A Process-Oriented View of Procedural Memory Can Help Better Understand Tourette’s Syndrome

Tourette’s syndrome (TS) is a neurodevelopmental disorder characterized by repetitive movements and vocalizations, also known as tics. The phenomenology of tics and the underlying neurobiology of the disorder have suggested that the altered functioning of the procedural memory system might contribute to its etiology. However, contrary to the robust findings of impaired procedural memory in neurodevelopmental disorders of language, results from TS have been somewhat mixed. We review the previous studies in the field and note that they have reported normal, impaired, and even enhanced procedural performance. These mixed findings may be at least partially be explained by the diversity of the samples in both age and tic severity, the vast array of tasks used, the low sample sizes, and the possible confounding effects of other cognitive functions, such as executive functions, working memory or attention. However, we propose that another often overlooked factor could also contribute to the mixed findings, namely the multiprocess nature of the procedural system itself. We propose that a process-oriented view of procedural memory functions could serve as a theoretical framework to help integrate these varied findings. We discuss evidence suggesting heterogeneity in the neural regions and their functional contributions to procedural memory. Our process-oriented framework can help to deepen our understanding of the complex profile of procedural functioning in TS and atypical development in general.

Targeted Interventions in Tourette’s using Advanced Neuroimaging and Stimulation (TITANS): study protocol for a double-blind, randomised controlled trial of transcranial magnetic stimulation (TMS) to the supplementary motor area in children with Tourette’s syndrome

IntroductionTourette’s syndrome (TS) affects approximately 1% of children. This study will determine the efficacy and safety of paired comprehensive behavioural intervention for tics (CBIT) plus repetitive transcranial magnetic stimulation (rTMS) treatment in children with Tourette’s syndrome. We hypothesise that CBIT and active rTMS to the supplementary motor area (SMA) will (1) decrease tic severity, and (2) be associated with changes indicative of enhanced neuroplasticity (eg, changes in in vivo metabolite concentrations and TMS neurophysiology measures).Methods and analysisThis study will recruit 50 youth with TS, aged 6–18 for a phase II, double-blind, block randomised, sham-controlled trial comparing active rTMS plus CBIT to sham rTMS plus CBIT in a 1:1 ratio. The CBIT protocol is eight sessions over 10 weeks, once a week for 6 weeks and then biweekly. The rTMS protocol is 20 sessions of functional MRI-guided, low-frequency (1 Hz) rTMS targeted to the bilateral SMA over 5 weeks (weeks 2–6). MRI, clinical and motor assessments and neurophysiological evaluations including motor mapping will be performed 1 week before CBIT start, 1 week after rTMS treatment and 1 week after CBIT completion. The primary outcome measure is Tourette’s symptom change from baseline to post-CBIT treatment, as measured by the Yale Global Tic Severity Scale. Secondary outcomes include changes in imaging, neurophysiological and behavioural markers.Ethics and disseminationEthical approval by the Conjoint Health Research Ethics Board (REB18-0220). The results of this study will be published in peer-reviewed scientific journals, on ClinicalTrials.gov and shared with the Tourette and OCD Alberta Network. The results will also be disseminated through the Alberta Addictions and Mental Health Research Hub.Trial registrationNCT03844919.

Predicting Clinical Course from Subcortical Shape in Provisional Tic Disorder

The ongoing NewTics study examines children who have had tics for less than 9 months (NT group) - a population on which little research exists. Here, we further investigate relationships between subcortical shape and tic symptom outcomes. 138 children were assessed at baseline and a 12-month follow-up: 79 with NT, 27 tic-free healthy controls (HC), and 32 with chronic tic disorder or Tourette syndrome (TS), using T1-weighted MRI and total tic scores (TTS) from the Yale Global Tic Severity Scale to evaluate symptom change. Subcortical surface maps were generated using FreeSurfer-initialized large deformation diffeomorphic metric mapping, and linear regression models were constructed to correlate structural shapes with TTS while accounting for covariates, with relationships mapped onto structure surfaces. When compared to healthy controls, smaller mean volumes were found in the TS group for the caudate, nucleus accumbens, pallidum, and thalamus. NT had smaller mean volumes than controls in the caudate, pallidum, and thalamus. Surface maps illustrate distinct patterns of inward deformation (localized volume loss) in the TS group compared to NT children. In the NT group, a larger hippocampus at baseline significantly correlated with the worsening of tic symptoms at 12 months. Outward deformation in the hippocampus and inward deformation in the accumbens at baseline are also related to worsening tic symptoms at follow-up. Since the NT group has had tics only for a few months, we can rule out the possibility that these subcortical volume differences are caused by living with tics for years; they are more likely related to the cause of tics. These observations constitute some of the first prognostic biomarkers for tic disorders and suggest localized circuitry that may be associated with outcome of tic disorders.

