White-matter abnormalities in Tourette syndrome extend beyond motor pathways
Introduction
Tourette syndrome (TS) is a developmental neuropsychiatric disorder with the cardinal symptoms of motor and vocal tics. Often tics are accompanied by comorbidities such as obsessive–compulsive disorder (OCD), attention-deficit–hyperactivity disorder (ADHD) or depression. A “pure” Tourette syndrome without any comorbidity occurs in only ∼ 10% of patients (Freeman et al., 2000, Khalifa & von Knorring, 2005). Its clinical course is characterized by the waxing and waning of symptoms (Leckman, 2003, Singer, 2005). The onset occurs during childhood; many patients experience a subsequent reduction of tic frequency and severity suggesting that the pathways involved play a significant developmental role. Research on Tourette syndrome has focused on the volumes of the basal ganglia and the cortico-striato-thalamo-cortical circuitry in terms of the underlying pathophysiological brain circuit (Singer, 2005, Saka & Graybiel, 2003, Albin & Mink, 2006, Leckman et al., 2006).
Several decades of investigation have confirmed a substantial genetic contribution of Tourette syndrome, but Tourette syndrome is a genetically heterogeneous disorder, probably involving multiple alleles at different loci. Genetic mutations, e.g. such as in Slit and Trk-like family member 1 (SLITRK1) are discussed in terms of playing a role in the pathophysiology of Tourette syndrome, but findings for the SLITRK1 gene in Tourette syndrome are heterogeneous (Abelson et al., 2005, Scharf et al., 2008, Miranda et al., 2009). Neuroimaging studies in Tourette syndrome have reported reduced caudate nucleus volumes (Peterson et al., 2003), altered volumes (smaller in children with Tourette syndrome, larger in adults with Tourette syndrome) of the total corpus callosum (Plessen et al., 2004) and thinning of sensorimotor cortices (Sowell et al., 2008). Church et al. (2009) measured immature and anomalous patterns of functional connectivity via resting-state functional magnetic resonance imaging (fMRI). They reported widespread abnormal connectivity patterns with the most prominent deficits in the Tourette syndrome group between the middle cingulate cortex, the dorsolateral prefrontal cortex and the inferior parietal lobe (Church et al., 2009). In an event-related fMRI study Bohlhalter et al. (2006) identified a network consisting of anterior cingulate and insular cortex, supplementary motor area and parietal operculum as being predominantly activated before tic onset.
In summary, in the literature on the pathophysiology of the Tourette syndrome two principles emerge: one is the alteration of basal ganglia volumes and the other is an altered connectivity pattern.
In order to investigate whether white-matter abnormalities contribute to these dysfunctional connectivity patterns in Tourette syndrome, a non-invasive, robust imaging method is needed.
Diffusion tensor imaging (DTI) answers this need. Fractional anisotropy is very sensitive to microstructural tissue organization, but it is not a specific marker for a certain pathophysiologic mechanism (Basser, 1995, Basser & Jones, 2002). Axial diffusivity λ1 (diffusivity parallel to the principle axis of the fibre) and radial diffusivity λ23 = (λ2 + λ3) / 2 (diffusivity perpendicular to the principle axis of the fibre) contribute valuable information (Hasan, 2006, Alexander et al., 2007). Results from animal research suggest that radial diffusivity is modulated by myelin in white matter (Tyszka et al., 2006, Song et al., 2005), whereas axial diffusivity might be more specific to axonal degeneration (Song et al., 2003). These measures have been obtained in mice with MRI at high field strength and their translation to human data is a matter of ongoing research (Xu et al., 2008, Qiu et al., 2008).
Based on DTI, Smith et al. (2006) developed tract-based spatial statistics (TBSS). TBSS aims to improve the sensitivity, objectivity and interpretability of the analysis of multi-subject diffusion imaging studies. In contrast to voxel-based morphometry (VBM) -style analysis, TBSS takes advantage of the spatial determinants of major white-matter tracts and thereby minimizes registration errors, thus eliminating the need for arbitrary smoothing.
In the current study where TBSS is applied to adult patients, we investigate which white-matter tracts show abnormalities in Tourette syndrome. We hypothesize that the microstructural organization is altered and aim to describe these change via FA, MD and axial as well as radial diffusivity. Given the cardinal symptoms of tics we hypothesized an impairment of the main motor tracts. Given the impaired resting networks as described by Church et al. (2009) and the modulation of tics by cortical areas (Stern et al., 2000, Bohlhalter et al., 2006, Kawohl et al., 2008, Peterson et al., 1998), we hypothesize that the white-matter changes would extend beyond motor regions and also implicate commissural and association fibres.
Section snippets
Data acquisition
Diffusion-weighted data and high-resolution 3-dimensional T1-weighted images were acquired for each subject on a 1.5 T scanner (SonataVision, Siemens) with an 8-channel phased array head coil and maximum gradient strength of 40 mT/m.
The diffusion-weighted data were acquired using a twice-refocused spin-echo diffusion-weighted echo-planar imaging (EPI) sequence with the following parameters: 2 mm slice thickness, no inter-slice gap, repetition time (TR) = 11,000 ms, echo time (TE) = 89 ms, field-of-view
Whole group — TBSS results
Patients with Tourette syndrome in comparison to healthy controls showed a significant reduction of FA in the corticospinal tract, the corpus callosum and long association fibre pathways such as the inferior fronto-occipital fascicle and the superior longitudinal fascicle as well as in the uncinate fascicle. The coordinates of the local maxima are listed in Table 4. Reductions in FA are displayed in Fig. 1. The FA reduction in the internal capsule is displayed in detail in Fig. 2.
Significant
Discussion
DTI analysis in our adult Tourette syndrome patients shows a decrease of FA and increase in radial diffusivity in the corticospinal tract. There are widespread changes (reduced FA and increased radial diffusivity) in the anterior and posterior limb of the internal capsule. Furthermore, a FA-decrease in the corpus callosum in combination with increased radial diffusivity indicates altered interhemispheric connectivity via the corpus callosum. In addition our results indicate that TS is not
Acknowledgments
The work of I.N. was funded by a fellowship (“Rotationsprogramm”) of the Medical Faculty RWTH (Rheinisch-Westfälische Technische Hochschule) Aachen, Germany. We thank all Tourette patients and their families for participating in the study. We are grateful to the German Tourette Association and its board of directors, Silvia Viertel, Michaela Flecken and Wolfgang Hartmann and members who supported this study by contributing travel funds. We thank Petra Engels, Barbara Elghahwagi and Gabriele
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Current position Brain Imaging Center, Beijing Normal University, Beijing, China.