An Online Mindfulness-Based Group Intervention for Tics: A Pilot Randomized Controlled Trial.

BACKGROUND: Current treatments for Tourette syndrome (TS) and persistent tic disorder (PTD) are often insufficiently effective, inaccessible, and frequently associated with adverse events. Thus, we must continue to develop and test effective, accessible, and safe treatment options. OBJECTIVE: We aimed to conduct a pilot randomized controlled trial (RCT) comparing a novel, videoconference-delivered group mindfulness-based intervention for tics (MBIT) to videoconference-delivered group psychoeducation, relaxation, and supportive therapy (PRST) for adults with TS or PTD. METHODS: Thirty-two adults with TS or PTD were randomly assigned to receive 8 weeks of either MBIT or PRST. Tic severity, tic-related impairment, and global improvement were assessed by a trained, independent evaluator who was masked to treatment condition at baseline (week 0), posttreatment (week 9), 1-month follow-up, and 6-month follow-up. All study procedures were conducted online via secure videoconferencing. RESULTS: Twenty-eight participants began treatment and were included in analyses. MBIT, relative to PRST, was associated with a significantly greater decline in tic severity (d = 0.85) and tic-related impairment (d = 0.99) from baseline to posttreatment. Treatment response was significantly higher in MBIT (69%) than in PRST (13%). Neither treatment resulted in serious adverse effects. The durability of treatment outcomes is also reported and discussed. CONCLUSIONS: The results from this pilot RCT suggest that videoconference-delivered group MBIT may be an efficacious, accessible, and safe intervention for adults with tics. Future research is necessary to confirm these preliminary findings. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Gamified Closed-Loop Intervention Enhances Tic Suppression in Children: A Randomized Trial.

BACKGROUND: Gamification of behavioral intervention for tic disorders (TDs) potentially enhances compliance and offers key clinical advantages. By delivering immediate positive feedback upon tic-suppression, games may counteract negative reinforcement, which presumably contribute to tic consolidation by relieving uncomfortable premonitory urges. OBJECTIVES: We developed a gamified protocol (XTics), which leverages this potential by combining gamified tic-triggering with immediate feedback, and evaluated its clinical value in enhancing tic suppression. METHODS: XTics encompasses two conditions: Immediate and Contingent Reward (ICR), where game progression is contingent upon successful tic suppression, and Delayed Reward (DR), where game events' outcomes are random. Employing a randomized crossover design, 35 participants (aged 7-15 years) underwent daily gaming sessions over a week per condition. Improvements in our primary measures, including the inter-tic interval (ITI) and tic severity assessment by blinded evaluators (Yale Global Tic Severity-Total Tic Score [YGTSS-TTS], Rush), and parents (Parent Tic Questionnaire [PTQ]), were compared between ICR and DR, and assessed across conditions for the 4-week protocol. RESULTS: No participant voluntarily left the study before completing its two-phase protocol. As expected, ITI showed significantly larger improvement (Z = 4.19, P = 2.85 × 10-5) after ICR (1442 ± 2250%) versus DR (242 ± 493%) training, increasing at a higher pace (t(67) = 3.15, P = 0.0025). Similarly, Rush tic severity scores reduced more post-ICR versus DR (t(47) = 3.47, P = 0.002). We observed a clinically significant reduction of 25.69 ± 23.39% in YGTSS-TTS following a f4-week protocol including both conditions. Parent-reported tic severity decreased by 42.99 ± 31.69% from baseline to 3 months post-treatment. CONCLUSIONS: The combination of gamified tic-triggering with immediate and contingent rewards demonstrates a promising approach for enhancing treatment efficacy in TDs, boosting traditional therapeutic methods. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

White matter alterations predict outcomes of comprehensive behavioral intervention for tics in children with Tourette syndrome: A diffusion MRI study.

