From urges to tics in children with Tourette syndrome: associations with supplementary motor area GABA and right motor cortex physiology.

Tourette syndrome (TS) is a childhood-onset disorder in which tics are often preceded by premonitory sensory urges. More severe urges correlate with worse tics and can render behavioral therapies less effective. The supplementary motor area (SMA) is a prefrontal region believed to influence tic performance. To determine whether cortical physiological properties correlate with urges and tics, we evaluated, in 8-12-year-old right-handed TS children (n = 17), correlations of urge and tic severity scores and compared both to cortical excitability (CE) and short- and long-interval cortical inhibition (SICI and LICI) in both left and right M1. We also modeled these M1 transcranial magnetic stimulation measures with SMA gamma-amino butyric acid (GABA) levels in TS and typically developing control children (n = 16). Urge intensity correlated strongly with tic scores. More severe urges correlated with lower CE and less LICI in both right and left M1. Unexpectedly, in right M1, lower CE and less LICI correlated with less severe tics. We found that SMA GABA modulation of right, but not left, M1 CE and LICI differed in TS. We conclude that in young children with TS, lower right M1 CE and LICI, modulated by SMA GABA, may reflect compensatory mechanisms to diminish tics in response to premonitory urges.

Frequency and Intensity of Premonitory Urges-to-Tic in Tourette Syndrome Is Associated With Supplementary Motor Area GABA+ Levels.

BACKGROUND: Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS. OBJECTIVE: The aim of this study was to examine the contribution of brain γ-aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS. METHODS: Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing control subjects (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity. RESULTS: GABA+ and Glx of the right SM1, SMA, and insula were comparable between the children with TS and typically developing control subjects. In children with TS, lower levels of SMA GABA+ were associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity. CONCLUSIONS: These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS. © 2021 International Parkinson and Movement Disorder Society.

Cannabis-based medicine in treatment of patients with Gilles de la Tourette syndrome.

INTRODUCTION: Gilles de la Tourette syndrome (GTS) is a childhood onset disorder characterised by the presence of motor and vocal tics. The guidelines of both the American Academy of Neurology (AAN) as well as the European Society for the Study of Tourette Syndrome (ESSTS) recommend behavioural therapy and pharmacotherapy, mainly with antipsychotics, as first line treatments for tics. In spite of these well-established therapeutic approaches, a significant number of patients are dissatisfied because of insufficient tic reduction or intolerable side effects. Previous studies have suggested that cannabis-based medicine (CBM) might be an alternative treatment in these patients. MATERIAL AND METHODS: Two reviewers (KS, NS) searched the electronic database of PubMed on 1 July, 2021 for relevant studies using the search terms: ('Tourette syndrome' [MeSH Terms] OR 'Gilles de la Tourette syndrome' [MeSH Terms] OR 'tic disorders' [MeSH Terms] OR 'tics' [MeSH Terms] OR 'tic disorders'[Title/Abstract]) AND ('cannabis-based medicine' [Title/Abstract] OR 'cannabis' [Title/Abstract] OR 'dronabinol' [Title/Abstract] OR 'nabiximols' [Title/Abstract] OR 'tetrahydrocannabinol' [Title/Abstract] OR 'THC' [Title/Abstract] OR 'cannabidiol' [Title/Abstract], limit: 'humans'. These studies were further reviewed for additional relevant citations. The titles and abstracts of the studies obtained through this search were examined by two reviewers (KS, NS) in order to determine article inclusion. Discrepancies were addressed by the reviewers through discussion and eventually conversation with the senior reviewer (KMV). RESULTS: Although the amount of evidence supporting the use of CBM in GTS is growing, the majority of studies are still limited to case reports, case series, and open uncontrolled studies. To date, only two small randomised controlled trials (RCTs) using tetrahydrocannabinol (THC, dronabinol) have been published demonstrating the safety and efficacy of this intervention in the treatment of tics in patients with GTS. On the other hand, another RCT with Lu AG06466 (formerly known as ABX-1431), a modulator of endocannabinoid neurotransmission, has failed to prove effective in the therapy of GTS. Accordingly, under the guidelines of both the ESSTS and the AAN, treatment with CBM is categorised as an experimental intervention that should be applied to patients who are otherwise treatment-resistant. CONCLUSIONS: Increasing evidence suggests that CBM is efficacious in the treatment of tics and psychiatric comorbidities in patients with GTS. The results of ongoing larger RCTs, such as CANNA-TICS (ClinicalTrials.gov Identifier: NCT03087201), will further clarify the role of CBM in the treatment of patients with GTS.

Speechlessness in Gilles de la Tourette Syndrome: Cannabis-Based Medicines Improve Severe Vocal Blocking Tics in Two Patients.

We report the cases of two young German male patients with treatment-resistant Tourette syndrome (TS), who suffer from incapacitating stuttering-like speech disfluencies caused by vocal blocking tics and palilalia. Case 1: a 19-year old patient received medical cannabis at a dose of 1 × 0.1 g cannabis daily. Case 2: a 16-year old patient initially received dronabinol at a maximum dose of 22.4-33.6 mg daily. Both treatments provided significant symptom improvement of vocal blocking tics as well as of comorbid conditions and were well tolerated. Thus, cannabis-based medicine appears to be effective in treatment-resistant TS patients with vocal blocking tics.

[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.

Effects of Chinese herbal medicine Ningdong granule on regulating dopamine (DA)/serotonin (5-TH) and gamma-amino butyric acid (GABA) in patients with Tourette syndrome.

Many studies have indicated that a variety of neurotransmitters are implicated in the pathophysiology of Tourette syndrome (TS), including dopamine (DA), serotonin (5-TH), homovanillic acid (HVA), and gamma-amino butyric acid (GABA). Our previous studies found that Ningdong granule (NDG) is effective on a rat model with TS. NDG can regulate the metabolic disturbance of DA, 5-TH and HVA in the rat brain. However, the mechanisms of NDG in patients with TS are still not clear. To further evaluate the efficiency, safety, and possible mechanisms of NDG, a randomized and double-blind study was carried out. One hundred and twenty patients with TS were enrolled in this study, that were randomly divided into 4 groups (NDG group, Haloperidol (Hal) group, NDG + Hal group and Control group). First, the efficiency of NDG was assessed using the Yale Global Tic Severity Score (YGTSS). Second, the concentration of DA, HVA, 5-TH, 5-hydroxyindoleacetic acid (5-HIAA) and GABA in sera were tested by ELISA. In addition, the influence of NDG on liver and renal function was recorded. We found that NDG could ameliorate tics significantly according the YGTSS score. The concentration of HVA and GABA were increased after treatment with NDG. Furthermore, we found that there was no liver or renal damage in children treated with NDG. We also found that the NDG + Hal group was more effective and safe compared with other groups. In conclusion, the current study indicates that NDG might be effective on patients with TS by regulating dopamine (DA)/serotonin (5-TH) and gamma-amino butyric acid (GABA).