Elsevier

NeuroImage

Volume 51, Issue 3, 1 July 2010, Pages 1184-1193
NeuroImage

White-matter abnormalities in Tourette syndrome extend beyond motor pathways

https://doi.org/10.1016/j.neuroimage.2010.02.049Get rights and content

Abstract

Tourette syndrome is a neuropsychiatric disorder with the cardinal symptoms of motor and vocal tics. Often tics are accompanied by comorbidities such as obsessive–compulsive disorder, attention-deficit–hyperactivity disorder or depression. Research has mainly focused on the cortico-striato-thalamo circuit, but clinical symptoms and recent neuroimaging studies reporting altered resting network connectivity have suggested abnormalities in Tourette syndrome beyond the major motor circuits.

We acquired diffusion-weighted data at 1.5 T in nineteen adult patients fulfilling the DSM-IV-TR criteria for Tourette syndrome and in a healthy control group.

Diffusion tensor imaging (DTI) analysis in our adult TS sample 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, it confirms prior findings of altered interhemispheric connectivity as indicated by a FA-decrease in the corpus callosum. In addition, our results indicate that TS is not restricted to motor pathways alone but affects association fibres such as the inferior fronto-occipitalis fascicle, the superior longitudinal fascicle and fascicle uncinatus as well.

Tics are the hallmark of Tourette syndrome, so the involvement of the corticospinal tract fits in well with clinical symptoms. Cortical regions as well as limbic structures take part in the modulation of tics. Our findings of alterations in long association fibre tracts and the corpus callosum are a potential source for hindered interhemispheric and transhemispheric interaction. The change in radial diffusivity points toward a deficit in myelination as one pathophysiological factor in Tourette syndrome.

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

References (60)

  • H.S. Singer

    Tourette's syndrome: from behaviour to biology

    Lancet Neurol.

    (2005)
  • S.M. Smith et al.

    Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference

    NeuroImage

    (2009)
  • S.M. Smith et al.

    Advances in functional and structural MR image analysis and implementation as FSL

    NeuroImage

    (2004)
  • S.M. Smith et al.

    Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data

    NeuroImage

    (2006)
  • S.K. Song et al.

    Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia

    NeuroImage

    (2003)
  • S.K. Song et al.

    Demyelination increases radial diffusivity in corpus callosum of mouse brain

    NeuroImage

    (2005)
  • J.M. Tyszka et al.

    Statistical diffusion tensor histology reveals regional dysmyelination effects in the shiverer mouse mutant

    NeuroImage

    (2006)
  • J.F. Abelson et al.

    Sequence variants in SLITRK1 are associated with Tourette's syndrome

    Science

    (2005)
  • Amunts, K., Zilles, C., Shah, N.J., Neuner, I., Pieperhoff, P., Schneider, F., 2007. Neuroanatomical changes for...
  • E.S. Barratt

    Factor analysis of some psychometric measures of impulsiveness and anxiety

    Psychol. Rep.

    (1965)
  • P.J. Basser

    Inferring microstructural features and the physiological state of tissues from diffusion-weighted images

    NMR Biomed.

    (1995)
  • P.J. Basser et al.

    Diffusion-tensor MRI : theory, experimental design and data analysis — a technical review

    NMR Biomed.

    (2002)
  • S. Bohlhalter et al.

    Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study

    Brain

    (2006)
  • B. Boroojerdi et al.

    Transcallosal inhibition and motor conduction studies in patients with schizophrenia using transcranial magnetic stimulation

    Br. J. Psychiatry

    (1999)
  • J.L. Cheong et al.

    Abnormal white matter signal on MR imaging is related to abnormal tissue microstructure

    AJNR Am. J. Neuroradiol.

    (2009)
  • J.A. Church et al.

    Control networks in paediatric Tourette syndrome show immature and anomalous patterns of functional connectivity

    Brain

    (2009)
  • L.R. Derogatis et al.

    The SCL-90 and the MMPI: a step in the validation of a new self-report scale

    Br. J. Psychiatry

    (1976)
  • A.W. Flaherty et al.

    Deep brain stimulation of the anterior internal capsule for the treatment of Tourette syndrome: technical case report

    Neurosurgery

    (2005)
  • Fossati, A., Di Ceglie, A., Acquarini, E., Barratt, E.S., 2001. Psychometric properties of an Italian version of the...
  • R.D. Freeman et al.

    An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries

    Dev. Med. Child Neurol.

    (2000)
  • Cited by (86)

    • Cingulate role in Tourette syndrome

      2019, Handbook of Clinical Neurology
    View all citing articles on Scopus
    1

    Current position Brain Imaging Center, Beijing Normal University, Beijing, China.

    View full text