Ahmad S. Kanaan

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 &ggr;-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.

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.

Significant Tic Reduction in An Otherwise Treatment-Resistant Patient with Gilles de la Tourette Syndrome Following Treatment with Nabiximols

Early anecdotal reports and preliminary studies suggested that cannabinoid-based medicines such as delta-9-tetrahydrocannabinol (THC) are effective in the treatment of Gilles de la Tourette syndrome (TS). We report a single case study of a patient with otherwise treatment-resistant TS successfully treated with nabiximols. Our patient was a 22-year-old male suffering from severe and complex TS. Treatment with nabiximols was commenced at a dose of 1 puff/day (= 100 μL containing 2.7 mg THC and 2.5 mg cannabidiol (CBD)) and slowly increased up to a dosage of 3 × 3 puffs/day (= 24.3 mg THC and 22.5 mg CBD). Several clinical measures for tics, premonitory urges, and global impairment were acquired before and after two weeks of treatment. Treatment with nabiximols resulted in major improvements of both tics and premonitory urges, but also global impairment and health-related quality of life according to all used measurements without causing relevant adverse effects. Our results provide further evidence that treatment with nabiximols may be effective in the treatment of patients with TS. Given the positive response exhibited by the patient highlighted in this report, further investigation of the effects of nabiximols is proposed on a larger group of patients in a clinical trial setting.

Brain Connections – Resting State fMRI Functional Connectivity

With the introduction of electroencephalography (EEG) in 1930, researchers began to explore spontaneous activity in the brain by recording the individual, independently of any task. Subsequently, evoked potential studies, where electrical potentials were recorded at the onset of a stimulus, marked a milestone in brain research. Utilizing such methods coupled with experimental psychology, researchers were able to explore task-related brain activity. These early methods paved the way for new approaches to exploring brain function.

Cannabinoid-based medicines for the treatment of Gilles de la Tourette syndrome

Abstract Gilles de la Tourette syndrome (GTS) is a common psychiatric movement disorder that is characterized by motor and vocal tics and a strong association with comorbid obsessive compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD). On a systems level, the primary abnormality has been shown to be related to dopaminergic neurotransmission within cortico-striato-thalamo-cortical (CSTC) circuits, though a complete picture of the disorder’s pathophysiology remains elusive. Clinically, the therapeutic spectrum for GTS has been expanding over the last decade, though current treatment strategies are often ineffective and unsatisfactory. As a result, there is an urgent need for uncovering novel treatment strategies that could ameliorate both motor and behavioral symptoms, are more effective in treatment resistant patients, and cause less adverse effects. Early anecdotal reports have provided evidence that patients with GTS choose cannabinoids as a form of self-medication. As a result, several groups began investigating the role of the endocannabinoid system in GTS pathophysiology and cannabinoid based medicines as a form of treatment. Currently, there are a limited number of studies suggesting that oral Δ9-tetrahydrocannabinol (THC) is effective in the treatment of tics and behavioral comorbidities. Consequently, the role of the endocannabinoid system in GTS pathophysiology remains speculative, as further investigation on the role of the endocannabinoid system in GTS is needed. In this chapter, we review the state of the art and highlight studies that explored the role of the endocannabinoid system and cannabinoids based medicine in GTS.