CANNA-TICS: Efficacy and safety of oral treatment with nabiximols in adults with chronic tic disorders - Results of a prospective, multicenter, randomized, double-blind, placebo controlled, phase IIIb superiority study.

Preliminary data suggest that cannabis-based medicines might be a promising new treatment for patients with Tourette syndrome (TS)/chronic tic disorders (CTD) resulting in an improvement of tics, comorbidities, and quality of life. This randomized, multicenter, placebo-controlled, phase IIIb study aimed to examine efficacy and safety of the cannabis extract nabiximols in adults with TS/CTD (n = 97, randomized 2:1 to nabiximols:placebo). The primary efficacy endpoint was defined as a tic reduction of ≥ 25% according to the Total Tic Score of the Yale Global Tic Severity Scale after 13 weeks of treatment. Although a much larger number of patients in the nabiximols compared to the placebo group (14/64 (21·9%) vs. 3/33 (9·1%)) met the responder criterion, superiority of nabiximols could formally not be demonstrated. In secondary analyses, substantial trends for improvements of tics, depression, and quality of life were observed. Additionally exploratory subgroup analyses revealed an improvement of tics in particular in males, patients with more severe tics, and patients with comorbid attention deficit/hyperactivity disorder suggesting that these subgroups may benefit better from treatment with cannabis-based medication. There were no relevant safety issues. Our data further support the role of cannabinoids in the treatment of patients with chronic tic disorders.

European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part III: pharmacological treatment.

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements.

Electro-Myo-Stimulation Induced Tic Exacerbation - Increased Tendencies for the Formation of Perception-Action Links in Tourette Syndrome.

Background: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder defined by motor and phonic tics. Sensory stimuli can trigger tics, which suggests that GTS is a disorder of perception-action processing rather than a pure motor disorder. Case report: We describe a GTS patient that developed exacerbation of tics after transcutaneous electro-myo-stimulation (YGTSS pre-EMS 27/100, post-EMS 69/100). Discussion: If behaviorally irrelevant stimuli exacerbate tics, there might be a high readiness of the motor system to respond to any stimulus in these patients. In addition to tighter binding between previously established perception-action links, the likelihood for the formation of automatic perception-action links might also be higher in GTS.

Harmonic expectancy violations elicit not-just-right-experiences: a paradigm for investigating obsessive-compulsive characteristics?

Obsessive-compulsive disorder (OCD)-like symptoms are commonly associated with sensations of incompleteness and not-just-right experiences (NJRE). Although NJRE have gained much attention in recent years, most studies have not gone beyond a description of their phenomenology and prevalence also in healthy adults. We applied a validated harmonic expectancy violation paradigm to experimentally investigate NJRE evoked by deviant auditory perceptions. We assessed reaction times (RT) to harmonic and disharmonic chord sequences as well as their emotional appraisal in 64 healthy young adults. The participants clearly indicated disharmonic chord sequences as sounding not-just-right and incomplete and rated them as unpleasant, arousing, and irritating. The RT to disharmonic chord sequences was significantly shorter than the RT to harmonic chord sequences. This effect tended to be greater in those participants who reported stronger general experiences of incompleteness as an underlying core dimension of OCD-like symptoms. In addition, general experience of incompleteness was correlated to the difference between RT to harmonic and that to disharmonic chord sequences, indicating that the intensity of general experience of incompleteness was associated with a more readily activated processing of the deviant auditory perceptions.

Brain iron deposition fingerprints in Parkinson's disease and progressive supranuclear palsy.

It can be difficult to clinically distinguish between classical Parkinson's disease (PD) and progressive supranuclear palsy. Previously, there have been no biomarkers that reliably allow this distinction to be made. We report that an abnormal brain iron accumulation is a marker for ongoing neurodegeneration in both conditions, but the conditions differ with respect to the anatomical distribution of these accumulations. We analyzed quantitative T2' maps as markers of regional brain iron content from PD and progressive supranuclear palsy patients and compared them to age-matched control subjects. T2-weighted and T2*-weighted images were acquired in 30 PD patients, 12 progressive supranuclear palsy patients, and 24 control subjects at 1.5 Tesla. Mean T2' values were determined in regions-of-interest in the basal ganglia, thalamus, and white matter within each hemisphere. The main findings were shortened T2' values in the caudate nucleus, globus pallidus, and putamen in progressive supranuclear palsy compared to PD patients and controls. A stepwise linear discriminant analysis allowed progressive supranuclear palsy patients to be distinguished from PD patients and the healthy controls. All progressive supranuclear palsy patients were correctly classified. No progressive supranuclear palsy patient was classified as a healthy control, no healthy controls were incorrectly classified as having progressive supranuclear palsy, and only 6.7% of the PD patients were incorrectly classified as progressive supranuclear palsy. Regional decreases of T2' relaxation times in parts of the basal ganglia reflecting increased brain iron load in these areas are characteristic for progressive supranuclear palsy but not PD patients.

The human dorsal premotor cortex facilitates the excitability of ipsilateral primary motor cortex via a short latency cortico-cortical route.

In non-human primates, invasive tracing and electrostimulation studies have identified strong ipsilateral cortico-cortical connections between dorsal premotor- (PMd) and the primary motor cortex (M1(HAND) ). Here, we applied dual-site transcranial magnetic stimulation (dsTMS) to left PMd and M1(HAND) through specifically designed minicoils to selectively probe ipsilateral PMd-to-M1(HAND) connectivity in humans. A suprathreshold test stimulus (TS) was applied to M1(HAND) producing a motor evoked potential (MEP) of about 0.5 mV in the relaxed right first dorsal interosseus muscle (FDI). A subthreshold conditioning stimulus (CS) was given to PMd 2.0-5.2 ms after the TS at intensities of 50-, 70-, or 90% of TS. The CS to PMd facilitated the MEP evoked by TS over M1(HAND) at interstimulus intervals (ISI) of 2.4 or 2.8 ms. There was a second facilitatory peak at ISI of 4.4 ms. PMd-to-M1(HAND) facilitation did not change as a function of CS intensity. Even at higher intensities, the CS alone failed to elicit a MEP or a cortical silent period in the pre-activated FDI, excluding a direct spread of excitation from PMd to M1(HAND). No MEP facilitation was present while CS was applied rostrally over lateral prefrontal cortex. Together our results indicate that our dsTMS paradigm probes a short-latency facilitatory PMd-to-M1(HAND) pathway. The temporal pattern of MEP facilitation suggests a PMd-to-M1(HAND) route that targets intracortical M1(HAND) circuits involved in the generation of indirect corticospinal volleys. This paradigm opens up new possibilities to study context-dependent intrahemispheric PMd-to-M1(HAND) interactions in the intact human brain.

Observing repetitive finger movements modulates response times of auditorily cued finger movements.

Our motor and perceptual representations of actions seem to be intimately linked and the human mirror neuron system (MNS) has been proposed as the mediator. In two experiments, we presented biological or non-biological movement stimuli that were either congruent or incongruent to a required response prompted by a tone. When the tone occurred with the onset of the last movement in a series, i.e., it was perceived during the movement presentation, congruent biological stimuli resulted in faster reaction times than congruent non-biological stimuli. The opposite was observed for incongruent stimuli. When the tone was presented after visual movement stimulation, however, no such interaction was present. This implies that biological movement stimuli only affect motor behaviour during visual processing but not thereafter. These data suggest that the MNS is an "online" system; longstanding repetitive visual stimulation (Experiment 1) has no benefit in comparison to only one or two repetitions (Experiment 2).