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.

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.

Art as relaxation for tic disorders: a pilot randomised control study.

BACKGROUND: Despite the known benefits of art therapy, there are a limited number of studies on art therapy for tic disorders. This pilot randomised controlled study investigated effects of art as a relaxation technique for tic disorders. METHODS: Twenty-two children aged 7-9 years were randomly allocated to art intervention (n= 11) and control (n= 11) groups. Pre- and post-test measurements included the Yale Global Tic Severity Scale (YGTSS), Heart Rate Variability (HRV), and Hassles Scale for Children (HSC). RESULTS: Art as relaxation significantly decreased the YGTSS total score, motor tic frequency, motor tic intensity, motor tic complexity, vocal tic complexity, and total daily stressors compared to the control group. The intervention group showed significantly greater physiological relaxation, as indicated by increases in HRV parameters. CONCLUSIONS: Art appears to be an effective relaxation technique for tic disorders. Extensive research is necessary for rigorous examination of its effectiveness.

Efficacy and safety of Jiu-Wei-Xi-Feng granules for treating tic disorders in children: study protocol for a randomized controlled equivalence trial.

BACKGROUND: Tic disorders (TD) is a neuropsychiatric disease with twitch as the main manifestation in childhood. Jiu-Wei-Xi-Feng granules has been marketed in China for treating children with TD. As Long Gu (Os Draconis) in the composition of this Chinese patent medicine is a rare and expensive medicinal material protected by the Chinese government, therefore, we consider replacing it with Mu Li (Concha Ostreae) that has the same effect and is cheaper. This study is designed to evaluate the clinical equivalence between Jiu-Wei-Xi-Feng granules (Os Draconis replaced by Concha Ostreae) (JWXFD) and Jiu-Wei-Xi-Feng granules (original formula) (JWXFO) in children with TD (consumption of renal yin and liver wind stirring up internally syndrome). METHODS/DESIGN: This is a multicenter, randomized, double-blind, equivalence trial comparing the efficacy and safety of JWXFD and JWXFO in treating Children with tic disorders (consumption of renal yin and liver wind stirring up internally syndrome). A total of 288 patients will be recruited and randomly assigned to two groups in a 1:1 ratio. The treatment course is 6 weeks, with a 2 weeks follow-up. The primary outcome is the mean change value from baseline to 6th week by the Yale Global Tic Severity Scale total tic score (YGTSS-TTS). Secondary outcomes include total effective rate of tic, Yale Global Tic Severity Scale (YGTSS) scores and its factor scores (the degree of motor tics, phonic tics and social function damage), Clinical Global Impression-Severity scale, and TCM syndrome efficacy. DISCUSSION: The design of this study refers to a large number of similar research design points, and asked for opinions of peer experts, and finally reached a consensus. This trial will provide high-quality evidence on the clinical equivalence between JWXFD and JWXFO and provide a basis for the marketing of JWXFD. TRIAL REGISTRATION: ChiCTR2000032312 Registered on 25 April 2020, http://www.chictr.org.cn/showproj.aspx?proj=52630.

Embedded Human Closed-Loop Deep Brain Stimulation for Tourette Syndrome: A Nonrandomized Controlled Trial.

