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      A Humanized Clinically Calibrated Quantitative Systems Pharmacology Model for Hypokinetic Motor Symptoms in Parkinson’s Disease

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          Abstract

          The current treatment of Parkinson’s disease with dopamine-centric approaches such as L-DOPA and dopamine agonists, although very successful, is in need of alternative treatment strategies, both in terms of disease modification and symptom management. Various non-dopaminergic treatment approaches did not result in a clear clinical benefit, despite showing a clear effect in preclinical animal models. In addition, polypharmacy is common, sometimes leading to unintended effects on non-motor cognitive and psychiatric symptoms. To explore novel targets for symptomatic treatment and possible synergistic pharmacodynamic effects between different drugs, we developed a computer-based Quantitative Systems Pharmacology (QSP) platform of the closed cortico-striatal-thalamic-cortical basal ganglia loop of the dorsal motor circuit. This mechanism-based simulation platform is based on the known neuro-anatomy and neurophysiology of the basal ganglia and explicitly incorporates domain expertise in a formalized way. The calculated beta/gamma power ratio of the local field potential in the subthalamic nucleus correlates well ( R 2 = 0.71) with clinically observed extra-pyramidal symptoms triggered by antipsychotics during schizophrenia treatment (43 drug-dose combinations). When incorporating Parkinsonian (PD) pathology and reported compensatory changes, the computer model suggests a major increase in b/g ratio (corresponding to bradykinesia and rigidity) from a dopamine depletion of 70% onward. The correlation between the outcome of the QSP model and the reported changes in UPDRS III Motor Part for 22 placebo-normalized drug-dose combinations is R 2 = 0.84. The model also correctly recapitulates the lack of clinical benefit for perampanel, MK-0567 and flupirtine and offers a hypothesis for the translational disconnect. Finally, using human PET imaging studies with placebo response, the computer model predicts well the placebo response for chronic treatment, but not for acute treatment in PD.

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          Most cited references 68

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          Reconstruction and Simulation of Neocortical Microcircuitry.

          We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies.
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            High frequency stimulation of the subthalamic nucleus eliminates pathological thalamic rhythmicity in a computational model.

            Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) has recently been recognized as an important form of intervention for alleviating motor symptoms associated with Parkinson's disease, but the mechanism underlying its effectiveness remains unknown. Using a computational model, this paper considers the hypothesis that DBS works by replacing pathologically rhythmic basal ganglia output with tonic, high frequency firing. In our simulations of parkinsonian conditions, rhythmic inhibition from GPi to the thalamus compromises the ability of thalamocortical relay (TC) cells to respond to depolarizing inputs, such as sensorimotor signals. High frequency stimulation of STN regularizes GPi firing, and this restores TC responsiveness, despite the increased frequency and amplitude of GPi inhibition to thalamus that result. We provide a mathematical phase plane analysis of the mechanisms that determine TC relay capabilities in normal, parkinsonian, and DBS states in a reduced model. This analysis highlights the differences in deinactivation of the low-threshold calcium T -current that we observe in TC cells in these different conditions. Alternative scenarios involving convergence of thalamic signals in the cortex are also discussed, and predictions associated with these results, including the occurrence of rhythmic rebound bursts in certain TC cells in parkinsonian states and their drastic reduction by DBS, are stated. These results demonstrate how DBS could work by increasing firing rates of target cells, rather than shutting them down. Copyright 2004 Kluwer Academic Publishers
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              Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics.

              The conductance activated in many mammalian CNS neurons by the glutamate analog NMDA is inhibited at hyperpolarized potentials by extracellular magnesium. Whole-cell recordings from hippocampal neurons in culture were used to determine the voltage dependence of the NMDA conductance in the presence of extracellular magnesium concentrations from 1 microM to 10 mM. The conductance-voltage data are well fitted by a gating function derived from rate constants determined in an earlier study of the kinetic behavior of single channels activated by NMDA. The results are consistent with the assumption that magnesium inhibits current through the NMDA-activated channel by directly blocking the ion pore. In addition, another voltage-dependent blocking or flicker-producing mechanism has to be invoked to account for the behavior of the conductance at both the single-channel and whole-cell level, especially at low concentrations of extracellular magnesium.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                02 February 2016
                2016
                : 7
                Affiliations
                1In Silico Biosciences Berwyn, PA, USA
                2Washington State University Vancouver, WA, USA
                3Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA
                Author notes

                Edited by: Chiranjib Chakraborty, Galgotias University, India

                Reviewed by: John M. Seubert, University of Alberta, Canada; Maria Grazia Morgese, University of Foggia, Italy

                *Correspondence: Hugo Geerts, hugo-geerts@ 123456in-silicobiosciences.com

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2016.00006
                4735425
                26869923
                Copyright © 2016 Roberts, Spiros and Geerts.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 79, Pages: 14, Words: 0
                Categories
                Pharmacology
                Original Research

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