Dystonia最新文献

{"title":"Subtle changes in Purkinje cell firing in Purkinje cell-specific <i>Dyt1 ΔGAG</i> knock-in mice.","authors":"Hong Xing, Pallavi Girdhar, Yuning Liu, Fumiaki Yokoi, David E Vaillancourt, Yuqing Li","doi":"10.3389/dyst.2025.14148","DOIUrl":"10.3389/dyst.2025.14148","url":null,"abstract":"<p><p>DYT1 dystonia is an inherited early-onset generalized dystonia characterized by sustained muscle contractions causing abnormal, repetitive movements or postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion (<i>ΔGAG</i>) in <i>DYT1/TOR1A</i>, coding for torsinA. <i>Dyt1</i> heterozygous ΔGAG knock-in (KI) mice or global KI mice show motor deficits and abnormal Purkinje cell firing. However, Purkinje cell-specific heterozygous ΔGAG conditional KI mice (Pcp2-KI) show improved motor performance, reduced sensory-evoked brain activation in the striatum and midbrain, and reduced functional connectivity of the striatum with the anterior medulla. Whether Pcp2-KI mice show similar abnormal Purkinje cell firing as the global KI mice, suggesting a cell-autonomous effect causes the abnormal Purkinje cell firing in the global KI mice, is unknown. We used acute cerebellar slice recording in Pcp2-KI mice to address this issue. The Pcp2-KI mice exhibited no changes in spontaneous firing and intrinsic excitability compared to the control mice. While membrane properties were largely unchanged, the resting membrane potential was slightly hyperpolarized, which was associated with decreased baseline excitability. Our results suggest that the abnormal Purkinje cell firing in the global KI mice was not cell-autonomous and was caused by physiological changes elsewhere in the brain circuits. Our results also contribute to the ongoing research of how basal ganglia and cerebellum interact to influence motor control in normal states and movement disorders.</p>","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"4 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebellar contributions to dystonia: unraveling the role of Purkinje cells and cerebellar nuclei.","authors":"Nichelle N Jackson, Jacob A Stagray, Heather D Snell","doi":"10.3389/dyst.2025.14006","DOIUrl":"10.3389/dyst.2025.14006","url":null,"abstract":"<p><p>Dystonias are a group of neurodegenerative disorders that result in altered physiology associated with motor movements. Both the basal ganglia and the cerebellum, brain regions involved in motor learning, sensory perception integration, and reward, have been implicated in the pathology of dystonia, but the cellular and subcellular mechanisms remain diverse and for some forms of dystonia, elusive. The goal of the current review is to summarize recent evidence of cerebellar involvement in different subtypes of dystonia with a focus on Purkinje cell (PC) and cerebellar nuclei (CN) dysfunction, to find commonalities in the pathology that could lay the groundwork for the future development of therapeutics for patients with dystonia. Here we will briefly discuss the physical and functional connections between the basal ganglia and the cerebellum and how these connections could contribute to dystonic symptoms. We proceed to use human and animal model data to discuss the contributions of cerebellar cell types to specific dystonias and movement disorders where dystonia is a secondary symptom. Ultimately, we suggest PC and CN irregularity could be a locus for dystonia through impaired calcium dynamics.</p>","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"4 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered Functional Brain Connectivity in Dyt1 Knock-in mouse models.","authors":"R Z Adury, B J Wilkes, P Girdhar, Y Li, D E Vaillancourt","doi":"10.3389/dyst.2025.13874","DOIUrl":"10.3389/dyst.2025.13874","url":null,"abstract":"<p><p>DYT1 dystonia is an early onset, generalized form of isolated dystonia characterized by sustained involuntary muscle co-contraction, leading to abnormal movements and postures. It is the most common hereditary form of primary dystonia, caused by a trinucleotide GAG deletion in the DYT1 gene, which encodes the TorsinA protein. Recent studies conceptualized dystonia as a functional network disorder involving basal ganglia, thalamus, cortex and cerebellum. However, how TorsinA dysfunction in specific cell types affects network connectivity and dystonia-related pathophysiology remains unclear. In this study, we aimed to elucidate the impact of the GAG TorsinA mutation present globally and when restricted to the cortical and hippocampal neurons. To accomplish this, we generated two distinct Dyt1 mouse models, one with Dyt1 dGAG knock-in throughout the body (dGAG) and another with a cerebral cortex-specific Dyt1 dGAG knock-in using Emx1 promoter (EMX). In both models, we performed <i>in vivo</i> neuroimaging at ultra-high field (11.1T). We employed functional magnetic resonance imaging (fMRI) to assess resting-state and sensory-evoked brain connectivity and activation, along with diffusion MRI (dMRI) to evaluate microstructural changes. We hypothesized that dGAG mice would exhibit widespread