Elevated common variant genetic risk for tourette syndrome in a densely-affected pedigree.

Tourette syndrome (TS) is a highly heritable neuropsychiatric disorder with complex patterns of genetic inheritance. Recent genetic findings in TS have highlighted both numerous common variants with small effects and a few rare variants with moderate or large effects. Here we searched for genetic causes of TS in a large, densely-affected British pedigree using a systematic genomic approach. This pedigree spans six generations and includes 122 members, 85 of whom were individually interviewed, and 53 of whom were diagnosed as "cases" (consisting of 28 with definite or probable TS, 20 with chronic multiple tics [CMT], and five with obsessive-compulsive behaviors [OCB]). A total of 66 DNA samples were available (25 TS, 15 CMT, 4 OCB cases, and 22 unaffecteds) and all were genotyped using a dense single nucleotide polymorphism (SNP) array to identify shared segments, copy number variants (CNVs), and to calculate genetic risk scores. Eight cases were also whole genome sequenced to test whether any rare variants were shared identical by descent. While we did not identify any notable CNVs, single nucleotide variants, indels or repeat expansions of near-Mendelian effect, the most distinctive feature of this family proved to be an unusually high load of common risk alleles for TS. We found that cases within this family carried a higher load of TS common variant risk similar to that previously found in unrelated TS cases. Thus far, the strongest evidence from genetic data for contribution to TS risk in this family comes from multiple common risk variants rather than one or a few variants of strong effect.

Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

BACKGROUND: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. OBJECTIVE: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. METHODS: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature. RESULTS: Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. CONCLUSIONS: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Gilles de la Tourette syndrome and disruptive behavior disorders: prevalence, associations, and explanation of the relationships.

Gilles de la Tourette syndrome and conduct disorder (CD) are both heterogeneous childhood onset conditions, and although patients with CD have been described in Gilles de la Tourette syndrome cohorts, little is known about the etiology of CD in Gilles de la Tourette syndrome or of the interrelationships. A cohort of 578 consecutive patients with Gilles de la Tourette syndrome was assessed using standard assessment protocols. A total of 13.5% of participants had only Gilles de la Tourette syndrome, whereas the rest had associated comorbidities and psychopathology. CD occurred in 14.5% of Gilles de la Tourette syndrome probands. These findings suggest that CD is not an integral part of Gilles de la Tourette syndrome but rather that CD in the context of Gilles de la Tourette syndrome is related to the presence of attention deficit hyperactivity disorder, as well as, and importantly, a family history of aggressive and violent behavior and forensic encounters.

Serial pharmacological prescribing practices for tic management in Tourette syndrome.

Pharmacological treatments for Tourette syndrome (TS) vary in efficacy between different patients. The evidence base is limited as even high quality controlled studies tend to be of relatively short duration which may lose relevance in clinical usage. Patients are frequently treated with serial agents in the search for efficacy and tolerability. The success of this strategy has not been previously documented. We examined 400 consecutive TS patients seen over a 10-year period, some with a longer prior history in other clinics; 255/400 (64%) were prescribed medication. We present this heterogeneous cohort in terms of the number of drugs they had tried, and as a proxy measure of some benefit of the last drug used, whether it had been prescribed under our supervision for ≥ 5 months. The most commonly prescribed medications were aripiprazole (64%), clonidine (40%), risperidone (30%) and sulpiride (29%) with changes in prescribing practises over the period examined. The number of different drugs tried were one (n = 155), two (n = 69), three (n = 36), four (n = 14), five (n = 15), six (n = 5), seven (n = 2) and eight (n = 1). The data illustrate the difficulty in drug treatment of tics and suggest that even after trials of several agents there is potential benefit in trying further options.

Biofeedback treatment for Tourette syndrome: a preliminary randomized controlled trial.