AIM: Tourette syndrome (TS) is a neurodevelopmental disorder that cause sudden uncontrolled rapid and repeated vocal sounds or movements called tics. Herein, diffusion magnetic resonance imaging (dMRI) connectometry was implemented to evaluate the white matter connectivity differences among TS patients. METHODS: A total of 63 TS and 77 typically developed (TD) individuals were enrolled in the present study. dMRI connectometry was utilized to identify differences in connectivity patterns of white matter tracts in TS patients based on quantitative anisotropy (QA). QA was compared between TS and TD patients and correlated with severity scores such as Yale Global Tic Severity Scale (YGTSS) and Premonitory Urge for Tics Scale (PUTS). RESULTS: Higher white matter connectivity of corpus callosum and bilateral cingulum as well as lower connectivity of corticothalamic and corticostriatal pathways were evident in TS relative to TD. The baseline YGTSS motor, YGTSS total, and PUTS were negatively correlated with corticostriatal pathway, corticothalamic pathway, and bilateral cingulum integrity, respectively. The changes in tic severity scores were also positively correlated with alterations in the white matter integrity of these brain regions following behavioral therapy. CONCLUSION: Patients with TS have several abnormalities in their white matter microstructure particularly in the cortico-striato-thalamo-cortical (CSTC) circuit, correlated with the severity of the disease. Besides, the post-behavioral therapy changes in the white matter integrity of these regions are demonstrated as response predictors.

Tics emergencies and malignant tourette syndrome: Assessment and management.

Tourette syndrome (TS) is a complex neurodevelopmental disorder characterized by the presence of tics, frequently accompanied by a variety of neuropsychiatric comorbidities. A subset of patients with TS present with severe and disabling symptoms, requiring prompt therapeutic intervention. Some of these manifestations may result in medical emergencies when severe motor or phonic tics lead to damage of anatomical structures closely related to the tic. Examples include myelopathy or radiculopathy following severe neck ("whiplash") jerks or a variety of self-inflicted injuries. In addition to self-aggression or, less commonly, allo-aggression, some patients exhibit highly inappropriate behavior, suicidal tendencies, and rage attacks which increase the burden of the disease and are important components of "malignant TS". This subset of TS is frequently associated with comorbid obsessive-compulsive disorder. Therapeutic measures include intensive behavioral therapy, optimization of oral pharmacotherapy, botulinum toxin injections, and deep brain stimulation.

Responsive deep brain stimulation for the treatment of Tourette syndrome.

To report the results of 'responsive' deep brain stimulation (DBS) for Tourette syndrome (TS) in a National Institutes of Health funded experimental cohort. The use of 'brain derived physiology' as a method to trigger DBS devices to deliver trains of electrical stimulation is a proposed approach to address the paroxysmal motor and vocal tic symptoms which appear as part of TS. Ten subjects underwent bilateral staged DBS surgery and each was implanted with bilateral centromedian thalamic (CM) region DBS leads and bilateral M1 region cortical strips. A series of identical experiments and data collections were conducted on three groups of consecutively recruited subjects. Group 1 (n = 2) underwent acute responsive DBS using deep and superficial leads. Group 2 (n = 4) underwent chronic responsive DBS using deep and superficial leads. Group 3 (n = 4) underwent responsive DBS using only the deep leads. The primary outcome measure for each of the 8 subjects with chronic responsive DBS was calculated as the pre-operative baseline Yale Global Tic Severity Scale (YGTSS) motor subscore compared to the 6 month embedded responsive DBS setting. A responder for the study was defined as any subject manifesting a ≥ 30 points improvement on the YGTSS motor subscale. The videotaped Modified Rush Tic Rating Scale (MRVTRS) was a secondary outcome. Outcomes were collected at 6 months across three different device states: no stimulation, conventional open-loop stimulation, and embedded responsive stimulation. The experience programming each of the groups and the methods applied for programming were captured. There were 10 medication refractory TS subjects enrolled in the study (5 male and 5 female) and 4/8 (50%) in the chronic responsive eligible cohort met the primary outcome manifesting a reduction of the YGTSS motor scale of ≥ 30% when on responsive DBS settings. Proof of concept for the use of responsive stimulation was observed in all three groups (acute responsive, cortically triggered and deep DBS leads only). The responsive approach was safe and well tolerated. TS power spectral changes associated with tics occurred consistently in the low frequency 2-10 Hz delta-theta-low alpha oscillation range. The study highlighted the variety of programming strategies which were employed to achieve responsive DBS and those used to overcome stimulation induced artifacts. Proof of concept was also established for a single DBS lead triggering bi-hemispheric delivery of therapeutic stimulation. Responsive DBS was applied to treat TS related motor and vocal tics through the application of three different experimental paradigms. The approach was safe and effective in a subset of individuals. The use of different devices in this study was not aimed at making between device comparisons, but rather, the study was adapted to the current state of the art in technology. Overall, four of the chronic responsive eligible subjects met the primary outcome variable for clinical effectiveness. Cortical physiology was used to trigger responsive DBS when therapy was limited by stimulation induced artifacts.