Importance: Because Tourette syndrome (TS) is a paroxysmal disorder, symptomatic relief in individuals with TS may be possible through the application of stimulation only during the manifestation of human tic neural signatures. This technique could be capable of suppressing both motor and vocal tics and would have similar effectiveness to conventional continuous deep brain stimulation (DBS). Objective: To evaluate the feasibility, safety, and clinical effectiveness of bilateral centromedian-parafascicular complex thalamic closed-loop DBS as a treatment for medication-refractory TS. Design, Setting, and Participants: This single-center double-blinded safety and feasibility trial was conducted between February 2014 and June 2020. Six individuals with TS were screened and recruited from the Norman Fixel Institute at the University of Florida. The primary outcome was measured at 6 months, and participants were followed up for the duration of the neurostimulator battery life. Independent ratings that compared closed-loop and conventional DBS were videotaped. The first 2 of 6 individuals with TS were excluded from the study because the technology for embedded closed-loop capability was not yet available. The date of analysis was August 2020. Interventions: DBS therapy controlled by an embedded closed-loop stimulation system. Main Outcomes and Measures: The primary clinical outcome measure was a minimum of a 40% reduction in the YGTSS score at 6 months following DBS. There was also a comparison of conventional DBS with closed-loop DBS using the Modified Rush Videotape Rating Scale for Tic. Results: The mean (SD) age at TS diagnosis for the cohort was 8.5 (2.9), and the mean (SD) disease duration was 23.7 (5.8) years. Four individuals with TS were analyzed (2 male, 2 female; mean [SD] age, 23.7 [5.8] years). The study showed the closed-loop approach was both feasible and safe. One of the novelties of this study was that a patient-specific closed-loop paradigm was created for each participant. The features and stimulation transition speed were customized based on the signal quality and the tolerance to adverse reactions. The mean (SD) therapeutic outcome with conventional DBS was 33.3% (35.7%) improvement on the YGTSS and 52.8% (21.9%) improvement on the Modified Rush Videotape Rating Scale. Two of 4 participants had a primary outcome variable improvement of 40% meeting the primary efficacy target. When comparing closed-loop DBS with conventional DBS using a Wilcoxon sign-rank test, there was no statistical difference between tic severity score and both approaches revealed a lower tic severity score compared with baseline. The study was feasible in all 4 participants, and there were 25 total reported adverse events with 3 study-related events (12%). The most common adverse events were headache and anxiety. Conclusions and Relevance: Embedded closed-loop deep DBS was feasible, safe, and had a comparable outcome to conventional TS DBS for the treatment of tics. Trial Registration: ClinicalTrials.gov Identifier: NCT02056873.

Tourette Syndrome Treatment Updates: a Review and Discussion of the Current and Upcoming Literature.

PURPOSE OF REVIEW: This study aims to examine the treatments currently available for Tourette syndrome (TS) and to discuss evolving therapies, spanning behavioral, pharmacologic, complementary and alternative medicine, and neuromodulation approaches. RECENT FINDINGS: Behavioral therapies have undergone several modifications to improve accessibility, including transitioning to a virtual format which is particularly important in the current pandemic. There are several recent or ongoing pharmacologic studies that have shown promise including the selective D1 receptor antagonist ecopipam and various cannabinoid compounds. Adaptive DBS may enable the physiologic markers of tics to determine stimulation parameters and improve tic outcomes related to neuromodulation. In recent years, there has been a wealth of research across multiple treatment domains in the TS field. This review highlights exciting and new potential options for the future treatment of patients with TS.

Randomized, Sham-Controlled Trial of Real-Time Functional Magnetic Resonance Imaging Neurofeedback for Tics in Adolescents With Tourette Syndrome.

BACKGROUND: Activity in the supplementary motor area (SMA) has been associated with tics in Tourette syndrome (TS). The aim of this study was to test a novel intervention-real-time functional magnetic resonance imaging neurofeedback from the SMA-for reduction of tics in adolescents with TS. METHODS: Twenty-one adolescents with TS were enrolled in a double-blind, randomized, sham-controlled, crossover study involving two sessions of neurofeedback from their SMA. The primary outcome measure of tic severity was the Yale Global Tic Severity Scale administered by an independent evaluator before and after each arm. The secondary outcome was control over the SMA assessed in neuroimaging scans, in which subjects were cued to increase/decrease activity in SMA without receiving feedback. RESULTS: All 21 subjects completed both arms of the study and all assessments. Participants had significantly greater reduction of tics on the Yale Global Tic Severity Scale after real neurofeedback as compared with the sham control (p < .05). Mean Yale Global Tic Severity Scale Total Tic score decreased from 25.2 ± 4.6 at baseline to 19.9 ± 5.7 at end point in the neurofeedback condition and from 24.8 ± 8.1 to 23.3 ± 8.5 in the sham control condition. The 3.8-point difference is clinically meaningful and corresponds to an effect size of 0.59. However, there were no differences in changes on the secondary measure of control over the SMA. CONCLUSIONS: This first randomized controlled trial of real-time functional magnetic resonance imaging neurofeedback in adolescents with TS suggests that this neurofeedback intervention may be helpful for improving tic symptoms. However, no effects were found in terms of change in control over the SMA, the hypothesized mechanism of action.