OBJECTIVE: To study the clinical effectiveness of biofeedback treatment in reducing tics in patients with Tourette syndrome. BACKGROUND: Despite advances in the pharmacologic treatment of patients with Tourette syndrome, many remain troubled by their tics, which may be resistant to multiple medications at tolerable doses. Electrodermal biofeedback is a noninvasive biobehavioral intervention that can be useful in managing neuropsychiatric and neurologic conditions. METHODS: We conducted a randomized controlled trial of electrodermal biofeedback training in 21 patients with Tourette syndrome. RESULTS: After training the patients for 3 sessions a week over 4 weeks, we observed a significant reduction in tic frequency and improved indices of subjective well-being in both the active-biofeedback and sham-feedback (control) groups, but there was no difference between the groups in these measurements. Furthermore, the active-treatment group did not demonstrably learn to reduce their sympathetic electrodermal tone using biofeedback. CONCLUSIONS: Our findings indicate that this form of biofeedback training was unable to produce a clinical effect greater than placebo. The main confounding factor appeared to be the 30-minute duration of the training sessions, which made it difficult for patients to sustain a reduction in sympathetic tone when their tics themselves were generating competing phasic electrodermal arousal responses. Despite a negative finding in this study, electrodermal biofeedback training may have a role in managing tics if optimal training schedules can be identified.

The effects of comorbid obsessive-compulsive disorder and attention-deficit hyperactivity disorder on quality of life in tourette syndrome.

Tourette syndrome (TS) is a complex neuropsychiatric disorder affecting patients' quality of life (QoL). The authors compared QoL measures in young patients with "pure" TS (without comorbid conditions) versus those with TS+OCD (obsessive-compulsive disorder), TS+ADHD (attention-deficit hyperactivity disorder), or TS+OCD+ADHD. Age and scores on scales assessing tic severity, depression, anxiety, and behavioral problems were included as covariates. Young patients with both comorbidities exhibited significantly lower Total and Relationship Domain QoL scores, versus patients with pure TS. Across the whole sample, high ADHD-symptom scores were related to poorer QoL within the Self and Relationship domains, whereas high OCD symptom scores were associated with more widespread difficulties across the Self, Relationship, Environment, and General domains. Significant differences in QoL may be most likely when both comorbidities are present, and features of OCD and ADHD may have different impacts on QoL across individual domains.

Judgements of social inappropriateness in adults with Tourette's syndrome.

INTRODUCTION: Socially inappropriate behaviour has frequently been reported in Tourette's syndrome (TS), but has not been studied experimentally. The current study was designed to examine the appropriateness of self-disclosures in TS using an emotional self-disclosure task. METHODS: Adult participants with TS-alone (20) and matched controls (20) were compared on two social judgement tasks, one examining the regulation of behaviour in an emotional self-disclosure task requiring participants to generate examples of autobiographical events, and the other examining mentalistic judgement of others' behaviour on a faux pas task. RESULTS: Those with TS-alone and controls showed no group differences for judges' or participants' ratings of inappropriateness on the self-disclosure task, although only the self-ratings of the control group corresponded to the judges' ratings. On the faux pas task, those with TS-alone were impaired relative to controls in detecting socially inappropriate behaviour. There was also some evidence of executive dysfunction in the TS-alone group. CONCLUSIONS: TS-alone is linked to a mixed pattern of preserved and impaired performance on social cognition measures, and further work is needed to determine the contributions of social and/or executive contributions to everyday functioning.

Dissecting the Gilles de la Tourette spectrum: a factor analytic study on 639 patients.

BACKGROUND: Recent studies using quantitative methods, such as principal component factor analysis, hierarchical cluster analysis and latent class analysis have suggested that Gilles de la Tourette syndrome (GTS) should no longer be considered a unitary condition as in current classification systems. OBJECTIVE: To identify quantitative components of GTS symptomatology using a large, well characterised cohort of singleton individuals with GTS in order to inform future genetic studies with more homogeneous phenotypes. METHODS: Principal component factor analysis with oblique rotation was used to analyse symptom data from a sample of 639 patients recruited at two tertiary referral centres using identical schedules during the period 1980-2008. RESULTS: Three Factors were identified: (1) complex motor tics and echo-paliphenomena; (2) attention deficit and hyperactivity symptoms plus aggressive behaviours; and (3) complex vocal tics and coprophenomena. Obsessive compulsive behaviours loaded significantly on the first two factors. The three factors accounted for 48.5% of the total symptomatic variance. CONCLUSIONS: GTS is a phenotypically heterogeneous condition encompassing simple tics, specific complex tics and associated behavioural problems. The results, coupled with previous findings, identified a clinical continuum of complex tics, hyperactivity/impulsivity symptoms and semantically relevant utterances and gestures. A better characterisation of the GTS phenotypes will help to identify susceptibility genes.

