scholarly journals Short-term dosage regimen for stimulation-induced long-lasting desynchronization

2017 ◽  
Author(s):  
Thanos Manos ◽  
Magteld Zeitler ◽  
Peter A. Tass
Keyword(s):  
Dosage Regimen ◽  
Computational Study ◽  
Spike Timing ◽  
Stimulation Frequency ◽  
Dose Finding ◽  
Short Term ◽  
Neuronal Synchrony ◽  
Stimulation Parameters ◽  
Human Dose ◽  
Parameter Values

AbstractIn this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e. an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g. if the CR stimulation frequency (i.e. stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long-term desynchronization at comparably short stimulation duration and low integral stimulation duration. Currently, clinical proof of concept is available for deep brain CR stimulation for Parkinson’s therapy and acoustic CR stimulation for tinnitus therapy. Promising first in human data is available for vibrotactile CR stimulation for Parkinson’s treatment. For the clinical development of these treatments it is mandatory to perform dose-finding studies to reveal optimal stimulation parameters and dosage regimens. Our findings can straightforwardly be tested in human dose-finding studies.

scholarly journals How stimulation frequency and intensity impact on the long-lasting effects of coordinated reset stimulation

2017 ◽  
Author(s):  
Thanos Manos ◽  
Magteld Zeitler ◽  
Peter A. Tass
Keyword(s):  
Clinical Studies ◽  
Computational Study ◽  
Stimulation Frequency ◽  
Therapeutic Effects ◽  
Neuronal Synchronization ◽  
Neuronal Synchrony ◽  
Non Invasive ◽  
Stimulation Parameters ◽  
Coordinated Reset

AbstractSeveral brain diseases are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was computationally designed to specifically counteract abnormal neuronal synchronization processes by desynchronization. In the presence of spike-timing-dependent plasticity (STDP) this may lead to a decrease of synaptic excitatory weights and ultimately to an anti-kindling, i.e. unlearning of abnormal synaptic connectivity and abnormal neuronal synchrony. The long-lasting desynchronizing impact of CR stimulation has been verified in pre-clinical and clinical proof of concept studies. However, as yet it is unclear how to optimally choose the CR stimulation frequency, i.e. the repetition rate at which the CR stimuli are delivered. This work presents the first computational study on the dependence of the acute and long-term outcome on the CR stimulation frequency in neuronal networks with STDP. For this purpose, CR stimulation was applied with Rapidly Varying Sequences (RVS) as well as with Slowly Varying Sequences (SVS) in a wide range of stimulation frequencies and intensities. Our findings demonstrate that acute desynchronization, achieved during stimulation, does not necessarily lead to long-term desynchronization after cessation of stimulation. By comparing the long-term effects of the two different CR protocols, the RVS CR stimulation turned out to be more robust against variations of the stimulation frequency. However, SVS CR stimulation can obtain stronger anti-kindling effects. We revealed specific parameter ranges that are favorable for long-term desynchronization. For instance, RVS CR stimulation at weak intensities and with stimulation frequencies in the range of the neuronal firing rates turned out to be effective and robust, in particular, if no closed loop adaptation of stimulation parameters is (technically) available. From a clinical standpoint, this may be relevant in the context of both invasive as well as non-invasive CR stimulation.Author SummaryAbnormally strong neuronal synchronization is found in a number of brain disorders. To specifically counteract abnormal neuronal synchrony and, hence, related symptoms, Coordinated Reset (CR) stimulation was developed. CR stimulation employs basic plasticity and dynamic self-organization principles of the nervous system. Its fundamental goal is to induce long-lasting desynchronizing effects that persist cessation of stimulation. The latter are key to reducing side effects of invasive therapies such as deep brain stimulation. Furthermore, sustained stimulation effects pave the way for non-invasive neuromodulation treatments, where a few hours of stimulation delivered regularly or occasionally may provide substantial relief. Long-lasting CR-induced desynchronizing therapeutic effects have been verified in several pre-clinical and clinical studies. However, we here present the first computational study that systematically investigates the impact of key stimulation parameters on the stimulation outcome. Our results provide experimentally testable predictions that are relevant for pre-clinical and clinical studies. Furthermore, our results may contribute to stimulation techniques that enable to probe the functional role of brain rhythms in general.

scholarly journals Computational study of synchrony in fields and microclusters of ephaptically coupled neurons

