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dc.contributor.authorNeymotin, Samuel A
dc.contributor.authorDura-Bernal, Salvador
dc.contributor.authorLakatos, Peter
dc.contributor.authorSanger, Terence D
dc.contributor.authorLytton, William W
dc.date.accessioned2023-04-10T16:47:07Z
dc.date.available2023-04-10T16:47:07Z
dc.date.issued2016-06-14
dc.identifier.citationNeymotin SA, Dura-Bernal S, Lakatos P, Sanger TD, Lytton WW. Multitarget Multiscale Simulation for Pharmacological Treatment of Dystonia in Motor Cortex. Front Pharmacol. 2016 Jun 14;7:157. doi: 10.3389/fphar.2016.00157. PMID: 27378922; PMCID: PMC4906029.en_US
dc.identifier.issn1663-9812
dc.identifier.doi10.3389/fphar.2016.00157
dc.identifier.pmid27378922
dc.identifier.urihttp://hdl.handle.net/20.500.12648/8574
dc.description.abstractA large number of physiomic pathologies can produce hyperexcitability in cortex. Depending on severity, cortical hyperexcitability may manifest clinically as a hyperkinetic movement disorder or as epilpesy. We focus here on dystonia, a movement disorder that produces involuntary muscle contractions and involves pathology in multiple brain areas including basal ganglia, thalamus, cerebellum, and sensory and motor cortices. Most research in dystonia has focused on basal ganglia, while much pharmacological treatment is provided directly at muscles to prevent contraction. Motor cortex is another potential target for therapy that exhibits pathological dynamics in dystonia, including heightened activity and altered beta oscillations. We developed a multiscale model of primary motor cortex, ranging from molecular, up to cellular, and network levels, containing 1715 compartmental model neurons with multiple ion channels and intracellular molecular dynamics. We wired the model based on electrophysiological data obtained from mouse motor cortex circuit mapping experiments. We used the model to reproduce patterns of heightened activity seen in dystonia by applying independent random variations in parameters to identify pathological parameter sets. These models demonstrated degeneracy, meaning that there were many ways of obtaining the pathological syndrome. There was no single parameter alteration which would consistently distinguish pathological from physiological dynamics. At higher dimensions in parameter space, we were able to use support vector machines to distinguish the two patterns in different regions of space and thereby trace multitarget routes from dystonic to physiological dynamics. These results suggest the use of in silico models for discovery of multitarget drug cocktails.
dc.language.isoenen_US
dc.relation.urlhttps://www.frontiersin.org/articles/10.3389/fphar.2016.00157/fullen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectbeta oscillationsen_US
dc.subjectcomputer simulationen_US
dc.subjectcorticospinal neuronsen_US
dc.subjectdystoniaen_US
dc.subjectmotor cortexen_US
dc.subjectmultiscale modelingen_US
dc.subjectmultitarget pharmacologyen_US
dc.subjectsupport vector machinesen_US
dc.titleMultitarget Multiscale Simulation for Pharmacological Treatment of Dystonia in Motor Cortex.en_US
dc.typeArticle/Reviewen_US
dc.source.journaltitleFrontiers in pharmacologyen_US
dc.source.volume7
dc.source.beginpage157
dc.source.endpage
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countrySwitzerland
dc.description.versionVoRen_US
refterms.dateFOA2023-04-10T16:47:07Z
html.description.abstractA large number of physiomic pathologies can produce hyperexcitability in cortex. Depending on severity, cortical hyperexcitability may manifest clinically as a hyperkinetic movement disorder or as epilpesy. We focus here on dystonia, a movement disorder that produces involuntary muscle contractions and involves pathology in multiple brain areas including basal ganglia, thalamus, cerebellum, and sensory and motor cortices. Most research in dystonia has focused on basal ganglia, while much pharmacological treatment is provided directly at muscles to prevent contraction. Motor cortex is another potential target for therapy that exhibits pathological dynamics in dystonia, including heightened activity and altered beta oscillations. We developed a multiscale model of primary motor cortex, ranging from molecular, up to cellular, and network levels, containing 1715 compartmental model neurons with multiple ion channels and intracellular molecular dynamics. We wired the model based on electrophysiological data obtained from mouse motor cortex circuit mapping experiments. We used the model to reproduce patterns of heightened activity seen in dystonia by applying independent random variations in parameters to identify pathological parameter sets. These models demonstrated degeneracy, meaning that there were many ways of obtaining the pathological syndrome. There was no single parameter alteration which would consistently distinguish pathological from physiological dynamics. At higher dimensions in parameter space, we were able to use support vector machines to distinguish the two patterns in different regions of space and thereby trace multitarget routes from dystonic to physiological dynamics. These results suggest the use of in silico models for discovery of multitarget drug cocktails.
dc.description.institutionSUNY Downstateen_US
dc.description.departmentPhysiology and Pharmacologyen_US
dc.description.departmentNathan Kline Institute for Psychiatric Researchen_US
dc.description.degreelevelN/Aen_US
dc.identifier.journalFrontiers in pharmacology


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