Clinical correlates of quality of life in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder involving tics, which is frequently accompanied by comorbid obsessive compulsive (OCD) or attention deficit hyperactivity disorder (ADHD). Individuals with TS often report poor quality of life (QoL) in comparison with the general population. This study investigated the clinical correlates of QoL in young people with TS using a self-report multidimensional QoL measure, and a range of clinical scales used to assess tic severity and the symptoms of anxiety, depression, OCD, ADHD and other emotional and behavioral symptoms. Symptoms of depression, OCD, and ADHD appeared to have a widespread negative impact on QoL, but poorer QoL was not associated with increased tic severity. Greater emotional and behavioral difficulties, including symptoms of OCD, were among the best predictors of poor QoL in young people with TS.

Multispectral brain morphometry in Tourette syndrome persisting into adulthood.

Tourette syndrome is a childhood-onset neuropsychiatric disorder with a high prevalence of attention deficit hyperactivity and obsessive-compulsive disorder co-morbidities. Structural changes have been found in frontal cortex and striatum in children and adolescents. A limited number of morphometric studies in Tourette syndrome persisting into adulthood suggest ongoing structural alterations affecting frontostriatal circuits. Using cortical thickness estimation and voxel-based analysis of T1- and diffusion-weighted structural magnetic resonance images, we examined 40 adults with Tourette syndrome in comparison with 40 age- and gender-matched healthy controls. Patients with Tourette syndrome showed relative grey matter volume reduction in orbitofrontal, anterior cingulate and ventrolateral prefrontal cortices bilaterally. Cortical thinning extended into the limbic mesial temporal lobe. The grey matter changes were modulated additionally by the presence of co-morbidities and symptom severity. Prefrontal cortical thickness reduction correlated negatively with tic severity, while volume increase in primary somatosensory cortex depended on the intensity of premonitory sensations. Orbitofrontal cortex volume changes were further associated with abnormal water diffusivity within grey matter. White matter analysis revealed changes in fibre coherence in patients with Tourette syndrome within anterior parts of the corpus callosum. The severity of motor tics and premonitory urges had an impact on the integrity of tracts corresponding to cortico-cortical and cortico-subcortical connections. Our results provide empirical support for a patho-aetiological model of Tourette syndrome based on developmental abnormalities, with perturbation of compensatory systems marking persistence of symptoms into adulthood. We interpret the symptom severity related grey matter volume increase in distinct functional brain areas as evidence of ongoing structural plasticity. The convergence of evidence from volume and water diffusivity imaging strengthens the validity of our findings and attests to the value of a novel multimodal combination of volume and cortical thickness estimations that provides unique and complementary information by exploiting their differential sensitivity to structural change.

European clinical guidelines for Tourette syndrome and other tic disorders. Part IV: deep brain stimulation.

Ten years ago deep brain stimulation (DBS) has been introduced as an alternative and promising treatment option for patients suffering from severe Tourette syndrome (TS). It seemed timely to develop a European guideline on DBS by a working group of the European Society for the Study of Tourette Syndrome (ESSTS). For a narrative review a systematic literature search was conducted and expert opinions of the guidelines group contributed also to the suggestions. Of 63 patients reported so far in the literature 59 had a beneficial outcome following DBS with moderate to marked tic improvement. However, randomized controlled studies including a larger number of patients are still lacking. Although persistent serious adverse effects (AEs) have hardly been reported, surgery-related (e.g., bleeding, infection) as well as stimulation-related AEs (e.g., sedation, anxiety, altered mood, changes in sexual function) may occur. At present time, DBS in TS is still in its infancy. Due to both different legality and practical facilities in different European countries these guidelines, therefore, have to be understood as recommendations of experts. However, among the ESSTS working group on DBS in TS there is general agreement that, at present time, DBS should only be used in adult, treatment resistant, and severely affected patients. It is highly recommended to perform DBS in the context of controlled trials.