2015 ◽  
Vol 113 (9) ◽  
pp. 3229-3241 ◽  
Author(s):  
R. Greg Stacey ◽  
Lennart Hilbert ◽  
Thomas Quail
Keyword(s):  
Electric Fields ◽  
Computational Study ◽  
Extracellular Volume ◽  
Low Frequency ◽  
Spike Timing ◽  
Single Action ◽  
Neuronal Synchrony ◽  
Single Spike ◽  
Ephaptic Coupling

Neuronal hypersynchrony is implicated in epilepsy and other diseases. The low-frequency, spatially averaged electric fields from many thousands of neurons have been shown to promote synchrony. It remains unclear whether highly transient, spatially localized electric fields from single action potentials (ephaptic coupling) significantly affect spike timing of neighboring cells and in consequence, population synchrony. In this study, we simulated the extracellular potentials and the resulting coupling between neurons in the NEURON environment and generalized their connection rules to create an oscillator network model of a sheet of ephaptically coupled neurons. With the use of both models, we explained several aspects of epileptiform behavior not previously modeled by synaptically coupled networks. Importantly, reduction of neuron spacing induced synchronization via single-spike ephaptic coupling, agreeing with seizure suppression seen clinically and in vitro via extracellular volume adjustment. Further reduction of neuron spacing yielded locally synchronized clusters, providing a mechanism for recent in vitro observations of localized neuronal synchrony in the absence of synaptic and gap-junction coupling.

Combined eye-head gaze shifts produced by electrical stimulation of the superior colliculus in rhesus monkeys

1996 ◽  
Vol 76 (2) ◽  
pp. 927-952 ◽  
Author(s):  
E. G. Freedman ◽  
T. R. Stanford ◽  
D. L. Sparks
Keyword(s):  
Rhesus Monkeys ◽  
Stimulation Frequency ◽  
Head Movements ◽  
Visually Guided ◽  
Maximal Amplitude ◽  
Gaze Shifts ◽  
Gaze Shift ◽  
Site Specific ◽  
Stimulation Parameters ◽  
Frequency Of Stimulation

1. We electrically stimulated the intermediate and deep layers of the superior colliculus (SC) in two rhesus macaques free to move their heads both vertically and horizontally (head unrestrained). Stimulation of the primate SC can elicit high-velocity, combined, eye-head gaze shifts that are similar to visually guided gaze shifts of comparable amplitude and direction. The amplitude of gaze shifts produced by collicular stimulation depends on the site of stimulation and on the parameters of stimulation (frequency, current, and duration of the stimulation train). 2. The maximal amplitude gaze shifts, produced by electrical stimulation at 56 sites in the SC of two rhesus monkeys, ranged in amplitude from approximately 7 to approximately 80 deg. Because the head was unrestrained, stimulation-induced gaze shifts often included movements of the head. Head movements produced at the 56 stimulation sites ranged in amplitude from 0 to approximately 70 deg. 3. The relationships between peak velocity and amplitude and between duration and amplitude of stimulation-induced head movements and gaze shifts were comparable with the relationships observed during visually guided gaze shifts. The relative contributions of the eyes and head to visually guided and stimulation-induced gaze shifts were also similar. 4. As was true for visually guided gaze shifts, the head contribution to stimulation-induced gaze shifts depended on the position of the eyes relative to the head at the onset of stimulation. When the eyes were deviated in the direction of the ensuing gaze shift, the head contribution increased and the latency to head movement onset was decreased. 5. We systematically altered the duration of stimulation trains (10-400 ms) while stimulation frequency and current remained constant. Increases in stimulation duration systematically increased the amplitude of the evoked gaze shift until a site specific maximal amplitude was reached. Further increases in stimulation duration did not increase gaze amplitude. There was a high correlation between the end of the stimulation train and the end of the evoked gaze shift for movements smaller than the site-specific maximal amplitude. 6. Unlike the effects of stimulation duration on gaze amplitude, the amplitude and duration of evoked head movements did not saturate for the range of durations tested (10-400 ms), but continued to increase linearly with increases in stimulation duration. 7. The frequency of stimulation was systematically varied (range: 63-1,000 Hz) while other stimulation parameters remained constant. The velocity of evoked gaze shifts was related to the frequency of stimulation; higher stimulation frequencies resulted in higher peak velocities. The maximal, site-specific amplitude was independent of stimulation frequency. 8. When stimulating a single collicular site using identical stimulation parameters, the amplitude and direction of stimulation-induced gaze shifts, initiated from different initial positions, were relatively constant. In contrast, the amplitude and direction of the eye component of these fixed vector gaze shifts depended upon the initial position of the eyes in the orbits; the endpoints of the eye movements converged on an orbital region, or "goal," that depended on the site of collicular stimulation. 9. When identical stimulation parameters were used and when the eyes were centered initially in the orbits, the gaze shifts produced by caudal collicular stimulation when the head was restrained were typically smaller than those evoked from the same site when the head was unrestrained. This attenuation occurred because stimulation drove the eyes to approximately the same orbital position when the head was restrained or unrestrained. Thus movements produced when the head was restrained were reduced in amplitude by approximately the amount that the head would have contributed if free to move. 10. When the head was restrained, only the eye component of the intended gaze shift