network disruptions compared to the cortex-specific EMX mice, due to broader TorsinA dysfunction across the basal ganglia and cerebellum. We also hypothesized that EMX mice would exhibit altered functional connectivity and activation patterns, supporting the idea that TorsinA dysfunction in the sensorimotor cortex alone can induce network abnormalities. In dGAG animals, we observed significantly lower functional connectivity between key sensorimotor nodes, such as the globus pallidus, somatosensory cortex, thalamus, and cerebellum. EMX mice, while showing less extensive network disruptions, exhibited increased functional connectivity between cerebellum and seeds in the striatum and brainstem. These functional connectivity alterations between nodes in the basal ganglia and the cerebellum in both dGAG, EMX models underscore the involvement of cerebellum in dystonia. No significant structural changes were observed in either model. Overall, these results strengthen the concept of dystonia as a network disorder where multiple nodes across the brain network contribute to pathophysiology, supporting the idea that therapeutic strategies in dystonia may benefit from consideration of network properties across multiple brain regions.</p>","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"4 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific alterations of Purkinje cell firing in <i>Sgce</i> knockout mice and correlations with myoclonus.","authors":"Hong Xing, Pallavi Girdhar, Fumiaki Yokoi, Yuqing Li","doi":"10.3389/dyst.2025.14415","DOIUrl":"10.3389/dyst.2025.14415","url":null,"abstract":"<p><p>Myoclonus is a hyperkinetic movement disorder characterized by sudden, brief, involuntary jerks of single or multiple muscles. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Myoclonus-dystonia (M-D) or DYT11 dystonia is an early-onset genetic disorder characterized by subcortical myoclonus and less pronounced dystonia. DYT11 dystonia is the primary genetic M-D caused by loss of function mutations in <i>SGCE</i>, which codes for ε-sarcoglycan. <i>Sgce</i> knockout (KO) mice model DYT11 dystonia and exhibit myoclonus, motor deficits, and psychiatric-like behaviors. Neuroimaging studies show abnormal cerebellar activity in DYT11 dystonia patients. Acute small hairpin RNA (shRNA) knockdown of <i>Sgce</i> mRNA in the adult cerebellum leads to motor deficits, myoclonic-like jerky movements, and altered Purkinje cell firing. Whether <i>Sgce</i> KO mice show similar abnormal Purkinje cell firing as the acute shRNA knockdown mice is unknown. We used acute cerebellar slice recording in <i>Sgce</i> KO mice to address this issue. The Purkinje cells from <i>Sgce</i> KO mice showed spontaneous and intrinsic excitability changes compared to the wild-type (WT) mice. Intrinsic membrane properties were not altered. The female <i>Sgce</i> KO mice had more profound alterations in Purkinje cell firing than males, which may correspond to the early onset of the symptoms in female human patients and more pronounced myoclonus in female KO mice. Our results suggest that the abnormal Purkinje cell firing in the <i>Sgce</i> KO mice contributes to the manifestation of the myoclonus and other motor symptoms in DYT11 dystonia patients.</p>","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"4 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of botulinum neurotoxin on regularity of head oscillations in cervical dystonia","authors":"Hanieh Agharazi, H. A. Jinnah, David S. Zee, A. Shaikh","doi":"10.3389/dyst.2024.12347","DOIUrl":"https://doi.org/10.3389/dyst.2024.12347","url":null,"abstract":"Introduction: This study explores the effects of botulinum neurotoxin (BoNT) on the relationship between dystonia and tremor, specifically focusing on cervical dystonia (CD) and its connection to head tremor.Methods: Fourteen CD patients were recruited; eight (57%) with clinically observable head oscillations were included in further analysis. A high-resolution magnetic search coil system precisely measured head movements, addressing two questions: 1) BoNT’s effects on head movement amplitude, frequency, and regularity, and 2) BoNT’s influence on the relationship between head position and head oscillations. For the first question, temporal head position measurements of three patients were analyzed before and after BoNT injection. The second question examined the effects of BoNT injections on the dependence of the oscillations on the position of the head.Results: Three distinct trends were observed: shifts from regular to irregular oscillations, transitions from irregular to regular oscillations, and an absence of change. Poincaré analysis revealed that BoNT induced changes in regularity, aligning oscillations closer to a consistent “set point” of regularity. BoNT injections reduced head oscillation amplitude, particularly in head orientations linked to high-intensity pre-injection oscillations. Oscillation frequency decreased in most cases, and overall variance in the amplitude of head position decreased post-injection.Discussion: These findings illuminate the complexity of CD but also suggest therapeutic potential for BoNT. They show that co-existing mechanisms contribute to regular and irregular head oscillations in CD, which involve proprioception and central structures like the cerebellum and basal ganglia. These insights advocate for personalized treatment to optimize outcomes that is based on individual head oscillation characteristics.