Infratentorial gray matter atrophy and excess in primary craniocervical dystonia

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Abstract

Background

Primary craniocervical dystonia (CCD) is generally attributed to functional abnormalities in the cortico–striato–pallido–thalamocortical loops, but cerebellar pathways have also been implicated in neuroimaging studies. Hence, our purpose was to perform a volumetric evaluation of the infratentorial structures in CCD.

Methods

We compared 35 DYT1/DYT6 negative patients with CCD and 35 healthy controls. Cerebellar volume was evaluated using manual volumetry (DISPLAY software) and infratentorial volume by voxel based morphometry of gray matter (GM) segments derived from T1 weighted 3 T MRI using the SUIT tool (SPM8/Dartel). We used t-tests to compare infratentorial volumes between groups.

Results

Cerebellar volume was (1.14 ± 0.17) × 102 cm3 for controls and (1.13 ± 0.14) × 102 cm3 for patients; p = 0.74. VBM demonstrated GM increase in the left I–IV cerebellar lobules and GM decrease in the left lobules VI and Crus I and in the right lobules VI, Crus I and VIIIb. In a secondary analysis, VBM demonstrated GM increase also in the brainstem, mostly in the pons.

Conclusion

While gray matter increase is observed in the anterior lobe of the cerebellum and in the brainstem, the atrophy is concentrated in the posterior lobe of the cerebellum, demonstrating a differential pattern of infratentorial involvement in CCD. This study shows subtle structural abnormalities of the cerebellum and brainstem in primary CCD.

Introduction

Craniocervical dystonia (CCD) is the most common manifestation of adult-onset dystonia [1]. The term CCD encompasses blepharospasm, oromandibular, lingual, laryngeal and cervical dystonia or a combination of two or more of those. Based on prior studies, primary dystonia is thought to be a neurodevelopmental circuit disorder, which involves the cortico–striato–pallido–thalamo–cortical and cerebello–thalamo–cortical pathways [2]. Primary dystonia has been considered a manifestation of basal ganglia dysfunction; however, there is growing evidence that the cerebellum plays a crucial role in the pathophysiology of the disease. Nevertheless, there is still significant controversy as to whether these observed changes in cerebellar morphology and function are primary or secondary [3], [4].

There are few studies addressing the structural changes in the whole brain of patients with CCD. VBM studies in cervical dystonia (CD) showed increased gray matter (GM) volume bilaterally in the motor cortex [5], the cerebellar flocculus [5], the right globus pallidus internus (GPi) [5], [6]; bilateral orbitofrontal cortex, right medial frontal gyrus, left supplementary motor area and left cingulate gyrus [6]; superior left temporal lobe, thalamus, caudate head bilaterally and left cerebellum [7], as well as decreased GM in the right supplementary motor area, right prefrontal cortex, right visual cortex [5], and the putamen [7]. In primary blepharospasm the results have also been variable, revealing bilateral increased GM density in the caudate head, cerebellum [7], and putamen [8], but decreased GM in the putamen bilaterally, the thalamus [7], and the left inferior parietal lobule [8]. While some of these studies demonstrated cerebellar changes, none studied the infratentorial structures in detail.

There is also compelling evidence of cerebellar dysfunction in dystonia, which may represent a maladaptive response rather than a primary outcome of basal ganglia pathology [3], [4]. Deep brain stimulation of the ventral posterior thalamus, the major recipient of cerebellar outflow, improves CCD [9]. Furthermore, surgical removal of the cerebellum in mutant tottering mice eliminates the dystonic movements [4]. Brainstem structures seem also to be involved in the pathophysiology of dystonia. For example, brainstem lesions, without basal ganglia or thalamic lesions may produce dystonia [10], [11].

Hence, our main purpose was to perform a detailed analysis of the infratentorial structures in patients with primary CCD, using two different volumetric techniques of imaging analysis.

