Tourette syndrome, ADHD, and the limbic system: investigating the pathophysiology

See related article on page 524 The pathophysiology of Tourette syndrome (TS) is not well understood. Multiple converging lines of evidence point to a functional impairment of the cortico-striatal-thalamo-cortical circuitry. Based on close functional and anatomical connections between the prefrontal cortical and the ventral striatal portions of this network, and the limbic system, it has been hypothesized that the amygdala play an important role in the pathophysiology of TS.1 The study by Ludolph et al. in this issue tested the hypothesis that amygdala volumes are significantly different between individuals with TS and an age-matched comparison group of healthy children using volumetric, high-resolution magnetic resonance imaging (MRI). This technique has been used successfully to study the anatomical correlates of neurological and psychiatric disorders as diverse as schizophrenia, dyslexia, and epilepsy. Still, volumetric MRI is challenging, in particular due to difficulties in reliably delineating the brain structures under investigation. Ludolph et al. compared amygdala volumes between a small but well-characterized and relatively homogeneous sample of patients with TS (17 young males, age 9–16y), and age-matched, healthy individuals. A considerable portion of the TS group (8/17 males) fulfilled the diagnostic criteria for attention-deficit-hyperactivity disorder (ADHD) according to DSMV-IV criteria. The authors found significantly smaller amygdala volumes, standardized to total brain volume, in patients with TS compared with the healthy group. However, amygdala volumes were not correlated with tic severity, the leading symptom of TS. In contrast, the authors found significant correlations between amygdala volumes and behavioural impairment and symptoms of ADHD. Very recently, another study used volumetric MRI to test the hypothesis that TS is associated with alterations of amygdala volume and morphology.2 The studies by Ludolph et al. and Peterson et al.2 appear to point in different directions. While Ludolph et al. found smaller amygdala volumes in patients with TS and an association between amygdala volumes and ADHD symptoms, Peterson et al. observed larger amygdala volumes in patients with TS without association with ADHD comorbidity.2 These divergent results are difficult to interpret based on the existing data and might be due, at least in part, to differences in the distribution of age and sex in the two available studies. The findings of both studies generate a wealth of new questions that stimulates further research on the pathophysiology of TS. What are the next steps that might increase our understanding of the presumably complex pathophysiology of this disorder? First, researchers might want to study whether morphological changes are confined to the amygdala or also found in other parts of the limbic system, such as the anterior cingulate cortex. The study of Peterson et al. already investigated structural abnormalities of the hippocampus and found larger hippocampus volumes in patients with TS.2 The anterior cingulate cortex might be, at least in theory, a crucial area for the generation of TS symptoms, as it is an interface between motor initiation and programming, emotional processing, and cognitive function. Additional volumetric MRI studies in homogeneous patient samples might also help to integrate the divergent findings that were presented in the two published studies on amygdala volumes in TS. Second, we would like to know whether morphological alterations in the amygdala (and presumably other limbic areas) are a causal factor for the development of TS or, rather, the consequence of changes in brain function in TS. The cross-sectional data available today do not provide an answer. Given the long interval between tic onset and MRI (2–5y in the study by Ludolph et al.), the reported structural alterations might represent plastic changes, secondary to changes in neural networks and neurotransmitter release. Longitudinal volumetric studies, although difficult and expensive, with a first scan shortly after symptom onset and a second scan years later, might help to establish the relationship between structural changes of the limbic system and TS. Third, the functional significance of the observed morphological changes in the amygdala has to be determined. Human brain function can be studied non-invasively with functional MRI (fMRI). fMRI detects changes of blood oxygenation related to sensory stimulation, motor tasks, and cognitive processing, which are closely related to the underlying neural activity.3 fMRI has been successfully used to study emotional processing in the amygdala in healthy individuals and in patients, and will certainly be helpful for the study of limbic function in patients with TS.

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