Combined PET and MR Investigations of the Pathophysiology of Gilles de la Tourette Syndrome. Part 2: 7T MRI

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Gilles de la Tourette Syndrome (GTS) is characterized by the presence of motor and vocal tics, which have been defined as rapid, habitual, burst-like movements or utterances that typically mimic fragments of normal behavior. Patients often report unpleasant premonitory urge sensations preceding tics that are relieved by their execution. Although the therapeutic spectrum for GTS has recently been expanding, current treatment strategies are often unsatisfactory, thus provoking the need for further elucidation of the underlying pathophysiology.

In current models of GTS pathophysiology, symptoms are thought to arise as a result of the inappropriate activation of specific clusters of striatal neurons, which lead to a burst-like disinhibition of thalamocortical output. The bulk of current literature suggests a dysregulated dopaminergic system. This is supported by clinical evidence of improvements in tics following the administration of dopamine antagonists, synthesis blockers or depletion drugs, and the exacerbation of symptoms following the administration of dopaminergic stimulants. Dopamine drives movement by activating a direct, net excitatory basal ganglia pathway involving the dopamine receptor D1 or an indirect, net inhibitory basal ganglia pathway involving the dopamine receptor D2. Currently, the vast majority of the antipsychotics used for the treatment of tics in GTS aim at the D2 receptor, with aripiprazole, risperidone and pimozide being selective D2 receptor antagonists and haloperidol being mainly a D2 receptor antagonist. However, recent randomized controlled trials further indicate promising results for the selective dopamine receptor D1 antagonist ecopipam.

Methodologically varied work has revealed that patients with GTS exhibit alterations in (i) D2 receptor density or binding, (ii) Dopamine Active Transporter (DAT) density/binding, and (iii) phasic dopamine transmission in striatal and cortical regions. A very small number of post-mortem examinations further suggest potential abnormalities in D1 (and D2 and DAT) receptor densities in cortical regions. While this would be in line with the therapeutic efficiency of selective D1 receptor antagonists, thorough experimental verification is missing. In particular, D1 receptors in GTS patients have not yet been investigated in vivo, suggesting a need for additional research.

Both postsynaptic and presynaptic mechanisms have been postulated to offer explanations of the above observations: