Ahmet Kaymak PhD, Fabiana Colucci MD, PhD, Mahboubeh Ahmadipour PhD, Nico Golfrè Andreasi MD, Sara Rinaldo Tch, Zvi Israel MD, David Arkadir MD, PhD, Roberta Telese MD, Vincenzo Levi MD, Giovanna Zorzi MD, Jacopo Carpaneto PhD, Miryam Carecchio MD, PhD, Holger Prokisch PhD, Michael Zech MD, PhD, Barbara Garavaglia PhD, Hagai Bergman MD, PhD, Roberto Eleopra MD, Alberto Mazzoni PhD, Luigi M. Romito MD, PhD
{"title":"苍白球的尖峰模式突出了不同遗传性肌张力障碍综合征的收敛神经动力学。","authors":"Ahmet Kaymak PhD, Fabiana Colucci MD, PhD, Mahboubeh Ahmadipour PhD, Nico Golfrè Andreasi MD, Sara Rinaldo Tch, Zvi Israel MD, David Arkadir MD, PhD, Roberta Telese MD, Vincenzo Levi MD, Giovanna Zorzi MD, Jacopo Carpaneto PhD, Miryam Carecchio MD, PhD, Holger Prokisch PhD, Michael Zech MD, PhD, Barbara Garavaglia PhD, Hagai Bergman MD, PhD, Roberto Eleopra MD, Alberto Mazzoni PhD, Luigi M. Romito MD, PhD","doi":"10.1002/ana.27185","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>Genetic dystonia is a complex movement disorder with diverse clinical manifestations resulting from pathogenic mutations in associated genes. A recent paradigm shift emphasizes the functional convergence among dystonia genes, hinting at a shared pathomechanism. However, the neural dynamics supporting this convergence remain largely unexplored.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Herein, we analyzed microelectrode recordings acquired during pallidal deep brain stimulation surgery from 31 dystonia patients with pathogenic mutations in the <i>AOPEP</i>, <i>GNAL</i>, <i>KMT2B</i>, <i>PANK2</i>, <i>PLA2G6</i>, <i>SGCE</i>, <i>THAP1</i>, <i>TOR1A</i>, and <i>VPS16</i> genes. We identified 1,694 single units whose activity was characterized by a broad set of neural features.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p><i>AOPEP</i>, <i>PANK2</i>, and <i>THAP1</i> displayed higher firing regularity, whereas <i>GNAL</i>, <i>PLA2G6</i>, <i>KMT2B</i>, and <i>SGCE</i> shared a large fraction of bursting neurons (> 26.6%), significantly exceeding the rate in other genes. <i>TOR1A</i> and <i>VPS16</i> genes constituted an intermediate group, bridging these 2 groups, due to having the highest degree of spiking irregularity. Hierarchical clustering algorithms based on these dynamics confirmed the results obtained with first-order comparisons.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>Despite lacking common molecular pathways, dystonia genes share largely overlapping structures of neural patterns, in particular the degree of pallidal spiking regularity and bursting activity. We propose that the degree of desynchronization facilitated by pallidal neural bursts may explain the variability in deep brain stimulation (DBS) of the globus pallidus internus (GPi) surgery outcomes across genetic dystonia syndromes. Lastly, investigating the effects of genetic mutations on low-frequency pallidal activity could optimize personalized adaptive DBS treatments in patients with genetic dystonia. ANN NEUROL 2025;97:826–844</p>\n </section>\n </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 5","pages":"826-844"},"PeriodicalIF":8.1000,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27185","citationCount":"0","resultStr":"{\"title\":\"Spiking Patterns in the Globus Pallidus Highlight Convergent Neural Dynamics across Diverse Genetic Dystonia Syndromes\",\"authors\":\"Ahmet Kaymak PhD, Fabiana Colucci MD, PhD, Mahboubeh Ahmadipour PhD, Nico Golfrè Andreasi MD, Sara Rinaldo Tch, Zvi Israel MD, David Arkadir MD, PhD, Roberta Telese MD, Vincenzo Levi MD, Giovanna Zorzi MD, Jacopo Carpaneto PhD, Miryam Carecchio MD, PhD, Holger Prokisch PhD, Michael Zech MD, PhD, Barbara Garavaglia PhD, Hagai Bergman MD, PhD, Roberto Eleopra MD, Alberto Mazzoni PhD, Luigi M. Romito MD, PhD\",\"doi\":\"10.1002/ana.27185\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>Genetic dystonia is a complex movement disorder with diverse clinical manifestations resulting from pathogenic mutations in associated genes. A recent paradigm shift emphasizes the functional convergence among dystonia genes, hinting at a shared pathomechanism. However, the neural dynamics supporting this convergence remain largely unexplored.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Herein, we analyzed microelectrode recordings acquired during pallidal deep brain stimulation surgery from 31 dystonia patients with pathogenic mutations in the <i>AOPEP</i>, <i>GNAL</i>, <i>KMT2B</i>, <i>PANK2</i>, <i>PLA2G6</i>, <i>SGCE</i>, <i>THAP1</i>, <i>TOR1A</i>, and <i>VPS16</i> genes. We identified 1,694 single units whose activity was characterized by a broad set of neural features.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p><i>AOPEP</i>, <i>PANK2</i>, and <i>THAP1</i> displayed higher firing regularity, whereas <i>GNAL</i>, <i>PLA2G6</i>, <i>KMT2B</i>, and <i>SGCE</i> shared a large fraction of bursting neurons (> 26.6%), significantly exceeding the rate in other genes. <i>TOR1A</i> and <i>VPS16</i> genes constituted an intermediate group, bridging these 2 groups, due to having the highest degree of spiking irregularity. Hierarchical clustering algorithms based on these dynamics confirmed the results obtained with first-order comparisons.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Interpretation</h3>\\n \\n <p>Despite lacking common molecular pathways, dystonia genes share largely overlapping structures of neural patterns, in particular the degree of pallidal spiking regularity and bursting activity. We propose that the degree of desynchronization facilitated by pallidal neural bursts may explain the variability in deep brain stimulation (DBS) of the globus pallidus internus (GPi) surgery outcomes across genetic dystonia syndromes. Lastly, investigating the effects of genetic mutations on low-frequency pallidal activity could optimize personalized adaptive DBS treatments in patients with genetic dystonia. ANN NEUROL 2025;97:826–844</p>\\n </section>\\n </div>\",\"PeriodicalId\":127,\"journal\":{\"name\":\"Annals of Neurology\",\"volume\":\"97 5\",\"pages\":\"826-844\"},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2025-01-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27185\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ana.27185\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ana.27185","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Spiking Patterns in the Globus Pallidus Highlight Convergent Neural Dynamics across Diverse Genetic Dystonia Syndromes
Objective
Genetic dystonia is a complex movement disorder with diverse clinical manifestations resulting from pathogenic mutations in associated genes. A recent paradigm shift emphasizes the functional convergence among dystonia genes, hinting at a shared pathomechanism. However, the neural dynamics supporting this convergence remain largely unexplored.
Methods
Herein, we analyzed microelectrode recordings acquired during pallidal deep brain stimulation surgery from 31 dystonia patients with pathogenic mutations in the AOPEP, GNAL, KMT2B, PANK2, PLA2G6, SGCE, THAP1, TOR1A, and VPS16 genes. We identified 1,694 single units whose activity was characterized by a broad set of neural features.
Results
AOPEP, PANK2, and THAP1 displayed higher firing regularity, whereas GNAL, PLA2G6, KMT2B, and SGCE shared a large fraction of bursting neurons (> 26.6%), significantly exceeding the rate in other genes. TOR1A and VPS16 genes constituted an intermediate group, bridging these 2 groups, due to having the highest degree of spiking irregularity. Hierarchical clustering algorithms based on these dynamics confirmed the results obtained with first-order comparisons.
Interpretation
Despite lacking common molecular pathways, dystonia genes share largely overlapping structures of neural patterns, in particular the degree of pallidal spiking regularity and bursting activity. We propose that the degree of desynchronization facilitated by pallidal neural bursts may explain the variability in deep brain stimulation (DBS) of the globus pallidus internus (GPi) surgery outcomes across genetic dystonia syndromes. Lastly, investigating the effects of genetic mutations on low-frequency pallidal activity could optimize personalized adaptive DBS treatments in patients with genetic dystonia. ANN NEUROL 2025;97:826–844
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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