Relaxation therapy as a treatment for tics in patients with Tourette syndrome: a systematic literature review.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental condition characterized by the presence of multiple motor and phonic tics, often associated with co-morbid behavioural problems. Tics can be modulated by environmental factors and are characteristically exacerbated by psychological stress, among other factors. This observation has led to the development of specific behavioural treatment strategies, including relaxation therapy. OBJECTIVE: This review aimed to assess the efficacy of relaxation therapy to control or reduce tic symptoms in patients with TS. METHODS: We conducted a systematic literature review of original studies on the major scientific databases, including Medline, EMBASE, and PsycInfo, according to the standards outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Outcomes measures included both tic severity and tic frequency. RESULTS: Our literature search identified three controlled trials, with a total number of 40 participants (range: 6-18 participants). In all three studies, relaxation therapy decreased the severity and/or the frequency of tic symptoms. However, the only trial comparing relaxation therapy to two other behavioural techniques found relaxation therapy to be the least effective intervention, as it reduced the number of tics by 32% compared to 44% with self-monitoring and 55% with habit reversal. DISCUSSION: The results of this systematic literature review provide initial evidence for the use of relaxation therapy as a behavioural treatment intervention for tics in patients with TS. Caution is needed in the interpretation of these findings, because the reviewed trials had small sample sizes and there was high heterogeneity across the study protocols.

[The application of the acupuncture techniques for the combined treatment of neurotic tics in the children]. / Ispol'zovanie metodov refleksoterapii v kompleksnom lechenii nevroticheskikh tikov u detei.

At present, the frequency of neurosis in the children is growing under the influence of the increasingly intensive stressful factors. The neurotic ticks are one of the manifestations of neurosis in the children characterized by involuntary movements; they are often accompanied by hyperactivity, deficit of attention, fatigue, and headaches. AIM: The objective of the present study was to evaluate the effectiveness of acupuncture used for the treatment of neurotic tics in the children. MATERIAL AND METHODS: The study was carried out at the basis of the department of children's rehabilitation of the Moscow city polyclinic #39. All the children were counselled by a neurologist, psychologist, and acupuncturist. An electroencephalogram was obtained from each patient and a questionnaire study involving the patients' parents was conducted. The patients were treated with the application of reflexotherapy and were given recommendations of a psychologist. A total of 30 children at the age from 6 to 12 years were available for the examination. The participants of the study were allocated to two groups depending on the strategy of the outpatient care. Group 1 was comprised of the patients (n=17) who were given 3 courses of reflexotherapy in addition to pharmacotherapy and psychologist's recommendations. The patients included in group 2 served as controls (n=13) and received only medications and psychotherapy without acupuncture. The effectiveness of the treatment was evaluated based on the dynamics of the patients' complaints. RESULTS AND DISCUSSION: The resullts of the study give evidence of the higher effectiveness of the treatment of the children suffering from neurotic ticks with the application of acupuncture therapy compared with the conventional approach. A few courses of reflexotherapy provided in the combination with pharmacotherapy and the compliance with the recommendations of a psychologist resulted in the more efficient elimination of the neurotic tics together with the associated hyperactivity, deficit of attention, fatigue, and headaches than the use of medication therapy and psychotherapy without acupuncture.

Putting the Pieces Together in Gilles de la Tourette Syndrome: Exploring the Link Between Clinical Observations and the Biological Basis of Dysfunction.

