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      Cause or effect: Altered brain and network activity in cervical dystonia is partially normalized by botulinum toxin treatment

      research-article
      a , b , * , a , b , a , c , a , b , a , b , c , a
      NeuroImage : Clinical
      Elsevier
      BG, Basal ganglia, BNT, Botulinum toxin, CD, Cervical dystonia, EPI, Echo-planar imaging, FC, Functional connectivity, fMRI, Functional magnetic resonance imaging, FWE, Family wise error, GC, Granger causality, GA, Granger autonomy, GLM, General linear model, KCC, Kendall's coefficient of concordance, ReHo, Regional homogeneity, rs-fMRI, Resting-state fMRI, ROI, Region of interest, S1, Primary somatosensory cortex, S2, Secondary somatosensory cortex, TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale, Cervical dystonia, Sensorimotor integration, Basal ganglia, Thalamus, Botulinum toxin (BNT)

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          Abstract

          Background

          Idiopathic cervical dystonia (CD) is a chronic movement disorder characterized by impressive clinical symptoms and the lack of clear pathological findings in clinical diagnostics and imaging. At present, the injection of botulinum toxin (BNT) in dystonic muscles is an effective therapy to control motor symptoms and pain in CD.

          Objectives

          We hypothesized that, although it is locally injected to dystonic muscles, BNT application leads to changes in brain and network activity towards normal brain function.

          Methods

          Using 3 T functional MR imaging along with advanced analysis techniques (functional connectivity, Granger causality, and regional homogeneity), we aimed to characterize brain activity in CD (17 CD patients vs. 17 controls) and to uncover the effects of BNT treatment (at 6 months).

          Results

          In CD, we observed an increased information flow within the basal ganglia, the thalamus, and the sensorimotor cortex. In parallel, some of these structures became less responsive to regulating inputs. Furthermore, our results suggested an altered somatosensory integration. Following BNT administration, we noted a shift towards normal brain function in the CD patients, especially within the motor cortex, the somatosensory cortex, and the basal ganglia.

          Conclusion

          The changes in brain function and network activity in CD can be interpreted as related to the underlying cause, the effort to compensate or a mixture of both. Although BNT is applied in the last stage of the cortico-neuromuscular pathway, brain patterns are shifted towards those of healthy controls.

          Highlights

          • we characterized brain activity in CD and the effects of BNT using 3T fMR imaging and network analysis techniques

          • following treatment with botulinum toxin (BNT), abnormal brain activity patterns in primary dystonia are attenuated

          • critical key regions for both the pathophysiology and BNT-induced improvement in cervical dystonia are the BG

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          Most cited references88

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          Getting formal with dopamine and reward.

          Recent neurophysiological studies reveal that neurons in certain brain structures carry specific signals about past and future rewards. Dopamine neurons display a short-latency, phasic reward signal indicating the difference between actual and predicted rewards. The signal is useful for enhancing neuronal processing and learning behavioral reactions. It is distinctly different from dopamine's tonic enabling of numerous behavioral processes. Neurons in the striatum, frontal cortex, and amygdala also process reward information but provide more differentiated information for identifying and anticipating rewards and organizing goal-directed behavior. The different reward signals have complementary functions, and the optimal use of rewards in voluntary behavior would benefit from interactions between the signals. Addictive psychostimulant drugs may exert their action by amplifying the dopamine reward signal.
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            Behavioral dopamine signals.

            Lesioning and psychopharmacological studies suggest a wide range of behavioral functions for ascending midbrain dopaminergic systems. However, electrophysiological and neurochemical studies during specific behavioral tasks demonstrate a more restricted spectrum of dopamine-mediated changes. Substantial increases in dopamine-mediated activity, as measured by electrophysiology or voltammetry, are related to rewards and reward-predicting stimuli. A somewhat slower, distinct electrophysiological response encodes the uncertainty associated with rewards. Aversive events produce different, mostly slower, electrophysiological dopamine responses that consist predominantly of depressions. Additionally, more modest dopamine concentration fluctuations, related to punishment and movement, are seen at 200-18,000 times longer time courses using voltammetry and microdialysis in vivo. Using these responses, dopamine neurotransmission provides differential and heterogeneous information to subcortical and cortical brain structures about essential outcome components for approach behavior, learning and economic decision-making.
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              Mapping directed influence over the brain using Granger causality and fMRI.

              We propose Granger causality mapping (GCM) as an approach to explore directed influences between neuronal populations (effective connectivity) in fMRI data. The method does not rely on a priori specification of a model that contains pre-selected regions and connections between them. This distinguishes it from other fMRI effective connectivity approaches that aim at testing or contrasting specific hypotheses about neuronal interactions. Instead, GCM relies on the concept of Granger causality to define the existence and direction of influence from information in the data. Temporal precedence information is exploited to compute Granger causality maps that identify voxels that are sources or targets of directed influence for any selected region-of-interest. We investigated the method by simulations and by application to fMRI data of a complex visuomotor task. The presented exploratory approach of mapping influences between a region of interest and the rest of the brain can form a useful complement to existing models of effective connectivity.
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                Author and article information

                Contributors
                Journal
                Neuroimage Clin
                Neuroimage Clin
                NeuroImage : Clinical
                Elsevier
                2213-1582
                26 March 2019
                2019
                26 March 2019
                : 22
                : 101792
                Affiliations
                [a ]Hans Berger Department for Neurology, Friedrich Schiller University of Jena, Germany
                [b ]Brain Imaging Center, Friedrich Schiller University Jena, Germany
                [c ]Center for Healthy Aging, Jena University Hospital, Jena, Germany
                Author notes
                [* ]Corresponding author at: Hans Berger Department of Neurology, University Hospital Jena, Friedrich Schiller University, Am Klinikum 1, Jena 07747, Germany. stefan.brodoehl@ 123456med.uni-jena.de
                Article
                S2213-1582(19)30142-1 101792
                10.1016/j.nicl.2019.101792
                6444302
                30928809
                2735093e-4dbb-445f-8f06-295cd1380a09
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 12 December 2018
                : 14 March 2019
                : 24 March 2019
                Categories
                Regular Article

                bg, basal ganglia,bnt, botulinum toxin,cd, cervical dystonia,epi, echo-planar imaging,fc, functional connectivity,fmri, functional magnetic resonance imaging,fwe, family wise error,gc, granger causality,ga, granger autonomy,glm, general linear model,kcc, kendall's coefficient of concordance,reho, regional homogeneity,rs-fmri, resting-state fmri,roi, region of interest,s1, primary somatosensory cortex,s2, secondary somatosensory cortex,twstrs, toronto western spasmodic torticollis rating scale,cervical dystonia,sensorimotor integration,basal ganglia,thalamus,botulinum toxin (bnt)

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