title: Multitarget Multiscale Simulation for Pharmacological Treatment of Dystonia in Motor Cortex.
abstract: A 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.
authors.affiliation: Department Physiology and Pharmacology, SUNY Downstate Medical Center, State University of New YorkBrooklyn, NY, USA; Department Neuroscience, Yale University School of MedicineNew Haven, CT, USA.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Neymotin
authors.affiliation: Department Physiology and Pharmacology, SUNY Downstate Medical Center, State University of New York Brooklyn, NY, USA.
authors.forename: Salvador
authors.initials: S
authors.lastname: Dura-Bernal
authors.affiliation: Nathan S. Kline Institute for Psychiatric Research Orangeburg, NY, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Lakatos
authors.affiliation: Department Biomedical Engineering, University of Southern CaliforniaLos Angeles, CA, USA; Division Neurology, Child Neurology and Movement Disorders, Children's Hospital Los AngelesLos Angeles, CA, USA.
authors.forename: Terence D
authors.initials: TD
authors.lastname: Sanger
authors.affiliation: Department Physiology and Pharmacology, SUNY Downstate Medical Center, State University of New YorkBrooklyn, NY, USA; Department Neurology, SUNY Downstate Medical CenterBrooklyn, NY, USA; Department Neurology, Kings County Hospital CenterBrooklyn, NY, USA; The Robert F. Furchgott Center for Neural and Behavioral ScienceBrooklyn, NY, US.
authors.forename: William W
authors.initials: WW
authors.lastname: Lytton
keywords: beta oscillations; computer simulation; corticospinal neurons; dystonia; motor cortex; multiscale modeling; multitarget pharmacology; support vector machines