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"1 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140078011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ε-sarcoglycan myoclonus-dystonia—overview of neurophysiological, behavioral, and imaging characteristics","authors":"Feline Hamami, Skadi Gerkensmeier, Alexander Münchau, A. Weissbach","doi":"10.3389/dyst.2024.11693","DOIUrl":"https://doi.org/10.3389/dyst.2024.11693","url":null,"abstract":"Myoclonus-Dystonia is a rare, neurological movement disorder, clinically characterized by myoclonic jerks and dystonic symptoms, such as cervical dystonia and writer’s cramp. Psychiatric symptoms, like anxiety, depression, and addiction, are frequently reported. Monogenic Myoclonus-Dystonia is mostly caused by pathogenic variants in the ε-sarcoglycan gene, which is among other regions highly expressed in the cerebellum. The current pharmacological treatment is not satisfactory. Neurophysiological and imaging studies in this patient population are scarce with partly heterogeneous results and sometimes important limitations. However, some studies point towards subcortical alterations, e.g., of the cerebellum and its connections. Further studies addressing previous limitations are important for a better understanding of the underlying pathology of Myoclonus-Dystonia and might build a bridge for the development of future treatment.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"72 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140444739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling dystonia circuitry in rodent models using novel neuromodulation techniques","authors":"L. Rauschenberger, Chi Wang Ip","doi":"10.3389/dyst.2024.11793","DOIUrl":"https://doi.org/10.3389/dyst.2024.11793","url":null,"abstract":"Dystonia is a network disorder presumed to result from abnormalities in multiple brain regions and in multiple cell populations. The specific pathomechanisms affecting the motor circuits in dystonia are, however, still largely unclear. Animal models for dystonia have long been used to advance our understanding on how specific brain regions and cell populations are involved in dystonia symptomatogenesis. Lesioning, pharmacological modulation and electrical stimulation paradigms were able to highlight that both the basal ganglia and the cerebellum are pathologically altered in these animal models for dystonia. Techniques such as optogenetics and chemogenetics now offer the opportunity for targeted modulation of brain regions and most importantly cell populations and circuits. This could not only allow for a better understanding of the dystonic brain, but potentially improve and expand treatment options. In hopes that the insights from these neuromodulation techniques will eventually translate into therapies, we aim to summarize and critically discuss the findings from different in vivo approaches used to dissect the network dysfunctions underlying dystonia.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"180 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140449611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and physiological characteristics of tremor in a large cohort of focal and segmental dystonia.","authors":"Zakia Jabarkheel, Aparna Wagle Shukla","doi":"10.3389/dyst.2024.12551","DOIUrl":"10.3389/dyst.2024.12551","url":null,"abstract":"<p><strong>Objective: </strong>Tremor is a frequent co-occurring feature in patients with dystonia, especially in focal and segmental dystonia. Clinical studies have shown that tremor is more commonly observed when dystonia spreads to contiguous body regions. However, there is insufficient characterization of tremor physiology in focal and segmental forms of dystonia. We aimed to ascertain the characteristics of tremor presenting in these specific subtypes.</p><p><strong>Methods: </strong>We enrolled dystonia patients with head and arm tremors presenting to our center. We categorized these participants as focal and segmental dystonia following the Movement Disorders Society guidelines. We recorded the frequency, amplitude, rhythmicity, burst duration, and discharge pattern on accelerometer and electromyography recordings. We compared the physiology of tremors in focal vs. segmental dystonia. We determined whether the physiology was affected by clinical features such as demographics, age at onset, dystonia duration, alcohol responsiveness, family history, and botulinum toxin responsiveness.