Treating Tourette Together: An Agenda for Patient-Centered Research Focused on Comprehensive Behavioral Intervention for Tics.

To establish a patient-centered agenda for research that will lead to effective, widespread availability, adoption, and utilization of evidence-based behavioral treatment of Tourette syndrome and other tic disorders (TDs), we planned and executed a multistage, collaborative "Treating Tourette Together" research planning project with researchers, clinicians, patients, families, and other interested parties. Priorities for future behavioral treatment research were solicited from these parties via anonymous community surveys, a 2-day research planning summit with 46 individuals representing key stakeholder groups, and community response to summit reports. Four high-priority research domains were identified: (a) expanding treatment access, (b) improving treatment outcomes, (c) optimizing treatment within a broader care model, and (d) evaluating outcomes beyond tic severity. Community-engaged participatory research models can efficiently delineate clear and actionable priorities for clinical research. This approach holds promise for improving the impact of clinical research in TDs and other neuropsychiatric disorders.

Parent-Report Sleep Disturbances and Everyday Executive Functioning Difficulties in Children with Tourette Syndrome.

There is an increasing need to identify and treat sleep disturbances in Tourette syndrome (TS), a neurodevelopmental condition characterized by tics. This study explored sleep, tics, and executive functioning in children with TS (n=136) and neurotypical controls (n=101) through parent-report scales and open-ended questions. 85% of children with TS scored in the clinical range for a sleep disorder. Higher tic severity predicted increased sleep disturbances and executive difficulties. Qualitative insights indicated a bidirectional link between sleep and tics, which warrants consideration in clinical settings. Further research is needed to explore causal links.

Microlesion Effect Induced by Electrode Implantation in the Posteroventral Globus Pallidus Interna for Severe Dystonic Tics.

Background: Tourette syndrome (TS) is a neurologic condition characterized by motor and phonic tics. Dystonic tics, including blepharospasm, are considered atypical or unusual in severe TS. Case Report: We report a severe case of TS with facial dystonic tics resembling blepharospasm in which the microlesion effect and a sustained therapeutic effect was observed with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). Discussion: Bilateral GPi DBS can be beneficial for blepharospasm-like tics and severe symptoms of TS. The improvements seen can be explained by the microlesion effect induced by DBS lead placement in the GPi.

Efficacy of differential reinforcement of other behaviors therapy for tic disorder: a meta-analysis.

INTRODUCTION: Recently, studies on behavioral tic suppression techniques have gained popularity as opposed to pharmacological alternatives that often have potentially dangerous side effects. Differential Reinforcement of Other Behaviors therapy (DRO) is one such behavioral technique whose efficacy in tic suppression has been experimentally demonstrated albeit in studies with very few patients, and lacking statistical power. Here, we conducted a meta-analysis of these studies to improve their overall power and explore whether DRO intervention is really effective for tic suppression. MATERIALS AND METHODS: PubMed, Embase, PsycINFO, and Cochrane Library were searched from inception to August 30, 2023. Only original interventional studies that examined the efficacy of DRO for tic suppression were included. RESULTS: A total of 8 no control interventional studies involving 79 children with tic disorders were recruited. Most of the children had moderate tic severity. The pooled mean Yale Global Tic Severity Scale (YGTSS) score was 24.64 (95% CI: 21.99 - 30.12, p = < 0.00001, I2 = 87%). In terms of efficacy of the DRO technique for tic suppression, the results showed that DRO was effective in reducing tic frequency among the children. The pooled standardized mean difference (SMD) was -10.25 (95% CI: -14.71 - -5.79, p = < 0.00001) with I2 = 94%. CONCLUSION: In conclusion, this study revealed that DRO is potentially an effective tic suppression technique for temporarily managing tic disorder. It also showed that DRO could be employed for both moderate and severe tic disorders. However, the technique bears crucial limitations that limit its implementation outside of experimental settings. More studies are needed to address these limitations and improve its applicability in the real world.

