Determining Clinically Meaningful Improvement in Children and Adolescents with Tourette Syndrome Receiving Pharmacotherapy.

Defining tic severity and tic impairment in Tourette Disorder

To examine the internal consistency and distribution of the Yale Global Tic Severity Scale (YGTSS) scores to inform modification of the measure. This cross-sectional study included 617 participants with a tic disorder (516 children and 101 adults), who completed an age-appropriate diagnostic interview and the YGTSS to evaluate tic symptom severity. The distributions of scores on YGTSS dimensions were evaluated for normality and skewness. For dimensions that were skewed across motor and phonic tics, a modified Delphi consensus process was used to revise selected anchor points. Children and adults had similar clinical characteristics, including tic symptom severity. All participants were examined together. Strong internal consistency was identified for the YGTSS Motor Tic score (α = 0.80), YGTSS Phonic Tic score (α = 0.87), and YGTSS Total Tic score (α = 0.82). The YGTSS Total Tic and Impairment scores exhibited relatively normal distributions. Several subscales and individual item scales departed from a normal distribution. Higher scores were more often used on the Motor Tic Number, Frequency, and Intensity dimensions and the Phonic Tic Frequency dimension. By contrast, lower scores were more often used on Motor Tic Complexity and Interference, and Phonic Tic Number, Intensity, Complexity, and Interference. The YGTSS exhibits good internal consistency across children and adults. The parallel findings across Motor and Phonic Frequency, Complexity, and Interference dimensions prompted minor revisions to the anchor point description to promote use of the full range of scores in each dimension. Specific minor revisions to the YGTSS Phonic Tic Symptom Checklist were also proposed.

Deep Brain Stimulation for OCD in a Patient With Comorbidities: Epilepsy, Tics, Autism, and Major Depressive Disorder.

This study explores the roles of the precuneus and posterior cingulate cortex (pCunPCC) in the relationship between premonitory urge (PU) and tic severity in Tourette syndrome (TS). We recruited 58 children diagnosed with TS (age mean ± SD = 11.12 ± 2.56, F/M = 11/47). Tic and PU severity were measured using the Yale Global Tic Severity Scale (YGTSS) and the Premonitory Urge for Tics Scale (PUTS), respectively. We constructed brain functional networks for each subject based on resting-state fMRI and further calculated the degree centrality (DC), global efficiency (GE), and local efficiency (LE) of each pCunPCC region. A significant positive correlation was found between PUTS and YGTSS scores (t = 4.75, p < 0.001). The DC and GE of the right pCunPCC ROI 3 (Schaefer Atlas) showed significant negative correlations with YGTSS (t = -2.63, FDR-corrected p = 0.03 for DC; t = -2.85, FDR-corrected p = 0.04 for GE) and PUTS scores (t = -3.35, FDR-corrected p = 0.01 for DC; t = -2.95, FDR-corrected p = 0.03 for GE). Moderation analysis indicated that higher DC in the right pCunPCC ROI 3 reduced the effect of PU on tic severity. These moderation effects were also observed with PU and vocal tics, but not motor tics. The right pCunPCC serves as critical moderator in the relationship between PU and tic severity. This study highlighted the potential neural mechanisms underlying the relationship between PU and tic severity, providing potential targets for future intervention and treatment of TS.

