Randomized double-blind sham-controlled trial of thalamic versus GPi stimulation in patients with severe medically refractory Gilles de la Tourette syndrome.

BACKGROUND: There are still no sufficient data regarding the use of deep brain stimulation (DBS) in Gilles de la Tourette syndrome (GTS) and no agreement on optimal target. OBJECTIVE: To compare efficacy and safety of bilateral DBS of thalamus (centromedian-ventro-oral internus, CM-Voi) versus posteroventral lateral globus pallidus internus (pvl GPi)) versus sham stimulation, and baseline in severe medically refractory GTS. METHODS: In this randomized double-blind sham stimulation-controlled trial (RCT), 10 patients (3 women, mean age = 29.4 ± 10.2 SD, range 18-47) underwent three blinded periods each lasting three months including (i) sham, (ii) pvl GPi (on-GPi), and (iii) thalamic stimulation (on-thal) followed by an open uncontrolled long-term follow-up (up to 9 years) with individually determined target and stimulation settings. RESULTS: Nine patients completed the RCT. At group level, on-GPi - but not on-thal - resulted in a significant tic reduction compared to baseline, but had no effect on premonitory urges and psychiatric comorbidities. Direct comparisons of targets resulted in inconsistent or negative (compared to sham) findings. During follow-up, we found no improvement of tics, comorbidities, and quality of life at group level, however, single patients benefitted continuously from thalamic DBS. At last follow-up 89.9 months (mean) after surgery, 50% of patients had discontinued DBS. Hardware infections occurred in 3/10 patients. CONCLUSION: Our data suggest that the initial effect of pvl GPi DBS is superior to thalamic (CM-Voi) DBS. While half of the patients discontinued treatment, single patients benefitted from thalamic DBS even after years. It is likely that outcome is influenced by various factors beyond the mere change in tic severity.

Author Correction: Serotonin transporter binding is increased in Tourette syndrome with Obsessive Compulsive Disorder.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Serotonin transporter binding is increased in Tourette syndrome with Obsessive Compulsive Disorder.

While the importance of the serotonergic system in obsessive compulsive disorder (OCD) is well established, its role in Tourette syndrome (TS) is uncertain. Particularly in TS patients with comorbid OCD (TS + OCD), decreased serotonin transporter (SERT) binding has been suggested. Here, we investigated for the first time SERT binding in TS patients with and without OCD (TS - OCD) compared to both healthy controls (HC) and OCD patients as well as the influence of escitalopram using the potent SERT imaging ligand [123I]2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([123I]ADAM) and single-photon emission tomography (SPECT). We included 33 adult subjects (10 HC, 10 TS - OCD, 8 TS + OCD and 5 OCD). In patients with OCD and TS + OCD [123I]ADAM SPECT was repeated after 12-16 weeks treatment with escitalopram. SERT binding was normal in patients with OCD and TS - OCD, but significantly increased (p < 0.05) in those with TS + OCD, particularly in caudate and midbrain compared to both HC and TS - OCD. Treatment with escitalopram resulted in a significant overall reduction in SERT binding (range, 19 to 79%, p values between 0.0409 and <0.0001) without any correlation with clinical improvement. Our results provide further evidence that alterations in the serotonergic system in TS are related to comorbid OCD and do not represent the primary cause of the disease.

Altered modulation of intracortical excitability during movement preparation in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a neuropsychiatric disorder in which cortical disinhibition has been proposed as a pathophysiological mechanism involved in the generation of tics. Tics are typically reduced during task performance and concentration. How this task-dependent reduction of motor symptoms is represented in the brain is not yet understood. The aim of the current research was to study motorcortical excitability at rest and during the preparation of a simple motor task. Transcranial magnetic stimulation was used to examine corticospinal excitability, short-interval intracortical inhibition and intracortical facilitation in a group of 11 patients with Gilles de la Tourette syndrome and age-matched healthy controls. Parameters of cortical excitability were evaluated at rest and at six points in time during the preparation of a simple finger movement. Patients with Gilles de la Tourette syndrome displayed significantly reduced short-interval intracortical inhibition at rest, while no differences were apparent for unconditioned motor evoked potential or intracortical facilitation. During the premovement phase, significant differences between groups were seen for single pulse motor evoked potential amplitudes and short-interval intracortical inhibition. Short-interval intracortical inhibition was reduced in the early phase of movement preparation (similar to rest) followed by a transition towards more inhibition. Subsequently modulation of short-interval intracortical inhibition was comparable to controls, while corticospinal recruitment was reduced in later phases of movement preparation. The present data support the hypothesis of motorcortical disinhibition in Gilles de la Tourette syndrome at rest. During performance of a motor task, patients start from an abnormally disinhibited level of short-interval intracortical inhibition early during movement preparation with subsequent modulation of inhibitory activity similar to healthy controls. We hypothesize that while at rest, abnormal subcortical inputs from aberrant striato-thalamic afferents target the motor cortex, during motor performance, motor cortical excitability most likely underlies top-down control from higher motor areas and prefrontal cortex, which override these abnormal subcortical inputs to guarantee adequate behavioural performance.