Effectiveness of speech therapy in treating vocal blocking tics in children with Tourette syndrome: Two case reports.

Tourette syndrome is characterized by at least two motor tics and one vocal tic, which persist for over a year. Infrequently, tics can manifest as blocking tics in speech when they prevent a person from starting to speak or interrupt their speech flow. Vocal blocking tics (VBTs) resemble stuttering, and they can be difficult to differentiate from each other. A previous report described two patients with severe VBTs who did not benefit from stuttering-therapy-based speech therapy and were treated effectively with cannabis-based medicine. Here, we present the cases of two patients, seven- and nine-year-old boys, who benefited from speech therapy in which stuttering therapy techniques were used. Detailed descriptions of the interventions are included. Further research is needed to test the effectiveness of speech therapy in treating VBTs in a larger group of children with Tourette syndrome.

Applying an Established Exposure Response Prevention Protocol for Young People With Tourette Syndrome in an Intensive, Group Format: A Feasibility Study.

BACKGROUND: The motor and vocal tics that characterise Tourette syndrome are stigmatizing and impact on quality of life. Behavioural interventions such as Exposure Response Prevention or Comprehensive Behavioural Interventions for Tics are first line treatment for Tourette syndrome, but availability is limited. This study is the first to explore the impact of an established manualised Exposure Response Prevention treatment protocol, developed for individual therapy, but here uniquely delivered intensively, to a group. METHODS: A naturalistic study comprised of a consecutive series of children (N = 20), aged 8-16 years (M = 12, SD = 2.17) were offered Exposure Response Prevention in one of two groups, delivered in series within a specialist clinic. Young people received the equivalent of 12 sessions (matching the manualised individual protocol). RESULTS: The YGTSS and Giles de la Tourette Syndrome Quality of Life Scale for Children and Adolescents (Satisfaction Scale) showed significant improvement following treatment with moderate to large effect sizes. Thirty-five percent of children demonstrated a reliable improvement on the YGTSS Global Tic Severity score. CONCLUSIONS: These data suggest an established Exposure Response Prevention protocol can be delivered in an intensive, group setting with a positive clinical outcome. Replication in a randomized controlled trial is an important next step.

Protocol description for a randomized controlled trial of fMRI neurofeedback for tics in adolescents with Tourette Syndrome.

This article describes the protocol for a randomized, controlled clinical trial of a neurofeedback (NF) intervention for Tourette Syndrome (TS) and chronic tic disorder. The intervention involves using functional magnetic resonance imaging (fMRI) to provide feedback regarding activity in the supplementary motor area: participants practice controlling this brain area while using the feedback as a training signal. The previous version of this NF protocol was tested in a small study (n = 21) training adolescents with TS that yielded clinically promising results. Therefore, we plan a larger trial. Here we describe the background literature that motivated this work, the design of our original neurofeedback study protocol, and adaptations of the research study protocol for the new trial. We focus on those ideas incorporated into our protocol that may be of interest to others designing and running NF studies. For example, we highlight our approach for defining an unrelated brain region to be trained in the control group that is based on identifying a region with low functional connectivity to the target area. Consistent with a desire for transparency and open science, the new protocol is described in detail here prior to conducting the trial.

The CBIT + TMS trial: study protocol for a two-phase randomized controlled trial testing neuromodulation to augment behavior therapy for youth with chronic tics.

BACKGROUND: Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment for tic disorders that aims to improve controllability over tics that an individual finds distressing or impairing. However, it is only effective for approximately half of patients. Supplementary motor area (SMA)-directed neurocircuitry plays a strong role in motor inhibition, and activity in this region is thought to contribute to tic expression. Targeted modulation of SMA using transcranial magnetic stimulation (TMS) may increase CBIT efficacy by improving patients' ability to implement tic controllability behaviors. METHODS: The CBIT + TMS trial is a two-phase, milestone-driven early-stage randomized controlled trial. The trial will test whether augmenting CBIT with inhibitory, non-invasive stimulation of SMA with TMS modifies activity in SMA-mediated circuits and enhances tic controllability in youth ages 12-21 years with chronic tics. Phase 1 will directly compare two rTMS augmentation strategies (1 Hz rTMS vs. cTBS) vs. sham in N = 60 participants. Quantifiable, a priori "Go/No Go Criteria" guide the decision to proceed to phase 2 and the selection of the optimal TMS regimen. Phase 2 will compare the optimal regimen vs. sham and test the link between neural target engagement and clinical outcomes in a new sample of N = 60 participants. DISCUSSION: This clinical trial is one of few to date testing TMS augmentation of therapy in a pediatric sample. The results will provide insight into whether TMS is a potentially viable strategy for enhancing CBIT efficacy and reveal potential neural and behavioral mechanisms of change. TRIAL REGISTRATION: ClinicalTrials.gov NCT04578912 . Registered on October 8, 2020.