Efficacy and cost-effectiveness of therapist-guided internet-delivered behaviour therapy for children and adolescents with Tourette syndrome: study protocol for a single-blind randomised controlled trial

Background Treatment guidelines recommend behaviour therapy (BT) for patients with Tourette syndrome (TS) and chronic tic disorder (CTD). However, BT is rarely accessible due to limited availability of trained therapists and long travel distances to specialist clinics. Internet-delivered BT has the potential of overcoming these barriers through remote delivery of treatment with minimal therapist support. In the current protocol, we outline the design and methods of a randomised controlled trial (RCT) evaluating an internet-delivered BT programme referred to as BIP TIC. The trial’s primary objective is to determine the clinical efficacy of BIP TIC for reducing tic severity in young people with TS/CTD, compared with an active control intervention. Secondary objectives are to investigate the 12-month durability of the treatment effects and to perform a health economic evaluation of the intervention. Methods In this single-blind superiority RCT, 220 participants (9–17 years) with TS/CTD throughout Sweden will be randomised to 10–12 weeks of either therapist-supported internet-delivered BT based on exposure with response prevention (BIP TIC) or therapist-supported internet-delivered education. Data will be collected at baseline, 3 and 5 weeks into the treatment, at post-treatment, and 3, 6, and 12 months post-treatment. The primary endpoint is the 3-month follow-up. The primary outcome is tic severity as measured by the Yale Global Tic Severity Scale – Total Tic Severity Score. Treatment response is operationalised as scores of “Very much improved” or “Much improved” on the Clinical Global Impression – Improvement scale, administered at the primary endpoint. Outcome assessors will be blind to treatment condition at all assessment points. A health economic evaluation of BIP TIC will be performed, both in the short term (primary endpoint) and the long term (12-month follow-up). There are no planned interim analyses. Discussion Participant recruitment started on 26 April 2019 and finished on 9 April 2021. The total number of included participants was 221. The final participant is expected to reach the primary endpoint in September 2021 and the 12-month follow-up in June 2022. Data analysis for the primary objective will commence after the last participant reaches the primary endpoint. Trial registration ClinicalTrials.gov NCT03916055. Registered on 16 April 2019.

Microstructural Abnormalities of White Matter Across Tourette Syndrome: A Voxel-Based Meta-Analysis of Fractional Anisotropy

Introduction: Tourette syndrome (TS) is a neuropsychiatric disorder with multiple motor and vocal tics whose neural basis remains unclear. Diffusion tensor imaging (DTI) studies have demonstrated white matter microstructural alternations in TS, but the findings are inconclusive. In this study, we aimed to elucidate the most consistent white matter deficits in patients with TS.Method: By systematically searching online databases up to December 2020 for all DTI studies comparing fractional anisotropy (FA) between patients with TS and healthy controls (HCs), we conducted anisotropic effect size-signed differential mapping (AES-SDM) meta-analysis to investigate FA differences in TS, as well as performed meta-regression analysis to explore the effects of demographics and clinical characteristics on white matter abnormalities among TS.Results: A total of eight datasets including 168 patients with TS and 163 HCs were identified. We found that TS patients showed robustly decreased FA in the corpus callosum (CC) and right inferior longitudinal fasciculus (ILF) compared with HCs. These two regions preserved significance in the sensitivity analysis. No regions of increased FA were reported. Meta-regression analysis revealed that age, sex, tic severity, or illness duration of patients with TS were not linearly correlated with decreased FA.Conclusion: Patients with TS display deficits of white matter microstructure in the CC and right ILF known to be important for interhemispheric connections as well as long association fiber bundles within one hemisphere. Because the results reported in the primary literature were highly variable, future investigations with large samples would be required to support the identified white matter changes in TS.

