Ahmad Seif Kanaan | Elemental, neurochemical and network-based analysis of the pathophysiological mechanisms of Tourette syndrome

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder fundamentally characterized by tics and putative abnormalities in the neurotransmission of dopamine and GABA. As current treatment strategies are often unsatisfactory, there is an urgent need in further elucidating the nature of GTS pathophysiology to accelerate the drug development process. Exercising a hypothesis driven approach, we employed multi-parametric quantitative MRI techniques to investigate GTS pathophysiology at the elemental, neurochemical and network levels. Quantitative Susceptibility Mapping (QSM), 1H-Magnetic Resonance Spectroscopy (1H-MRS) and resting-state fMRI data were acquired from a well-characterized sample of patients/controls to investigate postulated abnormalities in (a) iron metabolism; (b) glutamatergic neurotransmission and (c) cortico-subcortical connectivity. A longitudinal study design was implemented to investigate the influence of antipsychotic treatment (Abilify®) on neurochemical profiles.

At the elemental level, we observed significant reductions in subcortical magnetic susceptibility, which is regarded as surrogate index for iron content in-vivo. Reductions were specific to subcortical nuclei key in coordinating mechanisms of motor/non-motor habit formation, and were mirrored by decreases in serum ferritin levels. At the neurochemical level, we report significant reductions in the concentrations of striatal glutamatergic signalling markers, which correlated with tic severity and were normalized with treatment. Importantly, significant associations were observed between surrogate measures of iron metabolism and glutamatergic neurotransmission. At the network level, little success was achieved in uncovering any differences between the groups. As such, we embarked on establishing a European wide consortium (The Tourettome Project) for the retrospective evaluation of the macro-scale cerebral architecture in GTS with enhanced statistical power. Preliminary results from N=291 subjects pooled from Paris, Hamburg, Leipzig and Hannover revealed cortical thinning in the primary motor cortex, which co-varied with striatal volume.

The employed multi-modal and multi-parametric investigations revealed the striatum as a key locus in GTS pathophysiology. Specifically, our results indicated that GTS patients exhibit an abnormality in the flux of metabolites in the GABA-glutamate-glutamine cycle, thus implying perturbations in mechanisms sustaining the subtle balance between excitatory and inhibitory neurotransmission. Such perturbations may be driven by disruptions in iron homeostasis and may have a profound influence on the neoplastic mechanisms involved in reinforcement learning and habit formation. This work sheds a new light on the neurobiological basis of GTS and provides novel clues that may prove critical in the future development of functionally selective pharmacological modulators that target multiple neurochemical systems.

Poster