent to traditional face-to-face interventions [57-59].

With the efficacy of CBIT in TS patients, the cortical silent period to motor-evoked potential ratio increased after treatment, suggesting that CBIT enhances inhibitory cognitive control in the cortex [60]. However, given the conflicting findings in the existing literature, further studies are warranted to elucidate the definitive effect of behavioral therapy on actual brain mechanisms [61]. Diverse theories such as habituation, associative learning, and motor function improvement have been proposed to explain the mechanisms of CBIT in tic disorders; however, evidence remains scarce [58].

Pharmacotherapies

Although behavioral therapies are recommended for wide use in patients with tic disorders, pharmacotherapies should be considered if tic symptoms significantly impair patients’ quality of life or daily functioning [62]. It is mainly due to the various side effects that can accompany the use of medications, and no evidence suggests that medication is useful for improving the prognosis of patients with tic disorders [63]. Notwithstanding these limitations of medication, diverse clinical scenarios remain in which pharmacological intervention is necessary. Therefore, a precise understanding of the available pharmacological options for tic disorders, coupled with their appropriate clinical applications, is of paramount importance.

A recent network meta-analysis revealed that, although both drug classes were effective in reducing tic severity, antipsychotics provided a significantly more robust therapeutic effect than alpha-2 adrenergic agonists. Among the antipsychotics, aripiprazole, olanzapine, pimozide, risperidone, and haloperidol were significantly effective in tic reduction, whereas aripiprazole and risperidone showed superior results to clonidine [64]. Although three agents (haloperidol, pimozide, and aripiprazole) are approved by the Food and Drug Administration (FDA) for TS, aripiprazole may be the most appropriate medication for use in children with tic disorders, considering its efficacy and side effect profiles [65]. Clonidine, an alpha-2 adrenergic agonist, is a highly valuable therapeutic option, particularly when concerns arise regarding antipsychotic-induced side effects or when comorbid attentiondeficit/hyperactivity disorder (ADHD) symptoms are present. Clonidine effectively reduced both ADHD and tic symptoms in patients with TS and ADHD [66].

Medications with distinct mechanisms of action are currently being investigated in patients with tic disorders. Vesicular monoamine transporter-2 (VMAT2) inhibitors, which are used to treat various movement disorders such as chorea and tardive dyskinesia by depleting dopamine, have been reported to be effective in several open-label studies; however, results were not replicated in placebo-controlled trials. Valbenazine, tetrabenazine, and deutetrabenazine are considered candidates for the treatment of tic disorders with acceptable tolerability [62,67], but require more sophisticated studies to be approved for the treatment of tic disorders. Cannabinoid-based pharmacotherapy has also been used for TS; tetrahydrocannabinol and cannabidiol administration reduces tic symptoms with controllable side effects [68]. However, owing to the relatively sparse evidence base and potential legal or regulatory issues, its application is currently recommended only under highly restricted circumstances [49]. Topiramate has also been reported to be effective in patients with TS [69]; however, its long-term use is limited owing to adverse effects such as cognitive dysfunction, tingling, or nephrolithiasis [70].

Ecopipam, a selective D1 receptor antagonist, has shown efficacy in several studies [71]. Moreover, no metabolic side effects or alterations in electrocardiograms were identified, and weight gain was not considered during the randomized controlled trials [72]. Although these findings suggest that ecopipam is a promising pharmacological agent for tic management, the current paucity of cumulative data requires a cautious approach regarding its efficacy and safety profile [73].

Neuromodulations

Although neuromodulation modalities are not currently considered the primary treatments for tic disorders, their therapeutic possibilities are expanding alongside technological advancements, as these interventions are engineered to directly modify the underlying pathophysiology, particularly the CSTC circuit.

DBS has been repeatedly reported to be effective in treating refractory TS, and nearly 70% of the patients with refractory TS show marked symptom reduction after surgery [74]. Traditionally, the target regions of DBS were subregions of the thalamus or globus pallidus, showing comparable results regardless of the stimulation site by stimulating each region, leading to circuit-level efficacy [75,76]. Transitioning from conventional focal, monophasic stimulation, stimulation strategies have significantly evolved alongside technological progress, with adaptive DBS emerging to deliver more precise, tailored treatment [77]. Owing to its significant invasiveness, DBS is currently limited to treatment-refractory TS. However, its clinical success in cases in which behavioral and pharmacological interventions fail highlights the promising prospects of broader neuromodulation treatments.

Most neuromodulation techniques used for tic disorders focus on targeting the motor and SMAs. Transcranial magnetic stimulation (TMS) is one of the most widely used noninvasive neuromodulations for tic disorders, with controversial results. A recent meta-analysis reported that although TMS was not significantly effective in reducing tic severity, it alleviated premonitory urges [78]. Median nerve stimulation (MNS) was also attempted for TS. A small-sample study reported positive results for tic reduction by stimulating the median nerve [79]. Transcranial direct current stimulation (tDCS) targeting the SMA presents conflicting results, with some studies showing the effect of tDCS [80] but others showing similar results to the sham control [81].

The inconsistent findings regarding noninvasive neuromodulation to date should not be interpreted as a lack of therapeutic value in tic disorders. Instead, they have indicated that further sophisticated research using large-scale longitudinal cohorts is required, as neuromodulation holds immense promise in highly personalized precision medicine.

Thus, the contemporary management of tic disorders relies on a tailored, sequential approach, prioritizing evidencebased behavioral therapies as first-line interventions and reserving pharmacotherapies for cases with significant functional impairment. While conventional antipsychotics and alpha-2 adrenergic agonists remain the cornerstones of medical treatment, the emerging landscape of novel pharmacological agents, such as VMAT2 inhibitors and selective D1 receptor antagonists, offers future alternatives. Although the neurobiological mechanisms of these pharmacotherapies were relatively well-defined, they were not originally developed to target specific pathways. Conversely, advanced neuromodulation strategies, including DBS and MNS, are structurally engineered based on pathological alterations in the CSTC circuit, thereby substantiating their distinct potential as precise mechanism-based therapeutics for tic disorders. Nevertheless, because of the currently limited level of empirical evidence, active clinical application of these novel pharmacological agents (e.g., VMAT2 inhibitors and selective D1 receptor antagonists) and most neuromodulation modalities, except DBS, cannot be strongly recommended at this stage. However, they warrant continuous attention as they hold substantial promise as pivotal treatment options in the near future.

CONCLUSION

The current understanding of tic disorders has advanced into a multidimensional framework that integrates refined neurobiological mechanisms with targeted therapeutic interventions. Expanding our knowledge of networks beyond the classic CSTC circuit has fundamentally redefined the pathophysiology of tics. Mirroring these neurobiological advancements, the treatment paradigm has transitioned from empirical symptom control to mechanism-based strategies. Evidencebased behavioral therapies and established pharmacotherapies remain essential for immediate management, whereas novel agents and adaptive neuromodulation hold immense promise for circuit-specific modulation.