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Gilles de la Tourette syndrome and deep brain stimulation.

Gilles de la Tourette Syndrome (GTS) is characterized by multiple motor and one or more vocal/phonic tics. Psychopathology and co-morbidity occur in approximately 80-90% of clinical cohorts. The most common psychopathologies are attention deficit hyperactivity disorder, obsessive-compulsive behaviours, obsessive-compulsive disorder, depression, anxiety and certain behavioural disorders. In severe GTS patients who are refractory to medication and other therapies, deep brain stimulation (DBS) is investigated. To date there have been some 50-55 patients who have received DBS in 19 centres worldwide. Nine different brain targets in the thalamus, the pallidum, and the ventral caudate and anterior internal capsule have been stimulated. This paper reviews critically and in detail all studies published to date. Only two studies on just a few patients fulfil some of the evidence-based criteria. DBS for GTS is therefore still highly experimental.

Corpus callosum abnormalities in Tourette syndrome: an MRI-DTI study of monozygotic twins.

BACKGROUND: Tourette syndrome (TS) is a chronic neurodevelopmental disorder characterised by the presence of multiple motor and phonic tics. Recent brain imaging investigations with diffusion tensor imaging (DTI) techniques found reduced measures of connectivity in the corpus callosum of children with TS compared with healthy controls, thus raising the hypothesis that the reduced interhemispherical connectivity in TS reflects neural plasticity processes. METHODS: We assessed corpus callosum white-matter connectivity with fractional anisotropy (FA) index from magnetic resonance-DTI in two monozygotic twins (male sex; age 20) discordant for the diagnosis of TS. RESULTS: Both conventional morphological magnetic resonance images and fibre-tracking reconstruction failed to show any difference between the two twins. On the other hand, mean corpus callosum FA values were significantly lower in the affected twin than in the unaffected twin (p<0.01). The differences in FA values were highest in the posterior portions of the corpus callosum, and lowest in the central area. CONCLUSIONS: Our findings of reduced interhemispherical white-matter connectivity in the affected twin support the hypothesis that plastic remodelling in the corpus callosum possibly represents an adaptation mechanism in TS.

Pathological laughter in Gilles de la Tourette syndrome: an unusual phonic tic.

Patients with Gilles de la Tourette syndrome (GTS) can display socially inappropriate behaviors as part of their multiform tic phenomenology. Pathological laughter (PL), defined as the presence of episodic and contextually inappropriate outbursts of laughter, has been detailed as a symptom of various psychiatric and neurological conditions. We present a case series of eight subjects diagnosed with GTS who reported PL as part of their tic repertoire. All subjects experienced PL as a simple phonic tic, accompanied by characteristic premonitory urges and significant impairment in social interactions. In addition, all patients presented with multiple tic-related symptoms (mainly self-injurious behaviors and echolalia, n = 7; palilalia, n = 6; coprolalia/mental coprolalia, n = 5), and six patients had comorbid conditions (in particular obsessive-compulsive disorder/behaviors, n = 7; attention-deficit hyperactivity disorder, n = 4). We suggest that the pathophysiological mechanisms underlying the expression of PL as a tic could involve a dissociation between frontostriatal and limbic networks.

Psychosocial outcome and psychiatric comorbidity in older adolescents with Tourette syndrome: controlled study.

BACKGROUND: Children with Tourette syndrome generally experience improvement of tics by age 18 years, but psychosocial and comorbidity outcomes at this age are unclear. AIMS: To compare psychosocial outcomes and lifetime comorbidity rates in older adolescents with Tourette syndrome and controls. We hypothesised a priori that individuals with Tourette syndrome would have lower Children's Global Assessment Scale (CGAS) scores. METHOD: A total of 65 individuals with Tourette syndrome, identified in childhood, and 65 matched community controls without tic or obsessive-compulsive disorder (OCD) symptoms were assessed around 18 years of age regarding psychosocial functioning and lifetime psychiatric disorders. RESULTS: Compared with controls, individuals with Tourette syndrome had substantially lower CGAS scores (P = 10(-8)) and higher rates of attention-deficit hyperactivity disorder (ADHD), major depression, learning disorder and conduct disorder (P< or =0.01). In the participants with Tourette syndrome, poorer psychosocial outcomes were associated with greater ADHD, OCD and tic severity. CONCLUSIONS: Clinically ascertained children with Tourette syndrome typically have impaired psychosocial functioning and high comorbidity rates in late adolescence.