Effects of Preactivated MC540 in the Treatment of Lymphocytic Plasmacytic Stomatitis in Feline Leukemia virus and Feline Immunodeficiency virus Positive Cats

1993 ◽  
Vol 10 (1) ◽  
pp. 9-13 ◽  
Author(s):  
Robert B. Wiggs ◽  
Heidi B. Lobprise ◽  
James L. Matthews ◽  
Kripal S. Gulliya
Keyword(s):  
Feline Immunodeficiency Virus ◽  
Dosage Regimen ◽  
Antitumor Agents ◽  
Leukemia Virus ◽  
Feline Leukemia Virus ◽  
Short Term ◽  
Merocyanine 540 ◽  
Immunodeficiency Virus

Photoactive compounds and drugs are used therapeutically as antibacterial, antiviral and antitumor agents. This report examines the use of a photoactive compound, preactivated merocyanine 540 (pMC540), in the treatment of stomatitis in two cats that are both feline immunodeficiency virus (FIV) positive. One of the cats was also feline leukemia virus (FeLV) positive. Dramatic short term improvement is reported with the dosage regimen and complications.

Restitution and adaptation measurements for the estimate of short-term cardiac action potential memory: comparison of five human ventricular models

EP Europace ◽  
2019 ◽  
Vol 21 (10) ◽  
pp. 1594-1602
Author(s):  
Massimiliano Zaniboni ◽  
Francesca Cacciani
Keyword(s):  
Steady State ◽  
Action Potential ◽  
Short Term Memory ◽  
Computational Study ◽  
Numerical Models ◽  
Cardiac Action Potential ◽  
Short Term ◽  
Term Memory ◽  
Cardiac Action

Abstract Aims This computational study refines our recently published pacing protocol to measure short-term memory (STM) of cardiac action potential (AP), and apply it to five numerical models of human ventricular AP. Methods and results Several formulations of electrical restitution (ER) have been provided over the years, including standard, beat-to-beat, dynamic, steady-state, which make it difficult to compare results from different studies. We discuss here the notion of dynamic ER (dER) by relating it to its steady-state counterpart, and propose a pacing protocol based on dER to measure STM under periodically varying pacing cycle length (CL). Under high and highly variable-pacing rate, all models develop STM, which can be measured over the entire sequence by means of dER. Short-term memory can also be measured on a beat-to-beat basis by estimating action potential duration (APD) adaptation after clamping CL constant. We visualize STM as a phase shift between action potential (AP) parameters over consecutive cycles of CL oscillations, and show that delay between CL and APD oscillation is nearly constant (around 92 ms) in the five models, despite variability in their intrinsic AP properties. Conclusion dER, as we define it and together with other approaches described in the study, provides an univocal way to measure STM under extreme cardiac pacing conditions. Given the relevance of AP memory for repolarization dynamics and stability, STM should be considered, among other usual biomarkers, to validate and tune cardiac AP models. The possibility of extending the method to in vivo cellular and whole organ models can also be profitably explored.

scholarly journals Computational study of bacterial depolymerization process of xenobiotic polymer

2018 ◽  
Vol 189 ◽  
pp. 02007
Author(s):  
Masaji Watanabe ◽  
Fusako Kawai
Keyword(s):  
Sole Carbon Source ◽  
Culture Media ◽  
Computational Study ◽  
Time Factor ◽  
Computational Techniques ◽  
Weight Distributions ◽  
Molecular Factor ◽  
Before And After ◽  
Parameter Values ◽  
Two Parameter

This study shows an efficient applicability of computational techniques to analyses of microbial depolymerisation process. Microorganisms were cultivated in a culture media in which a polymer was a sole carbon source, and weight distributions before and after cultivation were introduced into inverse analysis for a molecular factor and a time factor of a degradation rate. An inverse problem for two parameter values associated with the time factor was solved numerically. Once the molecular factor and the time factor were given, microbial depolymerization process was simulated.

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