Immunophenotyping in Tourette syndrome--a pilot study.

BACKGROUND AND PURPOSE: The cause of Tourette syndrome (TS) is not precisely known, although several lines of evidence point at an involvement of the immune system in its pathogenesis. RESULTS: Here, we report the results of a pilot study investigating frequently analysed lymphocyte surface markers in 20 adult patients with TS (16 males; 37.3 +/- 15.8 years) and 20 matched controls (16 males; 37.5 +/- 15.3 years). Statistical analysis revealed significant differences for the investigated lymphocyte surface markers. The difference in CD69+/CD22+-B cells (23.0 +/- 10.5% vs. 13.1 +/- 6.1%; P = 0.001) and in CD95+/CD4+-T cells (41.5 +/- 12.1% vs. 24.6 +/- 10.0%; P = 0.0001) was still significant after Bonferroni-Holm correction. CONCLUSION: Our preliminary data indicate that TS may be associated with an increased peripheral immune activity.

[The benzamides tiapride, sulpiride, and amisulpride in treatment for Tourette's syndrome]. / Die Benzamide Tiaprid, Sulpirid und Amisulprid in der Therapie des Tourette-Syndroms. Eine Standortbestimmung.

The treatment of Tourette's syndrome is a challenge. Dopamine receptor antagonists are the drugs of first choice for the treatment of tics. Because large controlled trials are lacking, there is no consensus about which of the different neuroleptic drugs should be preferred. In Germany, tiapride seems to be used most often for the treatment of tics in children - although only one small controlled trial has been performed on it till now. In adults, other dopamine receptor antagonists such as risperidone, pimozide, and sulpiride seem to be more effective than tiapride. Today it is unknown whether new atypical neuroleptic drugs including the benzamide amisulpride are more effective than the older benzamides tiapride and sulpiride.

[The endogenous cannabinoid system. Therapeutic implications for neurologic and psychiatric disorders]. / Das endogene Cannabinoidsystem. Therapeutische Implikationen der Cannabinoide bei neurologisch-psychiatrischen Erkrankungen.

For about 5,000 years, cannabis has been used as a therapeutic agent. There has been growing interest in the medical use of cannabinoids. This is based on the discovery that cannabinoids act with specific receptors (CB1 and CB2). CB1 receptors are located in specific brain areas (e.g. cerebellum, basal ganglia, and hippocampus) and CB2 receptors on cells of the immune system. Endogenous ligands of the cannabinoid receptors were also discovered (e.g. anandamids). Many physiologic processes are modulated by the two subtypes of cannabinoid receptor: motor functions, memory, appetite, and pain. These innovative neurobiologic/pharmacologic findings could possibly lead to the use of synthetic and natural cannabinoids as therapeutic agents in various areas. Until now, cannabinoids were used as antiemetic agents in chemotherapy-induced emesis and in patients with HIV-wasting syndrome. Evidence suggests that cannabinoids may prove useful in some other diseases, e.g. movement disorders such as Gilles de la Tourette's syndrome, multiple sclerosis, and pain. These new findings also explain the acute adverse effects following cannabis use.

Treatment of Tourette's syndrome with Delta 9-tetrahydrocannabinol (THC): a randomized crossover trial.

Anecdotal reports in Tourette's syndrome (TS) have suggested that marijuana (cannabis sativa) and delta-9-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive ingredient of marijuana, reduce tics and associated behavioral disorders. We performed a randomized double-blind placebo-controlled crossover single-dose trial of Delta(9)-THC (5.0, 7.5 or 10.0 mg) in 12 adult TS patients. Tic severity was assessed using a self-rating scale (Tourette's syndrome Symptom List, TSSL) and examiner ratings (Shapiro Tourette's syndrome Severity Scale, Yale Global Tic Severity Scale, Tourette's syndrome Global Scale). Using the TSSL, patients also rated the severity of associated behavioral disorders. Clinical changes were correlated to maximum plasma levels of THC and its metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). Using the TSSL, there was a significant improvement of tics (p=0.015) and obsessive-compulsive behavior (OCB) (p = 0.041) after treatment with Delta(9)-THC compared to placebo. Examiner ratings demonstrated a significant difference for the subscore "complex motor tics" (p = 0.015) and a trend towards a significant improvement for the subscores "motor tics" (p = 0.065), "simple motor tics" (p = 0.093), and "vocal tics" (p = 0.093). No serious adverse reactions occurred. Five patients experienced mild, transient side effects. There was a significant correlation between tic improvement and maximum 11-OH-THC plasma concentration. Results obtained from this pilot study suggest that a single-dose treatment with Delta(9)-THC is effective and safe in treating tics and OCB in TS. It can be speculated that clinical effects may be caused by 11-OH-THC. A more long-term study is required to confirm these results.