Gilles de la Tourette syndrome is a complex, idiopathic neuropsychiatric disorder whose pathophysiological mechanisms have yet to be elucidated. It is phenotypically heterogeneous and manifests more often than not with both motor and behavioral impairment, although tics are its clinical hallmark. Tics themselves present with a complex profile as they characteristically wax and wane and are often preceded by premonitory somatosensory sensations to which it is said a tic is the response. Highly comorbid with obsessive-compulsive disorder and attention deficit-hyperactivity disorder, it is purported to be an epigenetic, neurodevelopmental spectrum disorder with a complex genetic profile. It has a childhood onset, occurs disproportionately in males, and shows spontaneous symptomatic attenuation by adulthood in the majority of those afflicted. Although not fully understood, its neurobiological basis is linked to dysfunction in the cortico-basal ganglia-thalamo-cortical network. Treatment modalities for Tourette syndrome include behavioral, pharmacological and surgical interventions, but there is presently no cure for the disorder. For those severely affected, deep brain stimulation (DBS) has recently become a viable therapeutic option. A key factor to attaining optimal results from this surgery is target selection, a topic still under debate due to the complex clinical profile presented by GTS patients. Depending on its phenotypic expression and the most problematic aspect of the disorder for the individual, one of three brain regions is most commonly chosen for stimulation: the thalamus, globus pallidus, or nucleus accumbens. Neurophysiological analyses of intra- and post-operative human electrophysiological recordings from clinical DBS studies suggest a link between tic behavior and activity in both the thalamus and globus pallidus. In particular, chronic recordings from the thalamus have shown a correlation between symptomatology and (1) spectral activity in gamma band power and (2) theta/gamma cross frequency coherence. These results suggest gamma oscillations and theta/gamma cross correlation dynamics may serve as biomarkers for dysfunction. While acute and chronic recordings from human subjects undergoing DBS have provided better insight into tic genesis and the neuropathophysiological mechanisms underlying Tourette syndrome, these studies are still sparse and the field would greatly benefit from further investigations. This review reports data and discoveries of scientific and clinical relevance from a wide variety of methods and provides up-to-date information about our current understanding of the pathomechanisms underlying Tourette syndrome. It gives a comprehensive overview of the current state of knowledge and addresses open questions in the field.

[Clinical and neurophysiological data of neurofeedback therapy in children with ADHD]. / Wyniki kliniczne i neurofizjologiczne terapii neurofeedback u dzieci z zespolem ADHD.

INTRODUCTION: ADHD occurs in 3% of school-age children (and in 70% of them in adulthood) and represents an important medical and social problem. It is characterized by attention deficits, hyperactivity and impulsiveness. Neurofeedback therapy (EEG biofeedback, NF) is carried out based on the analysis of EEG. OBJECTIVE: To investigate the effect of NF therapy on clinical status and parameters of the EEG in ADHD. MATERIALS AND METHODS: In the years 2007-2014, 287 children (191 boys), aged 6-17 years were included into the study. Some children with ADHD had other coexisting disorders like: tics, dyslexia, emotional or behavior disorders. Visual analysis of EEG was made and 7 selected parameters of bioelectrical activity were assessed. EEG tracing before and after NF therapy were compared. NF therapy lasted from 9 months to 3 years (mean 1.5 years). 60-240 NF training sessions were performed with the use of NF device, video-games and 16-channel Elmiko devices. Statistical analysis of the results was made. RESULTS: Children with ADHD additionally presented low self-esteem, anxiety and sleep disorders. The baseline theta/beta ratio in children with ADHD and ADHD with cooccurring dyslexia was >4.0 and in children with ADHD and coexisting tics 3.0-3.8, with coexisting behavioral disorders 3.7-4.0 and emotional disorders 3.3-3.7. After therapy, this ratio decreased significantly in all groups, but most significantly in ADHD and ADHD with dyslexia group. In the group with dyslexia theta and alpha activity in the left fronto-temporo-parietal region (the speech centers) has been increased. In children with ADHD and behavior disorders right-sided paroxysmal changes in the form of slow and sharp waves in the temporo-centro-parietal regions were found. In emotionally disturbed children increased fast beta activity in the right hemisphere (anxiety, fear) was observed. Initially NF therapy reduced hyperactivity and impulsivity of children, subsequently improvement of attention was observed and eventually reduction of emotional and behavior disturbances was noticed. Noticeable improvement in the self-esteem was observed as well. The therapy had a positive impact on the spatial organization of EEG in each group. It proved to be particularly useful in children with ADHD and dyslexia. CONCLUSIONS: Neurofeedback therapy is a valuable tool with beneficial impact on children with ADHD and accompanying disorders. Characteristics of brain bioelectric activity provides a reliable basis to establish individual EEG bio-feedback protocols of therapy in children and monitor the effectiveness of treatment. In the last 4 years the number of children with ADHD and cooccurring tics who applied for neurofeedback therapy has increased significantly.

