Pathological glutamatergic neurotransmission in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome is a hereditary, neuropsychiatric movement disorder with reported abnormalities in the neurotransmission of dopamine and γ-aminobutyric acid (GABA). Spatially focalized alterations in excitatory, inhibitory and modulatory neurochemical ratios within specific functional subdivisions of the basal ganglia, may lead to the expression of diverse motor and non-motor features as manifested in Gilles de la Tourette syndrome. Current treatment strategies are often unsatisfactory thus provoking the need for further elucidation of the underlying pathophysiology. In view of (i) the close spatio-temporal synergy exhibited between excitatory, inhibitory and modulatory neurotransmitter systems; (ii) the crucial role played by glutamate (Glu) in tonic/phasic dopaminergic signalling; and (iii) the interdependent metabolic relationship exhibited between Glu and GABA via glutamine (Gln); we postulated that glutamatergic signalling is related to the pathophysiology of Gilles de la Tourette syndrome. As such, we examined the neurochemical profile of three cortico-striato-thalamo-cortical regions in 37 well-characterized, drug-free adult patients and 36 age/gender-matched healthy control subjects via magnetic resonance spectroscopy at 3 T. To interrogate the influence of treatment on metabolite concentrations, spectral data were acquired from 15 patients undergoing a 4-week treatment with aripiprazole. Test-retest reliability measurements in 23 controls indicated high repeatability of voxel localization and metabolite quantitation. We report significant reductions in striatal concentrations of Gln, Glu + Gln (Glx) and the Gln:Glu ratio, and thalamic concentrations of Glx in Gilles de la Tourette syndrome in comparison to controls. ON-treatment patients exhibited no significant metabolite differences when compared to controls but significant increases in striatal Glu and Glx, and trends for increases in striatal Gln and thalamic Glx compared to baseline measurements. Multiple regression analysis revealed a significant negative correlation between (i) striatal Gln and actual tic severity; and (ii) thalamic Glu and premonitory urges. Our results indicate that patients with Gilles de la Tourette syndrome exhibit an abnormality in the flux of metabolites in the GABA-Glu-Gln cycle, thus implying perturbations in astrocytic-neuronal coupling systems that maintain the subtle balance between excitatory and inhibitory neurotransmission within subcortical nuclei.

Aripiprazole Improves Associated Comorbid Conditions in Addition to Tics in Adult Patients with Gilles de la Tourette Syndrome.

Gilles de la Tourette Syndrome (GTS) is characterized by motor and vocal tics, as well as associated comorbid conditions including obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder (ADHD), depression, and anxiety which are present in a substantial number of patients. Although randomized controlled trials including a large number of patients are still missing, aripiprazole is currently considered as a first choice drug for the treatment of tics. The aim of this study was to further investigate efficacy and safety of aripiprazole in a group of drug-free, adult patients. Specifically, we investigated the influence of aripiprazole on tic severity, comorbidities, premonitory urge (PU), and quality of life (QoL). Moreover, we were interested in the factors that influence a patient's decision in electing for-or against- pharmacological treatment. In this prospective uncontrolled open-label study, we included 44 patients and used a number of rating scales to assess tic severity, PU, comorbidities, and QoL at baseline and during treatment with aripiprazole. Eighteen out of fortyfour patients decided for undergoing treatment for their tics with aripiprazole and completed follow-up assessments after 4-6 weeks. Our major findings were (1) aripiprazole resulted in significant reduction of tics, but did not affect PU; (2) aripiprazole significantly improved OCD and showed a trend toward improvement of other comorbidities including depression, anxiety, and ADHD; (3) neither severity of tics, nor PU or QoL influenced patients' decisions for or against treatment of tics with aripiprazole; instead patients with comorbid OCD tended to decide in favor of, while patients with comorbid ADHD tended to decide against tic treatment; (4) most frequently reported adverse effects were sleeping problems; (5) patients' QoL was mostly impaired by comorbid depression. Our results suggest that aripiprazole may improve associated comorbid conditions in addition to tics in patients with GTS. It can be hypothesized that these beneficial effects are related to aripiprazole's adaptive pharmacological profile, which exhibits an influence on the dopaminergic as well as a number of other neurotransmitter systems. For the first time, our data provide evidence that patients' decision making process for or against medical treatment is influenced by other factors than tic severity and QoL.

TS-EUROTRAIN: A European-Wide Investigation and Training Network on the Etiology and Pathophysiology of Gilles de la Tourette Syndrome.

Gilles de la Tourette Syndrome (GTS) is characterized by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency, and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), thus providing an excellent model for the exploration of shared etiology across disorders. TS-EUROTRAIN (FP7-PEOPLE-2012-ITN, Grant Agr.No. 316978) is a Marie Curie Initial Training Network (http://ts-eurotrain.eu) that aims to elucidate the complex etiology of the onset and clinical course of GTS, investigate the neurobiological underpinnings of GTS and related disorders, translate research findings into clinical applications, and establish a pan-European infrastructure for the study of GTS. This includes the challenges of (i) assembling a large genetic database for the evaluation of the genetic architecture with high statistical power; (ii) exploring the role of gene-environment interactions including the effects of epigenetic phenomena; (iii) employing endophenotype-based approaches to understand the shared etiology between GTS, OCD, and ADHD; (iv) establishing a developmental animal model for GTS; (v) gaining new insights into the neurobiological mechanisms of GTS via cross-sectional and longitudinal neuroimaging studies; and (vi) partaking in outreach activities including the dissemination of scientific knowledge about GTS to the public. Fifteen partners from academia and industry and 12 PhD candidates pursue the project. Here, we aim to share the design of an interdisciplinary project, showcasing the potential of large-scale collaborative efforts in the field of GTS. Our ultimate aims are to elucidate the complex etiology and neurobiological underpinnings of GTS, translate research findings into clinical applications, and establish Pan-European infrastructure for the study of GTS and associated disorders.