Gilles de la Tourette Syndrome: advice in the times of COVID-19.

The novel coronavirus disease (COVID-19) was identified as the cause of an outbreak of respiratory disease in China at the end of 2019. It then spread with enormous rapidity and by mid-March 2020 was declared a world pandemic. Gilles de la Tourette Syndrome (GTS) is a childhood-onset neurodevelopmental disorder with a worldwide prevalence of about 1% of the population. The clinical symptoms include multiple motor and one or more phonic (vocal) tics. Germane to this communication is that 85% of patients with GTS have associated psychiatric co-morbidities, many of which are being exacerbated in the current global health crisis. In addition, several symptoms of GTS may mimic COVID-19, such as a dry cough and sniffing (phonic tics), while other symptoms such as spitting, inappropriate touching of others and "non-obscene socially inappropriate symptoms" can potentially get patients with GTS into trouble with the law. We suggest that a clear explanation of the COVID-19 illness and GTS is important to enable colleagues of various specialities who tend to patients with GTS. It is important to acknowledge at the outset that the information available on the COVID-19 pandemic changes daily, including cases infected, deaths reported, and how various national health systems are planning and or coping or not. It is fair to say that having read the current medical and lay press we conclude that it is not easy to reassure our patients with absolute certainty. However, notwithstanding that, we hope our documentation is of some assistance.

Tourette's syndrome (TS): inhibitory performance in adults with uncomplicated TS.

Tourette's syndrome (TS) is a neurodevelopmental disorder linked with frontostriatal dysfunction. Previous work has shown some evidence of mild performance deficits on a range of different tasks that involve inhibitory processes. The present study evaluated this in adult participants with uncomplicated TS. Interference control was measured using the Stroop and flanker tasks and a Stroop-flanker task that combined the inhibitory demands of both. Motor inhibition was measured using a letter continuous performance test (CPT) task and word CPT tasks that manipulated the inhibitory demands using compatible and incompatible words. The TS group was found to be slower than the control group on most measures, but showed differential slowing under conditions with enhanced inhibitory demands on the combined Stroop-flanker and the incompatible CPT tasks. The findings suggest that TS-alone is linked to mild impairments in aspects of inhibitory function, and that these can be detected by relatively powerful inhibitory manipulations. A range of different types of inhibitory tasks may be sensitive to TS-alone, and this may depend on both the type of inhibition and the strength of the inhibitory manipulation.

Coprophenomena in Tourette syndrome.

The aims of this descriptive study were to examine the prevalence and associations of coprophenomena (involuntary expression of socially unacceptable words or gestures) in individuals with Tourette syndrome. Participant data were obtained from the Tourette Syndrome International Database Consortium. A specialized data collection form was completed for each of a subset of 597 consecutive new patients with Tourette syndrome from 15 sites in seven countries. Coprolalia occurred at some point in the lifetime of 19.3% of males and 14.6% of females, and copropraxia in 5.9% of males and 4.9% of females. Coprolalia was three times as frequent as copropraxia, with a mean onset of each at about 11 years, 5 years after the onset of tics. In 11% of those with coprolalia and 12% of those with copropraxia these coprophenomena were one of the initial symptoms of Tourette syndrome. The onsets of tics, coprophenomena, smelling of non-food objects, and spitting were strongly intercorrelated. Early onset of coprophenomena was not associated with its longer persistence. The most robust associations of coprophenomena were with the number of non-tic repetitive behaviors, spitting, and inappropriate sexual behavior. Although coprophenomena are a frequently feared possibility in the course of Tourette syndrome, their emergence occurs in only about one in five referred patients. Because the course and actual impact of coprophenomena are variable, additional prospective research is needed to provide better counseling and prognostic information.

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.