Functional connectivity during tic suppression predicts reductions in vocal tics following behavior therapy in children with Tourette syndrome.

BACKGROUND: Comprehensive Behavioral Intervention for Tics (CBIT) is recommended as a first-line treatment for Tourette syndrome in children and adults. While there is strong evidence proving its efficacy, the mechanisms of reduction in tic severity during CBIT are still poorly understood. In a recent study, our group identified a functional brain network involved in tic suppression in children with TS. We reasoned that voluntary tic suppression and CBIT may share some mechanisms and thus we wanted to assess whether functional connectivity during tic suppression was associated with CBIT outcome. METHODS: Thirty-two children with TS, aged 8 to 13 years old, participated in a randomized controlled trial of CBIT v. a treatment-as-usual control condition. EEG was recorded during tic suppression in all participants at baseline and endpoint. We used a source-reconstructed EEG connectivity pipeline to assess functional connectivity during tic suppression. RESULTS: Functional connectivity during tic suppression did not change from baseline to endpoint. However, baseline tic suppression-related functional connectivity specifically predicted the decrease in vocal tic severity from baseline to endpoint in the CBIT group. Supplementary analyses revealed that the functional connectivity between the right superior frontal gyrus and the right angular gyrus was mainly driving this effect. CONCLUSIONS: This study revealed that functional connectivity during tic suppression at baseline predicted reduction in vocal tic severity. These results suggest probable overlap between the mechanisms of voluntary tic suppression and those of behavior therapy for tics.

Group-based comprehensive behavioral intervention for tics (CBIT) for adults with Tourette syndrome or chronic tic disorders: A pilot study.

Comprehensive behavioral intervention for tics (CBIT) administered individually is an effective treatment for tics. However, the effectiveness of CBIT administered in groups for adults with Tourette syndrome and chronic tic disorders has not been investigated yet. This pilot study examined the effectiveness of group-based CBIT with respect to reduction of tic severity and tic-related impairment, as well as improvement of tic-related quality of life. Data from 26 patients were included in the intention-to-treat analyses. The Yale Global Tic Severity Scale was used to assess total tic severity and tic-related impairment. The Gilles de la Tourette - Quality of Life Scale was used to assess tic-related quality of life. These measures were administered at three points in time: at pretreatment, posttreatment, and 1-year follow-up. The results showed a significant reduction of total tic severity from pretreatment to 1-year follow-up, with larges effect sizes. Tic-related impairment and tic-related quality of life also improved significantly, although the effect sizes were smaller. Motor tics showed a stronger reduction than vocal tics. Additional analysis revealed that all change was achieved during treatment and that this effect was maintained from posttreatment to 1-year follow-up. The results of this study indicate that group-based CBIT is a promising treatment for tics.

Decoupling: adaptation of a treatment for body-focused repetitive behaviour to Tourette syndrome. A case report.

AIMS: Tourette syndrome (TS) is a neurological condition; its etiology is not yet fully understood. Cognitive behavioural therapy with habit reversal training is the recommended first-line treatment, but is not effective in all patients. This is the first report examining the usefulness of decoupling, a behavioural self-help treatment originally developed for patients with body-focused repetitive behaviours, in a patient with TS. METHOD: Patient P.Z. showed 10 motor and three vocal tics on the Adult Tic Questionnaire (ATQ) before treatment. He was taught decoupling by the first author. RESULTS: The application of decoupling led to a reduction of P.Z.'s eye tics, which was one of his first and most enduring and severe tics. It was not effective for other areas. Quality of life and depression improved, which P.Z. attributed to the improvement of his tics. CONCLUSION: Decoupling may be adopted as an alternative, when habit reversal training is not feasible. Future research, preferably using a controlled design with a large sample, may elucidate whether decoupling is only effective for tics relating to the eyes, the most common symptom in tic disorder/TS, or whether its effects extend to other symptoms.