Altered inhibition of motor responses in Tourette Syndrome and Obsessive-Compulsive Disorder.

OBJECTIVES: The Gilles de la Tourette Syndrome (TS) and Obsessive Compulsive Disorder (OCD) have been shown to display impaired cognitive and motor inhibition. This study investigated inhibitory mechanisms of motor responses in order to expand the understanding of sensorimotor integration processes in both disorders. We hypothesized that both patient groups would display altered frontal inhibitory activity. MATERIAL AND METHODS: To this end event-related brain potentials (ERPs) were recorded in a STOP-paradigm in groups of TS and OCD patients and in a control group. The paradigm required the execution of a motor response after a "go" signal was given and the occasional suppression of this response after a second "stop" signal occurred. RESULTS: Behavioral parameters and Lateralized Readiness Potential (LRP) confirmed that both patient groups were well able to initiate motor responses. "Go" and "stop" stimuli elicited an enhanced frontal negative activity in both patient groups. In addition, "stop" stimuli were associated with a frontal shift of the NoGo-Anteriorization (NGA) in the TS group but not in the OCD group. CONCLUSIONS: The data are interpreted to indicate altered frontal inhibitory functions. Similarities and dissimilarities between the findings for TS and OCD are discussed with respect to other pathophysiologic aspects of the disorders.

Electrophysiological measures and dual-task performance in Tourette syndrome indicate deficient divided attention mechanisms.

Tourette syndrome has been associated with impairments of attentional functions such as distractability, even in subjects without co-morbid attention deficit hyperactivity disorder. Based on the results of earlier research we hypothesized that Tourette syndrome patients might employ altered control mechanisms of attentional processes and have concurrent difficulties in allocating their attentional resources among competing tasks. Event-related brain potentials (ERPs) were recorded in a group of Tourette syndrome patients and in a matched control group during a dual task experiment. This experiment required the simultaneous detection of visual and auditory target stimuli which were manipulated to yield two different difficulty levels each of which were varied orthogonally. The behavioural parameters confirmed the intended performance differences between difficult-to-detect targets and easy-to-detect targets. This was paralleled by lower amplitudes and longer latencies of the corresponding P3b-ERP subcomponents. Although Tourette syndrome patients were unimpaired in overall performance they showed an increased interference of visual task demands with auditory target perception. In parallel they also exhibited a reduced amplitude of the P3b component to auditory targets. The findings show that Tourette syndrome patients are not generally impaired in their dual task performance. The allocation of attentional resources to competing tasks however, is altered. We speculate that this may be related to deficient inhibitory functions.

Influence of treatment of Tourette syndrome with delta9-tetrahydrocannabinol (delta9-THC) on neuropsychological performance.

Previous studies have suggested that marijuana (cannabis sativa) and delta-9-tetrahydrocannabinol (delta9-THC), the major psychoactive ingredient of marijuana, are effective in the therapy of tics and associated behavioral disorders in Tourette Syndrome (TS). Because there is also evidence that cannabis sativa may cause cognitive impairment in healthy users, we performed a randomized double-blind placebo-controlled crossover trial for delta9-THC in 12 adult TS patients to investigate whether treatment of TS with a single dose of delta9-THC at 5.0 to 10.0 mg causes significant side effects on neuropsychological performance. Using a variety of neuropsychological tests, we found no significant differences after treatment with delta9-THC compared to placebo treatment in verbal and visual memory, reaction time, intelligence, sustained attention, divided attention, vigilance, or mood. Only when using the Symptom Checklist 90-R (SCL-90-R) did our data provide evidence for a deterioration of obsessive-compulsive behavior (OCB) and a trend towards an increase in phobic anxiety. However, these results should be interpreted with caution as SCL-90-R has known limitations on measuring OCB. We suggest that the increase in phobic anxiety is mainly due to the fact that a single-dose treatment rules out the possibility of administering the dosage slowly. In contrast to results obtained from healthy marijuana users, a single-dose treatment with delta9-THC in patients suffering from TS does not cause cognitive impairment. We therefore suggest that further investigations should concentrate on the effects of a longer-term therapy of TS with delta9-THC.

[The importance of the endogenous cannabinoid system in various neuropsychiatric disorders]. / Die Bedeutung des endogenen Cannabinoidsystems bei verschiedenen neuropsychiatrischen Erkrankungen.

The endogenous cannabinoid system was first described in 1988. There are two specific receptors, the CB2-receptor, located in the lymphatic system (spleen, lymphocytes), and the CB1-receptor occurring predominantly in the central nervous system. The CB1-receptor shows a distinct distribution in the CNS with a very high density in the cerebellum, the basal ganglia and in the hippocampus. In 1992 endogenous ligands of the cannabinoid system were discovered for the first time (e.g. anandamide and 2-arachidonylglycerol). The physiological role of these arachidonic acid derivates is still unclear. Implications of these recent discoveries for the Gilles de la Tourette syndrome, ischaemic brain lesions, schizophrenic psychoses and opiate drug dependence are described. A dysregulation in the endogenous cannabinoid/anandamide system could possibly play an import role in the etiology of Gilles de la Tourette syndrome and schizophrenic psychoses; administration of cannabinoids affects the symptoms of the Gilles de la Tourette syndrome positively, whereas cannabinoids probably have rather negative effects in schizophrenic psychoses. In ischaemic brain lesions cannabinoids seem to have a neuroprotective effect; they appear to minimize the extent of a lesion by reduction of glutamate release. Additionally the meaning of the endogenous cannabinoid system for the development of opioid drug dependency is discussed and interactions between the endogenous opioid system and the endogenous cannabainoid system are pointed out. This is of interest since it could be shown in animal experiments that the absence of CB1 receptors reduces the positive reinforcement of opiate administration.

Dopamine transporter binding in Gilles de la Tourette syndrome.

Preliminary studies in patients with Gilles de la Tourette syndrome (TS) provided evidence of presynaptic dopaminergic dysfunction, demonstrating increased reuptake sites. Therefore we investigated striatal dopamine transporter binding in 12 TS patients and 9 control subjects using single photon emission computed tomography and 123I-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane. In TS patients we found significantly higher relative striatal activity ratios (mean +/- SD 12.33 +/- 3.58) than in controls (9.36 +/- 1.35, P< 0.05). Only five patients, however, showed striatum/occipital cortex ratios more than 2 SD above the normal means. Seven patients had activity ratios within the average ratio of the control group plus 2 SD. Regarding the relationship between clinical parameters and striatum/occipital cortex ratios, we found an association between binding ratios and "self-injurious behavior" and "lack of impulse control." This study corroborates previous data suggesting an involvement of the dopaminergic system in TS pathology. Our results demonstrate that an increase in dopamine transporter capacity is a possible but not a necessary alteration, and which appears more likely when self-injurious behavior and lack of impulse control are associated.

Dopamine D2 receptor imaging in Gilles de la Tourette syndrome.

OBJECTIVES: To examine postsynaptic dopamine D2 receptors in Tourette syndrome (TS). MATERIAL AND METHODS: Seventeen patients and a control group were investigated using single photon emission computed tomography (SPECT) and iodobenzamide (123I-IBZM). RESULTS: In neuroleptic treated patients (n = 7) 123I-IBZM-binding was significantly reduced compared to both normal controls (P < 0.0001) and unmedicated patients (P < 0.001). In unmedicated patients (n = 10) mean binding ratio did not differ from that of control group. Patients in advanced stages of the disease, however, revealed significantly reduced relative striatal binding compared to patients in the early stages (P<0.005) and normal controls (P<0.0001). CONCLUSION: The results lend further support to the hypothesis that the dopamine receptor is involved in TS pathology. During the natural course of the disease tics often improve in early adulthood. It is suggested that this spontaneous recovery from tics may be associated with reduced receptor binding capacity.

A frequent polymorphism in the coding exon of the human cannabinoid receptor (CNR1) gene.

The central cannabinoid receptor (CB1) mediates the pharmacological activities of cannabis, the endogenous agonist anandamide and several synthetic agonists. The cloning of the human cannabinoid receptor (CNR1) gene facilitates molecular genetic studies in disorders like Gilles de la Tourette syndrome (GTS), obsessive compulsive disorder (OCD), Parkinsons disease, Alzheimers disease or other neuro psychiatric or neurological diseases, which may be predisposed or influenced by mutations or variants in the CNR1 gene. We detected a frequent silent mutation (1359G-->A) in codon 453 (Thr) of the CNR1 gene that turned out to be a common polymorphism in the German population. Allele frequencies of this polymorphism are 0.76 and 0.24, respectively. We developed a simple and rapid polymerase chain reaction (PCR)-based assay by artificial creation of a Msp I restriction site in amplified wild-type DNA (G-allele), which is destroyed by the silent mutation (A-allele). The intragenic CNR1 polymorphism 1359(G/A) should be useful for association studies in neuro psychiatric disorders which may be related to anandamide metabolism disturbances.