Neuromodulation in Tourette syndrome: Dopamine and beyond

Abstract

Almost since the beginning of research on Tourette syndrome (TS), tics have been linked to a dysfunction of the dopamine (DA) system. At first, this assumption was mainly based on clinical findings of DA antagonists being the most effective drug in treating tics, but in recent years nuclear imaging has enabled a much deeper understanding of DA neurotransmission in TS. Based on the findings of various PET and SPECT studies the first part of the review discusses four hypotheses on DA dysfunctions in TS: (i) DA hyperinnervation, (ii) supersensitive DA receptors, (iii) pre-synaptic DA abnormality and (iv) DA tonic-phasic dysfunction. According to the latter hypothesis, reduced levels of tonic DA in the extracellular space lead to higher concentrations of DA in the axon terminal and an increase of stimulus-dependent DA release. The second part of the review addresses the modulating role of DA in some major clinical features of TS, like the exacerbation with stress or infection and the association with deficient sensorimotor gating.

Introduction

Tourette syndrome (TS) is a chronic tic disorder characterized by the presence of at least one phonic and several motor tics for more than one year with first-onset before the age of 18. Tics are sudden, rapid, non-rhythmic, recurrent and mainly involuntary behaviors. Typically the onset of first tic symptoms is between the age of four and eight years. Symptoms tend to be most severe around the age of 10–14. In most patients, tics improve or fully remit in late adolescence or early adulthood. Tics wax and wane over minutes, hours, weeks, months, and years in frequency, intensity, location and complexity both intra- and inter-individually. The reasons for these fluctuations are still unclear, but modulating effects of different context variables, such as psychosocial stress, anxiety, emotional tension and/or fatigue have been proposed (Lin et al., 2007).

Tic disorders are more common in males than in females. The prevalence of tic disorders varies: 1% for TS, 3–4% for chronic motor and chronic vocal/phonic tic disorders and 10-15% for transient tics (Robertson, 2008). Additionally, TS patients have a variety of associated problems like attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) or depression (Roessner et al., 2007a, Wanderer et al., 2012).

The precise pathophysiological mechanisms underlying TS with or without comorbid conditions remain unknown. Better understanding of the neurobiological basis of this common neuropsychiatric disorder will foster the development of new as well as the optimization of existing pharmacological and behavioral treatment options. Therefore, the aim of the present review is not only to summarize the actual base of knowledge on DA metabolism, function and modulation in TS but also to highlight possible links to interesting DA-related findings in humans and animals with promising potential to further clarify the pathophysiology of TS.