IntroductionVocal and motor tics are characteristic for Tic disorders (TD) and Tourette’s syndrome (APA 2022) . Because of the pathophysiology of the disorders not being fully understood and the presence of the externally measurable symptoms; great attention has been paid to the cortico-striatal regions of patients with TD . In addition to the alterations in motor symptoms patients can experience a premonitory urge (PU) which can be felt before a tic (Reese et al. Behav. Ther. 2014; 45 177–186) . Previous studies found an impact of these urges on sensory perception, attention and social cognition as well as an involvement of the brain regions insula, anterior cingulate cortex (ACC) and the temporoparietal junction (TPJ) (Seeley J. Neurosci. 2019; 39 9878–9882, Kucyi et al. J. Neurophysiol. 2012; 108 3382–3392, Uddin et al. Brain Topogr. 2019; 32 926–942) . These findings lead to the idea of altered functional connectivity of the salience network (SN) in patients with TD.ObjectivesThis study aims to investigate the connectivity changes of the SN in patients with TD. We examined functional resting-state scans of patients with TD and searched for possible correlations between the tic and PU severity and the connectivity of the SN.Methods 21 Patients (mean age: 30.9 years ± 10.0 [range = 19–57], 6 females) diagnosed with TD, and 20 healthy controls (mean age: 29.7 years ± 8.9 [range = 18–50], 5 females) underwent a resting-state fMRI scan. Functional and anatomical images were conducted on a 3T Siemens Prisma fit MRI scanner. PU and tic severity were measured by the Premonitory Urges for Tics Scale (PUTS) and the Yale Global Tic Severity Scale (YGTSS). The connectivity analysis of the resting-state scans was done using the CONN toolbox v21.a. After pre-processing and de-noising steps, a whole-brain seed-based connectivity analysis was carried out with the seeds being the major cortical nods of the SN. For the correlation analysis a linear regression of the YGTSS score/PUTS score and the brain connectivity of the seed regions was conducted.ResultsThe PUTS score was 25.3±5.4 (range 10-33) and the YGTSS total tic score was 23.1±7.9 (range 10-38) for the patients. The connectivity analysis revealed a significant difference in connectivity between the groups for the ACC, the right insula and the TPJ. A negative correlation between the YGTSS scores and the connectivity of the left insula and the right superior frontal gyrus (SFG) was shown in the correlation analysis. No significant correlation was found for the PUTS scores in the investigated seed regions.ConclusionsThe right SFG mediates motor urgency and inhibitory control. Since we found a negative correlation between the insula and the right SFG regarding to higher YGTSS scores of the patients, our results might shed some light on the pathophysiology regarding lower inhibitory control in patients which experience higher tic severity.Disclosure of InterestNone Declared

Double-Blind, Crossover Study of Clonidine and Levetiracetam in Tourette Syndrome

This study investigated the characteristic changes of brain function in children with Tourette syndrome (TS) based on resting-state functional MRI (rs-fMRI) and their correlation with the Yale Global Tic Severity Scale (YGTSS) scores. A total of 19 children diagnosed as TS at the Department of Pediatrics in China-Japan Friendship Hospital from October 2021 to April 2023 were enrolled prospectively as the TS group, and 20 healthy children matched for age and gender were field recruited from the community as the control group. All participants underwent head rs-fMRI scans, and regional homogeneity (ReHo) and amplitude of low-frequency fluctuations (ALFF) values were calculated. YGTSS scores were assessed for the TS group. Pearson correlation analysis and Spearman correlation analysis were used to evaluate the correlation between ReHo, ALFF and YGTSS scores. Receiver operating characteristic (ROC) curves were plotted and area under the curve (AUC) was calculated to evaluate the efficacy of brain function parameters related to YGTSS score in diagnosing TS. The TS group included 19 patients, and aged (8.5±2.6) years, including 13 males (68.4%). The control group included 20 children, and aged (5.5±1.8) years, including 7 males (35.0%). In the TS group, the ReHo values in the left lentiform nucleus gray matter, left occipital lobe fusiform gyrus, right occipital lobe medial gyrus, and right frontal lobe paracentral lobule white matter were lower than those in the control group. The ReHo values in the pons and right cerebellar tonsil region, as well as the ALFF values in the right lingual gyrus, were higher than those in the control group (all P<0.01). The ReHo values in the right frontal lobe paracentral lobule, right occipital lobe medial gyrus, and left occipital lobe fusiform gyrus were positively correlated with vocal frequency (r=0.466, 0.576, 0.491) and intensity (r=0.498, 0.593, 0.609); the ReHo values in the right occipital lobe medial gyruss (r=0.615) and left occipital lobe fusiform gyrus (r=0.661) were positively correlated with the number of vocal tics (all P<0.05). The AUC (95%CI) for discriminating TS based on the ReHo values in the right frontal lobe paracentral lobule, right occipital lobe medial gyrus, and left occipital lobe fusiform gyrus were 0.890 (0.774-1.000), 0.863 (0.745-0.982), and 0.858 (0.760-0.988), respectively, with no statistically significant differences in the efficacy of these 3 ReHo values for discriminating TS (all P>0.05). Children with TS have characteristic brain function changes, and there is a correlation between the characteristic brain regions of MRI brain function changes and vocal tic symptoms.

ObjectiveThe Yale Global Tic Severity Scale (YGTSS) is the most commonly used clinician-rated evaluation tool for Tourette syndrome (TS), with established reliability and validity. This study aims to determine whether...

