ReviewNeuromodulation in Tourette syndrome: Dopamine and beyond
Highlights
► Various nuclear imaging and post-mortem brain studies suggest dopaminergic abnormalities in TS. ► Clinical evidence supports the overactive phasic dopamine hypothesis of TS. ► The role of dopamine in stress, immunology and sensorimotor phenomena should be examined. ► More research is required to come to firmer conclusions.
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.
Section snippets
Considerations about etiology and pathophysiology of TS
Despite increasing research efforts the etiology and pathophysiology of TS remains unclear. Nevertheless, neurophysiological and neuroimaging studies as well as various biochemical and genetic studies suggest involvement of cortical and subcortical areas such as the prefrontal cortex (PFC), the thalamus and the basal ganglia (Leckman, 2002). These regions are linked by parallel cortico-striato-thalamo-cortical (CSTC) circuits which transmit information from the cortex to subcortical regions and
Neurotransmitter systems in TS: The pivotal role of the dopamine system
The fact that tic phenomenology varies and comorbidities are common suggests that more than one neurotransmitter system is affected in TS. Abnormalities have been described in noradrenergic, glutamatergic, opioid, cholinergic, Gamma-AminoButyric Acid (GABA)-ergic and serotonergic systems (Swain et al., 2007). Particularly the latter appears to be relevant in the pathophysiology of TS and associated OCD (Müller-Vahl et al., 2005, Steeves et al., 2010). Undoubtedly however, the most pivotal role
Dopamine (DA)
DA is involved in many motor functions, particularly movement selection, reward-driven learning, response inhibition and temporal processing (Hershey et al., 2004, Liang et al., 2008, Richard and Berridge, 2011). The DA system is often subdivided into the nigrostriatal, the mesolimbic, the mesocortical and the tuberoinfundibular DA system.
In the nigrostriatal DA system, DA neurons in the mesencephalic substantia nigra pars compacta predominantly project to dorsal areas of the basal ganglia,
Hypotheses on DA dysfunction in TS
On the basis of results from various nuclear imaging studies, hyperfunction or imbalance of the DA system has been documented in TS patients (George et al., 1994, Malison et al., 1995, Wolf et al., 1996, Wong et al., 1997, Wong et al., 2008, Ernst et al., 1999, Müller-Vahl et al., 2000a, Singer et al., 2002, Cheon et al., 2004, Mena et al., 2004, Serra-Mestres et al., 2004, Gilbert et al., 2006, Yeh et al., 2007, Albin et al., 2009, Steeves et al., 2010, Liu et al., 2010). This notion is also
Effects of pharmacotherapy of TS
Within the last decades the experience with DA modulating pharmacotherapy to alleviate tics further strengthened the hypothesis of an imbalance in the DA system. Based on abnormalities of DAT binding capacity in the basal ganglia (Singer et al., 1991, Serra-Mestres et al., 2004, Liu et al., 2010) and an increased number of striatal (Wong et al., 1997) and cortical (Minzer et al., 2004, Yoon et al., 2007) DA receptors, the main rationale for pharmacological treatment in TS is to modulate DA
Dopamine involvement in major clinical characteristics of TS
The DA system not only plays a role in the generation of tics, it might also help to explain major clinical characteristics of TS, including the fluctuation of symptom severity, the comorbidity with ADHD and the associated problem of dysfunctional sensorimotor integration. Therefore, the following section addresses the question of how DA modulates the exacerbation of tics with stress and infections, it discusses the putative contradiction between the hyperdomapinergic disorder TS and the
Conclusion
Taken together, it is becoming clear that the activity of DA circuits and its modulation by externally determined states (infection, stress) and the internal response to those states (e.g., autoimmunity, activation of HPA axis) plays a major role in the clinical manifestation of tics, particularly their severity, context dependency and fluctuation. Whether DA dysregulation though is the prime event setting off tics is another question. Any model explaining tic genesis has to take into account
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