Article Text
Abstract
Background Tourette syndrome (TS) is a chronic neurodevelopmental disorder characterised by the presence of multiple motor and phonic tics. Recent brain imaging investigations with diffusion tensor imaging (DTI) techniques found reduced measures of connectivity in the corpus callosum of children with TS compared with healthy controls, thus raising the hypothesis that the reduced interhemispherical connectivity in TS reflects neural plasticity processes.
Methods We assessed corpus callosum white-matter connectivity with fractional anisotropy (FA) index from magnetic resonance-DTI in two monozygotic twins (male sex; age 20) discordant for the diagnosis of TS.
Results Both conventional morphological magnetic resonance images and fibre-tracking reconstruction failed to show any difference between the two twins. On the other hand, mean corpus callosum FA values were significantly lower in the affected twin than in the unaffected twin (p<0.01). The differences in FA values were highest in the posterior portions of the corpus callosum, and lowest in the central area.
Conclusions Our findings of reduced interhemispherical white-matter connectivity in the affected twin support the hypothesis that plastic remodelling in the corpus callosum possibly represents an adaptation mechanism in TS.
- MRI
- Tourette syndrome
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Introduction
Tourette syndrome (TS) is a chronic neurodevelopmental disorder characterised by the presence of multiple motor and phonic tics that begin in childhood and that can be accompanied by a wide spectrum of behavioural problems.1 Little is known about the aetiology and pathophysiology of this condition. Over the last decades, brain-imaging studies have revealed specific neuroanatomical abnormalities within the cortico-striato-thalamo-cortical circuits in persons who are affected with TS.2 More recently, a magnetic resonance study employing diffusion tensor imaging (DTI) techniques reported that children with TS have reduced measures of connectivity in the corpus callosum compared with healthy controls.3 These findings suggested the hypothesis that reduced interhemispheric connectivity may represent a neural plastic process associated with the presence of tic symptoms.
Case study
We tested this hypothesis by assessing white-matter connectivity in the corpus callosum using the fractional anisotropy (FA) index from DTI images in two monozygotic twins (20-year-old males). Only one of these twins (Tb) fulfilled diagnostic criteria for TS, whereas the other (Ta) was healthy and completely tic-free.
Both twins underwent a thorough clinical assessment at the Tourette Clinic, Department of Neurology, Amedeo Avogadro University, Novara, Italy, where Tb was regularly seen. Symptoms began at the age of 6 years, with a number of motor and phonic tics that included eye blinking, staring, abdominal twitches, complex limb movements, grunting and whistling. In addition, this child had complex tic-related symptoms including stuttering, echolalia, palilalia, occasional coprolalia and minor obsessive compulsive symptoms (concerns for symmetry and evening-up behaviours). Tb fulfilled current DSM-IV-TR diagnostic criteria for ‘uncomplicated’ TS.4 He was otherwise healthy and scored 72% on the Diagnostic Confidence Index, consistent with scores reported in TS tertiary referral centres, and 28/55 on the Yale Global Tic Severity Scale, indicating moderate symptom severity.
MRI was performed in both twins on a 1.5 T scanner (Philips Achieva, rel 2.1). DTI was performed using a single-shot echo-planar EPI pulse sequence with SENSE (TR 18693, TEd 58, TSE factor 53, EPI factor 53, thk/gap 2.0/0.0, FOV 200). The diffusion gradients were applied in 32 noncollinear directions with a b-value of 1.000 s/mm2. According to our a priori hypothesis, we focused specifically on acquiring imaging data of the corpus callosum of high quality using standardised head-positioning tools (automated planning Smartbrain, Philips, coupled with an eight-channel head coil). We repeated any series that contained movement artefacts.
Both conventional MRIs and fibre-tracking reconstructions demonstrated comparable results in the twins. However, mean corpus callosum FA values were significantly lower in the affected twin compared with values in the unaffected twin (Ta: mean=0.69 SD=0.15; Tb: mean=0.59 SD=0.20; p<0.01 two-tailed t test). Further analyses were conducted after subdividing the corpus callosum area into five segments.3 Our results showed that the differences in FA values were greatest in the two posterior-most portions of the corpus callosum and least in the central portion of the callosum (figure 1).
Discussion
Family studies have consistently provided evidence that genetic vulnerabilities contribute to the development of tics and tic-related symptoms, including obsessive compulsive behaviours.5 In a study of 43 pairs of same-sex twins (30 monozygotic and 13 dizygotic), in which at least one co-twin had TS, concordance rates for TS were 53% and 8%, respectively.6 When diagnostic criteria were broadened to include any tics in co-twins, concordance rates rose to 77% and 23% for monozygotic and dizygotic pairs, respectively. Although these findings are consistent with a genetic aetiology in TS, the fact that only 53% of monozygotic twins were fully concordant indicates that non-genetic factors are also important determinants of the expression of TS vulnerability genes.
Our study tested the non-genetic origin of TS-related brain abnormalities within the midsagittal cross-sectional area of the corpus callosum in two drug-naïve monozygotic twins discordant for the diagnosis of TS who reached normal developmental milestones. The corpus callosum has been reported to be smaller and to correlate inversely in size with tic severity and prefrontal cortex volume in children with TS.7 8 Moreover, a preliminary DTI investigation on 20 boys with TS and 20 matched controls showed that FA indices are reduced in children with TS within all subregions of the corpus callosum.3
Lower FA values in the corpus callosum may reflect a reduction in the number of axons, reduced myelination or disrupted anatomical organisation of those axons. The differences in FA indices between the twins were greatest in the two posterior-most mid-sagittal regions of the corpus callosum, which are rich in large, fast-conducting fibres connecting widespread cortical areas, especially within the frontal lobe.9 10 Overall, these findings of reduced interhemispheric white-matter connectivity in TS provide additional support for the hypothesis that plastic remodelling in callosal inhibitory pathways to the prefrontal cortex is associated with the presence of tic symptoms.3 8 11
The simplest explanation would be that the decreased FA values in the affected co-twin represent an epiphenomenon of an undefined neurodevelopmental abnormality. Specifically, reduced corpus callosum connectivity could be associated with a reduction in transcallosal inhibition of cortical neurons, which in turn contributes to tic expression (through decreased control of motor outputs). Alternatively, the plastic remodelling within the corpus callosum could represent a compensatory adaptation mechanism to the presence of tics. In this case, a reduction in transcallosal inhibition of cortical neurons may ultimately enhance the ongoing frontostriatal control of tic symptoms within the aforementioned cortico-striato-thalamo-cortical circuits.2
The present study, like the previous DTI investigation of corpus callosum in TS,3 deals with brain morphology in a cross-sectional design. This is a major limitation, since it only allows limited conclusions concerning developmental trajectories and cannot make inferences about causation or about the temporal sequencing in the development. The suggested models should thus be further tested in longitudinal studies and confirmed on large case-series of monozygotic and dizygotic twin pairs.
Acknowledgments
We thank Professor G Miceli for his valuable comments on this manuscript.
References
Footnotes
All authors contributed equally to this manuscript.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.