Dysregulation of dopaminergic signaling has been hypothesized to underlie the motor and phonic tics in Tourette syndrome (TS). The objective of this trial was to evaluate the safety and tic-reducing activity of the selective dopamine D1 receptor antagonist ecopipam in adults with TS. This was a multicenter, nonrandomized, open-label study of 50-mg ecopipam daily (weeks 1-2) and then 100 mg daily (weeks 3-8), taken orally before bedtime. The primary efficacy end point was the change in the Yale Global Tic Severity Scale (YGTSS) total tic score. Comorbid psychiatric symptoms and premonitory urges were rated; weight, serum metabolic studies, and adverse effects were monitored. Eighteen adults (15 men; 15 white, 2 African American, 1 Asian), with a mean age of 36.2 years (range, 18-63 years), were enrolled, and 15 completed the study. Mean (SD) YGTSS Total Tic score was 30.6 (8.8) at baseline and 25.3 (9.2) at 8 weeks (2-tailed paired t17 = 4.4; P = 0.0004). Mean (SD) YGTSS impairment score was 29.7 (10.9) at baseline and 22.8 (13.7) at final visit (t17 = 2.2; P = 0.04). There was no significant change in premonitory urges or psychiatric symptoms. Mean change in weight was -0.7 kg (P = 0.07). The most commonly reported adverse events were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%). In this open-label study in adults with TS, tics were reduced after 8 weeks of treatment with ecopipam. To confirm safety and efficacy, randomized, double blind, placebo-controlled trials are warranted.

The Yale Global Tic Severity Scale (YGTSS) is a clinician-rated instrument considered as the gold standard for assessing tics in patients with Tourette's Syndrome and other tic disorders. Previous psychometric investigations of the YGTSS exhibit different limitations such as small sample sizes and insufficient methods. To overcome these shortcomings, we used a subsample of the large-scale “European Multicentre Tics in Children Study” (EMTICS) including 706 children and adolescents with a chronic tic disorder and investigated convergent, discriminant and factorial validity, as well as internal consistency of the YGTSS. Our results confirm acceptable convergent and good to very good discriminant validity, respectively, indicated by a sufficiently high correlation of the YGTSS total tic score with the Clinical Global Impression Scale for tics (rs = 0.65) and only low to medium correlations with clinical severity ratings of attention deficit/hyperactivity symptoms (rs = 0.24), obsessive–compulsive symptoms (rs = 27) as well as internalizing symptoms (rs = 0.27). Internal consistency was found to be acceptable (Ω = 0.58 for YGTSS total tic score). A confirmatory factor analysis supports the concept of the two factors “motor tics” and “phonic tics,” but still demonstrated just a marginal model fit (root mean square error of approximation = 0.09 [0.08; 0.10], comparative fit index = 0.90, and Tucker Lewis index = 0.87). A subsequent analysis of local misspecifications revealed correlated measurement errors, suggesting opportunities for improvement regarding the item wording. In conclusion, our results indicate acceptable psychometric quality of the YGTSS. However, taking the wide use and importance of the YGTSS into account, our results suggest the need for further investigations and improvements of the YGTSS. In addition, our results show limitations of the global severity score as a sum score indicating that the separate use of the total tic score and the impairment rating is more beneficial.

ABSTRACTAimsRepetitive transcranial magnetic stimulation (rTMS) targeting the supplementary motor area (SMA) may treat Tourette's syndrome (TS) by modulating the function of the globus pallidus internus (GPi) via the cortico‐striato‐thalamo‐cortical circuit.MethodsWe conducted a randomized longitudinal study to examine circuit functionality and clinical efficacy. The GPi was identified as an “effective region” for TS treatment. Using functional MRI, individualized targets within the SMA were identified. Function‐specific targets [left SMA (n = 19), right SMA (n = 16)] were compared with conventional scalp‐localized SMA targets (n = 19). Age‐ and gender‐matched typical developmental children (TDC) served as controls (n = 48). TS patients received 50 Hz continuous theta burst stimulation (cTBS) at 70% RMT over five consecutive days (1800 pulses/day). Clinical efficacy was assessed using the Yale Global Tic Severity Scale (YGTSS) at one and two weeks post‐cTBS. Functional connectivity (FC) analyses of the GPi evaluated the impact on brain function.ResultsThere was an approximately 3 cm Y‐axis distance between the function‐specific and conventional targets. TS patients exhibited significantly reduced GPi‐base FC in bilateral motor areas at baseline compared to TDC. Following cTBS, 4 out of 19 patients in the left SMA group achieved a ≥ 30% reduction in YGTSS scores. cTBS modulated brain function in the left inferior orbital frontal cortex and right Lingual/cerebellum, primarily influenced by the right SMA target, whereas the conventional target showed no effect on YGTSS scores. Changes in GPi‐target FC were significantly correlated with reduction in YGTSS total scores (r = 0.638, p = 0.026).ConclusionThese findings suggest that function‐specific SMA targets may yield more pronounced modulatory effects, with the left SMA target achieving “Effectiveness” after just one week of cTBS. Combining function‐specific SMA‐targeted cTBS with standard treatment shows promise in accelerating clinical efficacy for TS treatment, warranting further investigation.