Scheduled, intermittent stimulation of the thalamus reduces tics in Tourette syndrome.

INTRODUCTION: Personalized, scheduled deep brain stimulation in Tourette syndrome (TS) may permit clinically meaningful tic reduction while reducing side effects and increasing battery life. Here, we evaluate scheduled DBS applied to TS at two-year follow-up. METHODS: Five patients underwent bilateral centromedian thalamic (CM) region DBS. A cranially contained constant-current device delivering stimulation on a scheduled duty cycle, as opposed to the standard continuous DBS paradigm was utilized. Baseline vs. 24-month outcomes were collected and analyzed, and a responder analysis was performed. A 40% improvement in the Modified Rush Tic Rating Scale (MRTRS) total score or Yale Global Tic Severity Scale (YGTSS) total score defined a full responder. RESULTS: Three of the 4 patients followed to 24 months reached full responder criteria and had a mean stimulation time of 1.85 h per day. One patient lost to follow-up evaluated at the last time point (month 18) was a non-responder. Patients exhibited improvements in MRTRS score beyond the improvements previously reported for the 6 month endpoint; on average, MRTRS total score was 15.6% better at 24 months than at 6 months and YGTSS total score was 14.8% better. Combining the patients into a single cohort revealed significant improvements in the MRTRS total score (-7.6 [5.64]; p = 0.02). CONCLUSION: Electrical stimulation of the centromedian thalamic region in a scheduled paradigm was effective in suppressing tics, particularly phonic tics. Full responders were able to achieve the positive DBS effect with a mean of 2.3 ± 0.9 (SEM) hours of DBS per day.

Centromedian-Parafascicular Complex Deep Brain Stimulation for Tourette Syndrome: A Retrospective Study.

Deep brain stimulation (DBS) of the thalamic centromedian/parafascicular (CM-Pf) complex has been reported as a promising treatment for patients with severe, treatment-resistant Tourette syndrome (TS). In this study, safety and clinical outcomes of bilateral thalamic CM-Pf DBS were reviewed in a series of 12 consecutive patients with medically refractory TS, 11 of whom met the criteria of postsurgical follow-up at our institution for at least 2 months. Five patients were followed for a year or longer. Consistent with many patients with TS, all patients had psychiatric comorbidities. Tic severity and frequency were measured by using the Yale Global Tic Severity Scale (YGTSS) over time (average, 26 months) in 10 subjects. One patient was tested at 2-week follow-up only and thus was excluded from group YGTSS analysis. Final YGTSS scores differed significantly from the preoperative baseline score. The average (n=10) improvement relative to baseline in the total score was 54% (95% CI, 37-70); average improvement relative to baseline in the YGTSS Motor tic, Phonic tic, and Impairment subtests was 46% (95% CI, 34-64), 52% (95% CI, 34-72), and 59% (95% CI, 39-78), respectively. There were no intraoperative complications. After surgery, 1 subject underwent wound revision because of a scalp erosion and wound infection; the implanted DBS system was successfully salvaged with surgical revision and combined antibiotic therapy. Stimulation-induced adverse effects did not prevent the use of the DBS system, although 1 subject is undergoing a trial period with the stimulator off. This surgical series adds to the literature on CM-Pf DBS and supports its use as an effective and safe therapeutic option for severe refractory TS.

Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental condition characterised by chronic motor and vocal tics affecting up to 1% of school-age children and young people and is associated with significant distress and psychosocial impairment. OBJECTIVE: To conduct a systematic review of the benefits and risks of pharmacological, behavioural and physical interventions for tics in children and young people with TS (part 1) and to explore the experience of treatment and services from the perspective of young people with TS and their parents (part 2). DATA SOURCES: For the systematic reviews (parts 1 and 2), mainstream bibliographic databases, The Cochrane Library, education, social care and grey literature databases were searched using subject headings and text words for tic* and Tourette* from database inception to January 2013. REVIEW/RESEARCH METHODS: For part 1, randomised controlled trials and controlled before-and-after studies of pharmacological, behavioural or physical interventions in children or young people (aged < 18 years) with TS or chronic tic disorder were included. Mixed studies and studies in adults were considered as supporting evidence. Risk of bias associated with each study was evaluated using the Cochrane tool. When there was sufficient data, random-effects meta-analysis was used to synthesize the evidence and the quality of evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. For part 2, qualitative studies and survey literature conducted in populations of children/young people with TS or their carers or in health professionals with experience of treating TS were included in the qualitative review. Results were synthesized narratively. In addition, a national parent/carer survey was conducted via the Tourettes Action website. Participants included parents of children and young people with TS aged under 18 years. Participants (young people with TS aged 10-17 years) for the in-depth interviews were recruited via a national survey and specialist Tourettes clinics in the UK. RESULTS: For part 1, 70 studies were included in the quantitative systematic review. The evidence suggested that for treating tics in children and young people with TS, antipsychotic drugs [standardised mean difference (SMD) -0.74, 95% confidence interval (CI) -1.08 to -0.41; n = 75] and noradrenergic agents [clonidine (Dixarit(®), Boehringer Ingelheim) and guanfacine: SMD -0.72, 95% CI -1.03 to -0.40; n = 164] are effective in the short term. There was little difference among antipsychotics in terms of benefits, but adverse effect profiles do differ. Habit reversal training (HRT)/comprehensive behavioural intervention for tics (CBIT) was also shown to be effective (SMD -0.64, 95% CI -0.99 to -0.29; n = 133). For part 2, 295 parents/carers of children and young people with TS contributed useable survey data. Forty young people with TS participated in in-depth interviews. Four studies were in the qualitative review. Key themes were difficulties in accessing specialist care and behavioural interventions, delay in diagnosis, importance of anxiety and emotional symptoms, lack of provision of information to schools and inadequate information regarding medication and adverse effects. LIMITATIONS: The number and quality of clinical trials is low and this downgrades the strength of the evidence and conclusions. CONCLUSIONS: Antipsychotics, noradrenergic agents and HRT/CBIT are effective in reducing tics in children and young people with TS. The balance of benefits and harms favours the most commonly used medications: risperidone (Risperdal(®), Janssen), clonidine and aripiprazole (Abilify(®), Otsuka). Larger and better-conducted trials addressing important clinical uncertainties are required. Further research is needed into widening access to behavioural interventions through use of technology including mobile applications ('apps') and video consultation. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002059. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Tic-reducing effects of music in patients with Tourette's syndrome: Self-reported and objective analysis.

BACKGROUND: Self-reports by musicians affected with Tourette's syndrome and other sources of anecdotal evidence suggest that tics stop when subjects are involved in musical activity. For the first time, we studied this effect systematically using a questionnaire design to investigate the subjectively assessed impact of musical activity on tic frequency (study 1) and an experimental design to confirm these results (study 2). METHODS: A questionnaire was sent to 29 patients assessing whether listening to music and musical performance would lead to a tic frequency reduction or increase. Then, a within-subject repeated measures design was conducted with eight patients. Five experimental conditions were tested: baseline, musical performance, short time period after musical performance, listening to music and music imagery. Tics were counted based on videotapes. RESULTS: Analysis of the self-reports (study 1) yielded in a significant tic reduction both by listening to music and musical performance. In study 2, musical performance, listening to music and mental imagery of musical performance reduced tic frequency significantly. We found the largest reduction in the condition of musical performance, when tics almost completely stopped. Furthermore, we could find a short-term tic decreasing effect after musical performance. CONCLUSIONS: Self-report assessment revealed that active and passive participation in musical activity can significantly reduce tic frequency. Experimental testing confirmed patients' perception. Active and passive participation in musical activity reduces tic frequency including a short-term lasting tic decreasing effect. Fine motor control, focused attention and goal directed behavior are believed to be relevant factors for this observation.