A double-blind, sham-controlled, trial of home-administered rhythmic 10-Hz median nerve stimulation for the reduction of tics, and suppression of the urge-to-tic, in individuals with Tourette syndrome and chronic tic disorder.

Tourette syndrome (TS) and chronic tic disorder (CTD) are neurological disorders of childhood onset characterized by the occurrence of tics; repetitive, purposeless, movements or vocalizations of short duration which can occur many times throughout a day. Currently, effective treatment for tic disorders is an area of considerable unmet clinical need. We aimed to evaluate the efficacy of a home-administered neuromodulation treatment for tics involving the delivery of rhythmic pulse trains of median nerve stimulation (MNS) delivered via a wearable 'watch-like' device worn at the wrist. We conducted a UK-wide parallel double-blind sham-controlled trial for the reduction of tics in individuals with tic disorder. The device was programmed to deliver rhythmic (10 Hz) trains of low-intensity (1-19 mA) electrical stimulation to the median nerve for a pre-determined duration each day, and was intended to be used by each participant in their home once each day, 5 days each week, for a period of 4 weeks. Between 18th March 2022 and 26th September 2022, 135 participants (45 per group) were initially allocated, using stratified randomization, to one of the following groups; active stimulation; sham stimulation or to a waitlist (i.e. treatment as usual) control group. Recruited participants were individuals with confirmed or suspected TS/CTD aged 12 years of age or upward with moderate to severe tics. Researchers involved in the collection or processing of measurement outcomes and assessing the outcomes, as well as participants in the active and sham groups and their legal guardians were all blind to the group allocation. The primary outcome measure used to assess the 'offline' or treatment effect of stimulation was the Yale Global Tic Severity Scale-Total Tic Severity Score (YGTSS-TTSS) assessed at the conclusion of 4 weeks of stimulation. The primary outcome measure used to assess the 'online' effects of stimulation was tic frequency, measured as the number of tics per minute (TPM) observed, based upon blind analysis of daily video recordings obtained while stimulation was delivered. The results demonstrated that after 4-week stimulation, tic severity (YGTSS-TTSS) had reduced by 7.1 points (35 percentile reduction) for the active stimulation group compared to 2.13/2.11 points for the sham stimulation and waitlist control groups. The reduction in YGTSS-TTSS for the active stimulation group was substantially larger, clinically meaningful (effect size = .5) and statistically significant (p = .02) compared to both the sham stimulation and waitlist control groups, which did not differ from one another (effect size = -.03). Furthermore, blind analyses of video recordings demonstrated that tic frequency (tics per minute) reduced substantially (-15.6 TPM) during active stimulation compared to sham stimulation (-7.7 TPM). This difference represents a statistically significant (p < .03) and clinically meaningful reduction in tic frequency (>25 percentile reduction: effect size = .3). These findings indicate that home-administered rhythmic MNS delivered through a wearable wrist-worn device has the potential to be an effective community-based treatment for tic disorders.

Deep brain stimulation alleviates tics in Tourette syndrome via striatal dopamine transmission.

Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by intrusive motor and vocal tics that can lead to self-injury and deleterious mental health complications. While dysfunction in striatal dopamine neurotransmission has been proposed to underlie tic behaviour, evidence is scarce and inconclusive. Deep brain stimulation (DBS) of the thalamic centromedian parafascicular complex (CMPf), an approved surgical interventive treatment for medical refractory Tourette syndrome, may reduce tics by affecting striatal dopamine release. Here, we use electrophysiology, electrochemistry, optogenetics, pharmacological treatments and behavioural measurements to mechanistically examine how thalamic DBS modulates synaptic and tonic dopamine activity in the dorsomedial striatum. Previous studies demonstrated focal disruption of GABAergic transmission in the dorsolateral striatum of rats led to repetitive motor tics recapitulating the major symptom of Tourette syndrome. We employed this model under light anaesthesia and found CMPf DBS evoked synaptic dopamine release and elevated tonic dopamine levels via striatal cholinergic interneurons while concomitantly reducing motor tic behaviour. The improvement in tic behaviour was found to be mediated by D2 receptor activation as blocking this receptor prevented the therapeutic response. Our results demonstrate that release of striatal dopamine mediates the therapeutic effects of CMPf DBS and points to striatal dopamine dysfunction as a driver for motor tics in the pathoneurophysiology of Tourette syndrome.