There are few effective pharmacological treatments for Tourette's syndrome. Many patients with Tourette's syndrome experience impairing tic symptoms despite use of available evidence-based treatments. The investigators conducted a small, uncontrolled trial to examine the safety, tolerability, and dosing of THX-110, a combination of Δ9-tetrahydracannabinol (Δ9-THC) and palmitoylethanolamide (PEA), in Tourette's syndrome. A 12-week uncontrolled trial of THX-110 (maximum daily Δ9-THC dose, 10 mg, and a constant 800-mg dose of PEA) in 16 adults with Tourette's syndrome was conducted. The primary outcome was improvement on the Yale Global Tic Severity Scale (YGTSS) total tic score. Secondary outcomes included measures of comorbid conditions and the number of participants who elected to continue treatment in the 24-week extension phase. Tic symptoms significantly improved over time with THX-110 treatment. Improvement in tic symptoms was statistically significant within 1 week of starting treatment compared with baseline. THX-110 treatment led to an average improvement in tic symptoms of more than 20%, or a 7-point decrease in the YGTSS score. Twelve of the 16 participants elected to continue to the extension phase, and only two participants dropped out early. Side effects were common but were generally managed by decreasing Δ9-THC dosing, slowing the dosing titration, and shifting dosing to nighttime. Although the initial data from this trial in adults with refractory Tourette's syndrome are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of THX-110 treatment. The challenges raised by the difficulty in blinding trials due to the psychoactive properties of many cannabis-derived compounds need to be further appreciated in these trial designs.

Background and purposeVery little is known about the long‐term prognosis of patients with functional tic‐like behaviours (FTLBs). We sought to characterize the trajectory of symptom severity over a 12‐month period.MethodsPatients with FTLBs were included in our prospective longitudinal child and adult clinical tic disorder registries at the University of Calgary. Patients were prospectively evaluated 6 and 12 months after their first clinical visit. Tic inventories and severity were measured with the Yale Global Tic Severity Scale (YGTSS).ResultsEighty‐three youths and adults with FTLBs were evaluated prospectively until April 2023. Mean YGTSS total tic severity scores were high at baseline, with a mean score of 29.8 points (95% confidence interval [CI] = 27.6–32.1). Fifty‐eight participants were reevaluated at 6 months, and 32 participants were reevaluated at 12 months. The YGTSS total tic severity score decreased significantly from the first clinical visit to 6 months (raw mean difference = 8.9 points, 95% CI = 5.1–12.7, p < 0.0001), and from 6 to 12 months (raw mean difference = 6.4 points, 95% CI = 0.8–12.0, p = 0.01). Multivariable linear regression demonstrated that tic severity at initial presentation and the presence of other functional neurological symptoms were associated with higher YGTSS total tic scores at 6 months, whereas younger age at baseline, receiving cognitive behavioural therapy for anxiety and/or depression, and prescription of selective serotonin reuptake inhibitors were associated with lower YGTSS total tic scores at 6 months.ConclusionsWe observed a meaningful improvement in tic severity scores in youth and adults with FTLBs over a period of 6–12 months.

To investigate the reliability and validity of the Yale Global Tic Severity Scale (YGTSS), 28 youth aged 6 to 17 years with Tourette's syndrome (TS) participated in the study. Data included clinician reports of tics and obsessive-compulsive disorder (OCD) severity, parent reports of tics, internalizing and externalizing problems, and child reports of depression and anxiety. All children participated in a 2nd YGTSS administration by the same rater 48 days later. Good internal consistency and stability were found for the YGTSS scores. YGTSS scores demonstrated strong correlations with parent-rated tic severity (r = .58-.68). YGTSS scores were not significantly related to measures of clinician ratings of OCD severity (r = .01-.15), parent ratings of externalizing and internalizing behavior (r = -.07-.20), and child ratings of depression (r = .02-.26) and anxiety (r = -.06 -.28). Findings suggest that the YGTSS is a reliable and valid instrument for the assessment of pediatric TS.

Effectiveness of Low-Frequency Pallidal Deep Brain Stimulation at 65 Hz in Tourette Syndrome