Journal of Neuroscience

Isolated focal dystonia is a debilitating movement disorder of unknown pathophysiology. Early studies in focal dystonias have pointed to segregated changes in brain activity and connectivity. Only recently has the notion that dystonia pathophysiology may lie in abnormalities of large-scale brain networks appeared in the literature. Here, we outline a novel concept of functional connectome-wide alterations that are linked to dystonia phenotype and genotype. Using a neural community detection strategy and graph theoretical analysis of functional MRI data in human patients with the laryngeal form of dystonia (LD) and healthy controls (both males and females), we identified an abnormally widespread hub formation in LD, which particularly affected the primary sensorimotor and parietal cortices and thalamus. Left thalamic regions formed a delineated functional community that highlighted differences in network topology between LD patients with and without family history of dystonia. Conversely, marked differences in the topological organization of parietal regions were found between phenotypically different forms of LD. The interface between sporadic genotype and adductor phenotype of LD yielded four functional communities that were primarily governed by intramodular hub regions. Conversely, the interface between familial genotype and abductor phenotype was associated with numerous long-range hub nodes and an abnormal integration of left thalamus and basal ganglia. Our findings provide the first comprehensive atlas of functional topology across different phenotypes and genotypes of focal dystonia. As such, this study constitutes an important step toward defining dystonia as a large-scale network disorder, understanding its causative pathophysiology, and identifying disorder-specific markers.SIGNIFICANCE STATEMENT The architecture of the functional connectome in focal dystonia was analyzed in a large population of patients with laryngeal dystonia. Breaking with the empirical concept of dystonia as a basal ganglia disorder, we discovered large-scale alterations of neural communities that are significantly influenced by the disorder's clinical phenotype and genotype

Functional and structural neural bases of task specificity in isolated focal dystonia

BACKGROUND: Task-specific focal dystonias selectively affect movements during the production of highly learned and complex motor behaviors. Manifestation of some task-specific focal dystonias, such as musician's dystonia, has been associated with excessive practice and overuse, whereas the etiology of others remains largely unknown. OBJECTIVES: In this study, we aimed to examine the neural correlates of task-specific dystonias in order to determine their disorder-specific pathophysiological traits. METHODS: Using multimodal neuroimaging analyses of resting-state functional connectivity, voxel-based morphometry and tract-based spatial statistics, we examined functional and structural abnormalities that are both common to and distinct between four different forms of task-specific focal dystonias. RESULTS: Compared to the normal state, all task-specific focal dystonias were characterized by abnormal recruitment of parietal and premotor cortices that are necessary for both modality-specific and heteromodal control of the sensorimotor network. Contrasting the laryngeal and hand forms of focal dystonia revealed distinct patterns of sensorimotor integration and planning, again involving parietal cortex in addition to inferior frontal gyrus and anterior insula. On the other hand, musician's dystonia compared to nonmusician's dystonia was shaped by alterations in primary and secondary sensorimotor cortices together with middle frontal gyrus, pointing to impairments of sensorimotor guidance and executive control. CONCLUSION: Collectively, this study outlines a specialized footprint of functional and structural alterations in different forms of task-specific focal dystonia, all of which also share a common pathophysiological framework involving premotor-parietal aberrations. (c) 2019 International Parkinson and Movement Disorder Society

Modeling the dynamics of mouse iron body distribution: hepcidin is necessary but not sufficient

Abstract Background Iron is an essential element of most living organisms but is a dangerous substance when poorly liganded in solution. The hormone hepcidin regulates the export of iron from tissues to the plasma contributing to iron homeostasis and also restricting its availability to infectious agents. Disruption of iron regulation in mammals leads to disorders such as anemia and hemochromatosis, and contributes to the etiology of several other diseases such as cancer and neurodegenerative diseases. Here we test the hypothesis that hepcidin alone is able to regulate iron distribution in different dietary regimes in the mouse using a computational model of iron distribution calibrated with radioiron tracer data. Results A model was developed and calibrated to the data from adequate iron diet, which was able to simulate the iron distribution under a low iron diet. However simulation of high iron diet shows considerable deviations from the experimental data. Namely the model predicts more iron in red blood cells and less iron in the liver than what was observed in experiments. Conclusions These results suggest that hepcidin alone is not sufficient to regulate iron homeostasis in high iron conditions and that other factors are important. The model was able to simulate anemia when hepcidin was increased but was unable to simulate hemochromatosis when hepcidin was suppressed, suggesting that in high iron conditions additional regulatory interactions are important