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      Structural brain network fingerprints of focal dystonia

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          Abstract

          Background:

          Focal dystonias are severe and disabling movement disorders of a still unclear origin. The structural brain networks associated with focal dystonia have not been well characterized. Here, we investigated structural brain network fingerprints in patients with blepharospasm (BSP) compared with those with hemifacial spasm (HFS), and healthy controls (HC). The patients were also examined following treatment with botulinum neurotoxin (BoNT).

          Methods:

          This study included matched groups of 13 BSP patients, 13 HFS patients, and 13 HC. We measured patients using structural-magnetic resonance imaging (MRI) at baseline and after one month BoNT treatment, at time points of maximal and minimal clinical symptom representation, and HC at baseline. Group regional cross-correlation matrices calculated based on grey matter volume were included in graph-based network analysis. We used these to quantify global network measures of segregation and integration, and also looked at local connectivity properties of different brain regions.

          Results:

          The networks in patients with BSP were more segregated than in patients with HFS and HC ( p < 0.001). BSP patients had increased connectivity in frontal and temporal cortices, including sensorimotor cortex, and reduced connectivity in the cerebellum, relative to both HFS patients and HC ( p < 0.05). Compared with HC, HFS patients showed increased connectivity in temporal and parietal cortices and a decreased connectivity in the frontal cortex ( p < 0.05). In BSP patients, the connectivity of the frontal cortex diminished after BoNT treatment ( p < 0.05). In contrast, HFS patients showed increased connectivity in the temporal cortex and reduced connectivity in cerebellum after BoNT treatment ( p < 0.05).

          Conclusions:

          Our results show that BSP patients display alterations in both segregation and integration in the brain at the network level. The regional differences identified in the sensorimotor cortex and cerebellum of these patients may play a role in the pathophysiology of focal dystonia. Moreover, symptomatic reduction of hyperkinesia by BoNT treatment was associated with different brain network fingerprints in both BSP and HFS patients.

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          Most cited references44

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          Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia.

          A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.
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            Cerebellothalamocortical connectivity regulates penetrance in dystonia.

            Dystonia is a brain disorder characterized by sustained involuntary muscle contractions. It is typically inherited as an autosomal dominant trait with incomplete penetrance. While lacking clear degenerative neuropathology, primary dystonia is thought to involve microstructural and functional changes in neuronal circuitry. In the current study, we used magnetic resonance diffusion tensor imaging and probabilistic tractography to identify the specific circuit abnormalities that underlie clinical penetrance in carriers of genetic mutations for this disorder. This approach revealed reduced integrity of cerebellothalamocortical fiber tracts, likely developmental in origin, in both manifesting and clinically nonmanifesting dystonia mutation carriers. In these subjects, reductions in cerebellothalamic connectivity correlated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Nonmanifesting mutation carriers were distinguished by an additional area of fiber tract disruption situated distally along the thalamocortical segment of the pathway, in tandem with the proximal cerebellar outflow abnormality. In individual gene carriers, clinical penetrance was determined by the difference in connectivity measured at these two sites. Overall, these findings point to a novel mechanism to explain differences in clinical expression in carriers of genes for brain disease.
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              Rating scales for dystonia: a multicenter assessment.

              The evaluation of dystonia requires a reliable rating scale. The widely used Fahn-Marsden Scale (F-M) has not been sufficiently tested across multiple centers and investigators. The Dystonia Study Group developed the Unified Dystonia Rating Scale (UDRS) and a Global Dystonia Rating Scale (GDS) to serve as instruments to assess dystonia severity. In this study, 25 dystonia experts evaluated the UDRS, F-M, and GDS for internal consistency and reliability. One hundred dystonia patients were videotaped using a standardized videotape protocol. Each examiner rated 20 patients using the UDRS, F-M, and GDS in random order. The examiner then assessed each scale for ease of use. Statistical analysis used Cronbach's alpha, intraclass correlation coefficients (ICC), generalized weighted kappa statistic, and Kendall's coefficient of concordance. The UDRS, F-M, and GDS showed excellent internal consistency (Cronbach's alpha 0.89-0.93) and good to excellent correlation among the raters (ICC range from 0.71-0.78). Inter-rater agreement was fair to excellent (Kendall's 0.54-0.87; kappa 0.37-0.91) being lowest for eyes, jaw, face, and larynx. The modifying ratings (Duration in the UDRS and Provoking Factor in the F-M) showed less agreement than the motor severity ratings. Among scales, the total scores correlated (Pearson's r, 0.977-0.983). Overall, 74% of raters found the GDS the easiest to apply. The GDS with its simplicity and ease of application may be the most useful dystonia rating scale. Copyright 2002 Movement Disorder Society
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                Author and article information

                Contributors
                Journal
                Ther Adv Neurol Disord
                Ther Adv Neurol Disord
                TAN
                sptan
                Therapeutic Advances in Neurological Disorders
                SAGE Publications (Sage UK: London, England )
                1756-2856
                1756-2864
                16 November 2019
                2019
                : 12
                : 1756286419880664
                Affiliations
                [1-1756286419880664]Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
                [2-1756286419880664]Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
                [3-1756286419880664]Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
                [4-1756286419880664]Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
                [5-1756286419880664]Department of Neurology, University Hospital Schleswig-Holstein, University of Kiel, Kiel, Schleswig-Holstein, Germany
                [6-1756286419880664]Department of Neurology, University Hospital Schleswig-Holstein, University of Kiel, Kiel, Schleswig-Holstein, Germany
                [7-1756286419880664]Movement Disorders and Neurostimulation, Biomedical Statistics and Multimodal Signal Processing Unit, Department of Neurology, Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
                [8-1756286419880664]Movement Disorders and Neurostimulation, Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine-Main Neuroscience network (rmn 2), Johannes-Gutenberg-University Mainz, Langenbeckstr. 1, Mainz, 55131, Germany
                Author notes
                Author information
                https://orcid.org/0000-0002-0833-545X
                https://orcid.org/0000-0001-6158-2663
                Article
                10.1177_1756286419880664
                10.1177/1756286419880664
                6859688
                beafc682-59d1-4861-b7a2-edcc9a235029
                © The Author(s), 2019

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 27 November 2018
                : 10 September 2019
                Categories
                Original Research
                Custom metadata
                January-December 2019

                dystonia,blepharospasm,botulinum neurotoxin,mri,structural brain networks,graph theory

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