Section snippets

Subjects

The Institutional Review Board of our University Hospital approved the study and all subjects signed an informed consent prior to participation in any study related procedure. Patients were recruited from the Movement Disorders Outpatient Clinic, the Dystonia Outpatient Clinic and the Neurogenetic Outpatient Clinic at the University of Campinas (UNICAMP) University Hospital. We included 35 patients (mean age of 60.71 ± 12.47 years) with a clinical diagnosis of primary CCD. All tested negative

Manual volumetry analysis

There was no statistical difference in cerebellar volume between controls and patients, respectively: (1.14 ± 0.17) × 102 cm3 versus (1.13 ± 0.14) × 102 cm3, p = 0.74.

VBM analysis

VBM demonstrated significant differences in the cerebellar GM. To promote accurate anatomical identification of the cerebellar areas involved we based our results on the Probabilistic MR Atlas of Human Cerebellum [13] and considered the lobules > 100 voxels. Thus, we found GM excess in the left I–IV lobules and GM atrophy in the

Cerebellar analysis

Functional and structural imaging analysis points to an important role of the cerebellum in dystonia. In manifesting and non-manifesting dystonia mutation carriers, functional studies and Diffusion Tensor Imaging (DTI) revealed reduced integrity of cerebello–thalamo–cortical fiber tracts [15], [16]. Previous VBM studies demonstrated increased GM in some cerebellar areas, even though a clear pattern could not be established [5], [7]. Our findings strengthen the hypothesis that dystonia has a

Conclusion

In summary, we performed for the first time an infratentorial analysis in CCD using the SUIT tool for VBM. The use of this tool made our results more robust than the previous studies once the SUIT tool provides a better overlap of the cerebellar lobules, preserves the anatomical detail of the cerebellum and it does not allow the supratentorial structures to bias the results. We observed a differential pattern of cerebellar GM atrophy and excess. Increased GM was situated in anterior lobe of

Conflicts of interest

None of the authors have conflicts of interest directly related to the development of the manuscript. Full disclosure statement can be found at the end of the manuscript.

Funding statement

This work was supported by FAPESP (São Paulo Research Foundation), grant number 2010/11085-9.

Competing interests statements

None of the authors have conflicts of interest directly related to the development of the manuscript.

Financial disclosures of all authors

Camila C Piccinin: Research grant from FAPESP.

Maria C A Santos: Research grant from FAPESP.

Luiza G Piovesana: Educational grant from Ipsen.

Lidiane S Campos: Educational grant from Ipsen.

Rachel P Guimarães: Research grant from FAPESP.

Brunno M Campos: none.

Fabio R Torres: Supported by a Post-doctoral fellowship from CAPES, BRAZIL.

Marcondes C França Jr.: none.

Augusto C Amato-Filho: none.

Iscia Lopes-Cendes: Supported by grants from FAPESP and CNPq, BRAZIL.

Fernando Cendes: : Supported by grants from

Contributorship statement

Author Roles:

  • 1)

    Research project:

    • A.

      conception: Anelyssa D'Abreu; Camila C Piccinin; Maria C A Santos; Iscia Lopes-Cendes; Fernando Cendes.

    • B.

      organization: Anelyssa D'Abreu; Camila C Piccinin; Maria C A Santos

    • C.

      execution: Camila C Piccinin; Maria C A Santos; Luiza G Piovesana; Lidiane S Campos; Rachel P Guimarães; Brunno M Campos; Fabio R Torres; Marcondes C França Jr.; Augusto C Amato-Filho.

  • 2)

    Estatistical analysis

    • A.

      design: Anelyssa D'Abreu; Brunno M Campos; Rachel P Guimarães; Luiza G Piovesana; Lidiane S

Acknowledgment

The State of São Paulo Research Foundation (FAPESP) provided funds to support this project. We also acknowledge Dr Joseph Friedman for kindly agreeing to critically review this manuscript and for his invaluable input.

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