</p><p><strong>Results: </strong>72 patients, mainly focal cervical dystonia and focal cervical + arm or cranial dystonia (segmental) were enrolled. In the analysis of the head tremor recordings (n = 66; frequency range 3-6.5 Hz), we found that focal vs. segmental dystonia comparisons revealed a significantly lower frequency (mean ± standard deviation; 4.0 ± 0.9 Hz vs. 4.7 ± 1.0 Hz; <i>p</i> = 0.02), lower amplitude (0.004 ± 0.008 g²/Hz vs. 0.006 ± 0.008 g²/Hz; <i>p</i> = 0.03) and longer muscle burst durations (111.1 ± 40.4 ms vs. 91.5 ± 24 ms; <i>p</i> = 0.04). In the analysis of arm tremor recordings (n = 31; frequency range 3.5-7 Hz), we found focal vs. segmental dystonia comparison revealed a lower amplitude (0.04 ± 0.07 g²/Hz vs. 0.06 ± 0.06 g²/Hz; <i>p</i> = 0.045). In the stepwise regression analysis, the age at evaluation (β - 0.44; <i>p</i> = 0.006) and age at onset (β - 0.61; <i>p</i> = 0.005) significantly predicted the head tremor frequency whereas the alcohol responsiveness tended to predict the amplitude of the head tremor (β - 0.5; <i>p</i> = 0.04) and the arm tremor (β - 0.6; <i>p</i> = 0.02).</p><p><strong>Conclusion: </strong>Our study found that the physiological characteristics of tremor in focal and segmental dystonia are somewhat distinct, suggesting that the spread of dystonia symptoms from one body region to another may have a bearing on the physiology of co-occurring tremor. The frequency of head tremors in younger participants was observed to be higher compared to older participants. The head and arm tremor tended be less severe in patients reporting alcohol responsiveness.</p>","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12306709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Piecing together a complex puzzle: 5 key challenges in basic dystonia research","authors":"M. Scarduzio, David G. Standaert","doi":"10.3389/dyst.2023.11615","DOIUrl":"https://doi.org/10.3389/dyst.2023.11615","url":null,"abstract":"Dystonia refers to a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions leading to repetitive twisting movements and abnormal postures. Dystonia has a broad clinical spectrum and can affect different body regions, causing significant disability and reduced quality of life. Despite significant progress in understanding the disorder, many challenges in dystonia research remain. This mini-review aims to highlight the major challenges facing basic and translational research in this field, including 1) heterogeneity of the disorder, 2) limited understanding of its pathophysiology, 3) complications of using animal models, 4) lack of a framework linking genes, biochemistry, circuits, and clinical phenomenology, and 5) limited research funding. Identifying and discussing these challenges can help prioritize research efforts and resources, highlight the need for further investigation and funding, and inspire action towards addressing these challenges.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"70 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138953038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Function and dysfunction of the dystonia network: an exploration of neural circuits that underlie the acquired and isolated dystonias","authors":"Jason S. Gill, Megan X. Nguyen, Mariam Hull, Meike E. van der Heijden, Ken Nguyen, Sruthi P. Thomas, R. Sillitoe","doi":"10.3389/dyst.2023.11805","DOIUrl":"https://doi.org/10.3389/dyst.2023.11805","url":null,"abstract":"Dystonia is a highly prevalent movement disorder that can manifest at any time across the lifespan. An increasing number of investigations have tied this disorder to dysfunction of a broad “dystonia network” encompassing the cerebellum, thalamus, basal ganglia, and cortex. However, pinpointing how dysfunction of the various anatomic components of the network produces the wide variety of dystonia presentations across etiologies remains a difficult problem. In this review, a discussion of functional network findings in non-mendelian etiologies of dystonia is undertaken. Initially acquired etiologies of dystonia and how lesion location leads to alterations in network function are explored, first through an examination of cerebral palsy, in which early brain injury may lead to dystonic/dyskinetic forms of the movement disorder. The discussion of acquired etiologies then continues with an evaluation of the literature covering dystonia resulting from focal lesions followed by the isolated focal dystonias, both idiopathic and task dependent. Next, how the dystonia network responds to therapeutic interventions, from the “geste antagoniste” or “sensory trick” to botulinum toxin and deep brain stimulation, is covered with an eye towards finding similarities in network responses with effective treatment. Finally, an examination of how focal network disruptions in mouse models has informed our understanding of the circuits involved in dystonia is provided. Together, this article aims to offer a synthesis of the literature examining dystonia from the perspective of brain networks and it provides grounding for the perspective of dystonia as disorder of network function.","PeriodicalId":72853,"journal":{"name":"Dystonia","volume":"46 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139005146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}