A functional network target for tic reduction during thalamic stimulation for Tourette Syndrome

ABSTRACTBackgroundDeep brain stimulation (DBS) of the medial thalamus is an evolving therapy for severe, treatment-refractory Tourette syndrome (TS). It remains unanswered which functionally connected networks need to be modulated to obtain optimal treatment results.MethodsWe assessed treatment response of 15 patients with TS untergoing thalamic DBS six and twelve months postoperatively using the Yale Global Tic Severity Scale (YGTSS) tic score. For each time point, functional connectivity maps seeding from stimulation sites were calculated based on a normative functional connectome derived from 1000 healthy subjects. Resulting maps were analyzed in a voxel-wise mixed model for repeated measurements to identify patterns of connectivity associated with tic reduction.ResultsConnectivity of stimulation to the medial frontal cortex, bilateral insulae and sensorimotor cortex was associated with tic reduction. Connectivity with the temporal lobe, cerebellum, ventral striatum and orbitofrontal cortex was negatively associated. The overall connectivity pattern was robust to leave-one-out cross-validation, explaining 25 % of outcome variance (R = 0.500; p = 0.005).ConclusionsWe delineated a functional connectivity profile seeding from stimulation sites associated with TS-DBS outcome. This pattern comprised areas linked to the processing of premonitory urges and tic execution, thereby extending our current understanding of effective neuromodulation for TS.

Efficacy and cost-effectiveness of therapist-guided internet-delivered behaviour therapy for children and adolescents with Tourette syndrome: study protocol for a single-blind randomised controlled trial

Background: Treatment guidelines recommend behaviour therapy (BT) for patients with Tourette syndrome (TS) and chronic tic disorder (CTD). However, BT is rarely accessible due to limited availability of trained therapists and long travel distances to specialist clinics. Internet-delivered BT has the potential of overcoming these barriers through remote delivery of treatment with minimal therapist support. In the current protocol, we outline the design and methods of a randomised controlled trial (RCT) evaluating an internet-delivered BT programme referred to as BIP TIC. The trial’s primary objective is to determine the clinical efficacy of BIP TIC for reducing tic severity in young people with TS/CTD, compared with an active control intervention. Secondary objectives are to investigate the 12-month durability of the treatment effects and to perform a health economic evaluation of the intervention.Methods: In this single-blind superiority RCT, 220 participants (9-17 years) with TS/CTD throughout Sweden will be randomised to 10-12 weeks of either therapist-supported internet-delivered BT based on exposure with response prevention (BIP TIC) or therapist-supported internet-delivered education. Data will be collected at baseline, 3 and 5 weeks into the treatment, at post-treatment, and 3, 6, and 12 months post-treatment. The primary endpoint is the 3-month follow-up. The primary outcome is tic severity as measured by the Yale Global Tic Severity Scale – Total tic severity score. Treatment response is operationalised as scores of “Very much improved” or “Much improved” on the Clinical Global Impression – Improvement scale, administered at the primary endpoint. Outcome assessors will be blind to treatment condition at all assessment points. A health economic evaluation of BIP TIC will be performed, both in the short term (primary endpoint) and the long term (12-month follow-up). There are no planned interim analyses. Discussion: Participant recruitment started on 26 April 2019 and finished on 9 April 2021. The final participant will reach the primary endpoint in September 2021 and the 12-month follow-up in June 2022. Data analysis for the primary objective will commence after the last participant reaches the primary endpoint.

Investigation of gene–environment interactions in relation to tic severity

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies.

Revisiting the structure of the Yale Global Tic Severity Scale (YGTSS) in a sample of Chinese children with tic disorders

Background To the best of our knowledge, although the Chinese version of the Yale Global Tic Severity Scale (YGTSS) is widely used in child psychiatry departments in China, there is very little evidence focusing on the psychometric characteristics of the Chinese version of YGTSS. In this present study, we aim to re-examine the structure of the Chinese version of YGTSS and investigate its reliability and validity. Methods A total of 367 children and adolescents with tic disorders aged 5–16 years old participated in the study. The Cronbach’s alpha, test-retest reliability and concurrent validity will be calculated. Confirmatory Factor Analysis (CFA) also will be performed to assess the structure of YGTSS. Results The Cronbach’s alpha of the motor tic subscale of YGTSS was 0.84, for the phonic tic subscale of YGTSS, it was 0.90, but for the whole scale, it was 0.58. The test-retest reliability of YGTSS was 0.84. For the results of CFA, the Comparative Fit Index (CFI) of YGTSS based on the Two-Factor Model and Three-Factor Model was 0.97 and 0.96 respectively. The measurement invariance analysis suggested that the Two-Factor model of YGTSS across different age and sex groups was at the accepted level (≥0.90). Conclusion Overall, according to the results of this research, it suggested that the Chinese version of YGTSS showed good psychometric properties. It can be used in the assessment of tic disorders in the Chinese population. In the future, more comprehensive tools for assessing tics need to be further developed, which can cover the symptoms of premonitory urge and tic related obsessive-compulsive symptoms.