Precision Mapping of Thalamic Deep Brain Stimulation Lead Positions Associated With the Microlesion Effect in Tourette Syndrome.

BACKGROUND: The microlesion effect refers to the improvement of clinical symptoms after deep brain stimulation (DBS) lead placement and is suggested to indicate optimal lead placement. Very few studies have reported its implications in neuropsychiatric disorders. OBJECTIVE: To evaluate the magnitude of the microlesion effect in Tourette syndrome and the relationship between the microlesion effect and the anatomic location of implanted DBS leads. METHODS: Six male patients were included. Their median age at surgery and follow-up period were 25 years (range, 18-47) and 12 months (range, 6-24), respectively. All patients were videotaped pre- and postoperatively, and tic frequencies were counted. We also analyzed the precision of lead placement and evaluated the normative connectome associated with the microlesion area. RESULTS: The microlesion effect was observed as an improvement in tic symptoms in all patients, and the long-term clinical outcomes were favorable. The median motor tic frequency was 20.2 tics/min (range, 9.7-60) at baseline and decreased to 3.2 tics/min (1.2-11.3) in patients on postoperative day 1 ( P = .043) and to 5.7 tics/min (range, 1.9-16.6) in patients on postoperative day 7 ( P = .028). Phonic tic tended to improve immediately after surgery although the changes were not significant. Image analyses revealed that the precise position of the electrode was directed toward the anteromedial centromedian nucleus. Normative connectome analysis demonstrated connections between improvement-related areas and wide areas of the prefrontal cortex. CONCLUSION: This study shows that the microlesion effect may seem as an immediate improvement after optimal DBS lead placement in patients with Tourette syndrome.

Long-term clinical and cost-effectiveness of a therapist-supported online remote behavioural intervention for tics in children and adolescents: extended 12- and 18-month follow-up of a single-blind randomised controlled trial.

BACKGROUND: Little is known about the long-term effectiveness of behavioural therapy for tics. We aimed to assess the long-term clinical and cost-effectiveness of online therapist-supported exposure and response prevention (ERP) therapy for tics 12 and 18 months after treatment initiation. METHODS: ORBIT (online remote behavioural intervention for tics) was a two-arm (1:1 ratio), superiority, single-blind, multicentre randomised controlled trial comparing online ERP for tics with online psychoeducation. The trial was conducted across two Child and Adolescent Mental Health Services in England. Participants were recruited from these two sites, across other clinics in England, or by self-referral. This study was a naturalistic follow-up of participants at 12- and 18-month postrandomisation. Participants were permitted to use alternative treatments recommended by their clinician. The key outcome was the Yale Global Tic Severity Scale Total Tic Severity Score (YGTSS-TTSS). A full economic evaluation was conducted. Registrations are ISRCTN (ISRCTN70758207); ClinicalTrials.gov (NCT03483493). RESULTS: Two hundred and twenty-four participants were enrolled: 112 to ERP and 112 to psychoeducation. The sample was predominately male (177; 79%) and of white ethnicity (195; 87%). The ERP intervention reduced baseline YGTSS-TTSS by 2.64 points (95% CI: -4.48 to -0.79) with an effect size of -0.36 (95% CI: -0.61 to -0.11) after 12 months and by 2.01 points (95% CI: -3.86 to -0.15) with an effect size of -0.27 (95% CI -0.52 to -0.02) after 18 months, compared with psychoeducation. Very few participants (<10%) started new tic treatment during follow-up. The cost difference in ERP compared with psychoeducation was £304.94 (-139.41 to 749.29). At 18 months, the cost per QALY gained was £16,708 for ERP compared with psychoeducation. CONCLUSIONS: Remotely delivered online ERP is a clinical and cost-effective intervention with durable benefits extending for up to 18 months. This represents an efficient public mental health approach to increase access to behavioural therapy and improve outcomes for tics.