Tic related local field potentials in the thalamus and the effect of deep brain stimulation in Tourette syndrome: Report of three cases.

OBJECTIVE: Three patients with intractable Tourette syndrome (TS) underwent thalamic deep brain stimulation (DBS). To investigate the role of thalamic electrical activity in tic generation, local field potentials (LFP), EEG and EMG simultaneously were recorded. METHODS: Event related potentials and event related spectral perturbations of EEG and LFP, event related cross-coherences between EEG/LFP and LFP/LFP were analyzed. As time locking events, the tic onsets were used. Spontaneous tics were compared to voluntary tic mimicking. The effect of tic suppression and DBS on thalamic LFPs was evaluated. RESULTS: All three patients showed time-locked and prior to onset of spontaneous motor tics thalamic synchronization and thalamo-cortical cross-coherence. Also in three patients, not time-locked to motor tics, increased intra-thalamic coherences in the 1-8Hz frequency band were found. In one patient it was demonstrated that voluntary mimicked tics were preceded by premotor cortical and thalamic potentials. In this patient unilateral thalamic DBS contralaterally decreased the background thalamic activity. CONCLUSIONS: The present study in three cases with TS shows that spontaneous tics in TS are preceded by repetitive coherent thalamo-cortical discharges, indicating that preceding a tic the basal ganglia circuits are "charged up", ultimately leading to a motor tic. SIGNIFICANCE: Thalamic LFP recording may lead to more insight in underlying pathophysiological mechanisms in TS.

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.

Comprehensive behavioral intervention to improve occupational performance in children with Tourette disorder.

OBJECTIVE. We evaluated the efficacy of a comprehensive behavioral intervention for tics (CBIT) program to reduce tic severity and improve occupational performance in children with tic disorder using a one-group pretest-posttest design. METHOD. Thirty children with tic disorder completed an eight-session CBIT program. The program focused on habit reversal, relaxation training, and function-based approaches to address how the environment and social situations (antecedents and consequences) sustain or influence tic severity. RESULTS. We observed significant reduction in the number of tics and improvement in scores on the Parent Tic Questionnaire, Subjective Units of Distress Scale, and Child Occupational Self Assessment after CBIT compared with scores at baseline. CONCLUSION. Findings provided support that CBIT reduced the number of tic expressions, tic severity, and level of distress associated with tic and improved these children's self-perception of their competence in and importance of performing everyday activities (i.e., occupational performance).

Deep brain stimulation for Tourette syndrome: a prospective pilot study in Japan.

OBJECTIVE: Refractory Tourette syndrome (TS) disturbs the social life of patients. Deep brain stimulation (DBS) has recently been applied to relieve severe tics. We report a prospective open-labeled case series of DBS for TS as a pilot study. CASES AND METHODS: Three patients (19-21 years old, one male) with refractory TS were treated with DBS. They were targeted at the centromedian-parafascicular complex-ventral oral thalamic nuclei of the bilateral thalami. RESULTS: The scores for the Yale Global Tic Severity Scale decreased from 42.7 ± 2.7 (before DBS) to 26.0 ± 1.7 (one year after DBS) (means ± standard error of means). Intelligence levels of the patients showed no change after surgery. There was no morbidity or mortality. All patients presented an increase in satisfaction with activities of daily living. CONCLUSIONS: These results support the safety and efficacy of thalamic DBS for TS.