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 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 Long-Term Desynchronization by Coordinated Reset Stimulation in a Neural Network Model With Synaptic and Structural Plasticity

2021 ◽  
Vol 12 ◽  
Author(s):  
Thanos Manos ◽  
Sandra Diaz-Pier ◽  
Peter A. Tass
Keyword(s):  
Firing Rate ◽  
Computational Models ◽  
Structural Plasticity ◽  
Brain Disorders ◽  
Neuronal Synchronization ◽  
Neuronal Synchrony ◽  
Firing Rates ◽  
Coordinated Reset

Several brain disorders are characterized by abnormal neuronal synchronization. To specifically counteract abnormal neuronal synchrony and, hence, related symptoms, coordinated reset (CR) stimulation was computationally developed. In principle, successive epochs of synchronizing and desynchronizing stimulation may reversibly move neural networks with plastic synapses back and forth between stable regimes with synchronized and desynchronized firing. Computationally derived predictions have been verified in pre-clinical and clinical studies, paving the way for novel therapies. However, as yet, computational models were not able to reproduce the clinically observed increase of desynchronizing effects of regularly administered CR stimulation intermingled by long stimulation-free epochs. We show that this clinically important phenomenon can be computationally reproduced by taking into account structural plasticity (SP), a mechanism that deletes or generates synapses in order to homeostatically adapt the firing rates of neurons to a set point-like target firing rate in the course of days to months. If we assume that CR stimulation favorably reduces the target firing rate of SP, the desynchronizing effects of CR stimulation increase after long stimulation-free epochs, in accordance with clinically observed phenomena. Our study highlights the pivotal role of stimulation- and dosing-induced modulation of homeostatic set points in therapeutic processes.

scholarly journals Personalized Evaluation of Atrial Complexity of Patients Undergoing Atrial Fibrillation Ablation: A Clinical Computational Study

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 838
Author(s):  
Ana María Sánchez de la Nava ◽  
Ana González Mansilla ◽  
Esteban González-Torrecilla ◽  
Pablo Ávila ◽  
Tomás Datino ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Computational Study ◽  
P Value ◽  
Electrocardiographic Imaging ◽  
Non Invasive ◽  
Electrical Modelling ◽  
One Year ◽  
Improve Patient ◽  
Af Recurrence

Current clinical guidelines establish Pulmonary Vein (PV) isolation as the indicated treatment for Atrial Fibrillation (AF). However, AF can also be triggered or sustained due to atrial drivers located elsewhere in the atria. We designed a new simulation workflow based on personalized computer simulations to characterize AF complexity of patients undergoing PV ablation, validated with non-invasive electrocardiographic imaging and evaluated at one year after ablation. We included 30 patients using atrial anatomies segmented from MRI and simulated an automata model for the electrical modelling, consisting of three states (resting, excited and refractory). In total, 100 different scenarios were simulated per anatomy varying rotor number and location. The 3 states were calibrated with Koivumaki action potential, entropy maps were obtained from the electrograms and compared with ECGi for each patient to analyze PV isolation outcome. The completion of the workflow indicated that successful AF ablation occurred in patients with rotors mainly located at the PV antrum, while unsuccessful procedures presented greater number of driving sites outside the PV area. The number of rotors attached to the PV was significantly higher in patients with favorable long-term ablation outcome (1-year freedom from AF: 1.61 ± 0.21 vs. AF recurrence: 1.40 ± 0.20; p-value = 0.018). The presented workflow could improve patient stratification for PV ablation by screening the complexity of the atria.

Phytolaserophoresis as Integrative Approach to the Treatment of Chronic Internal Organs Diseases

10.12737/5764 ◽  
2014 ◽  
Vol 8 (1) ◽  
pp. 1-7
Author(s):  
Касаева ◽  
E. Kasaeva ◽  
Купеев ◽  
R. Kupeev ◽  
Купеев ◽  
...  
Keyword(s):  
Self Regulation ◽  
The Body ◽  
Integrative Approach ◽  
Therapeutic Effects ◽  
Primary Role ◽  
Endocrine Regulation ◽  
Material Resources ◽  
Non Invasive ◽  
Regulatory Functions

This article describes the development history and basic principles of a modern therapy method - phytolaserophoresis. It provides complex treating impact on chronic diseases, taking into account additional pathogenic disorders of nerve and endocrine regulation. Data analysis of patients with various internal chronic pathologies, revealed the primary role of osteochondrosis and other degenerative disc diseases in maintaining chronic pathological processes. Osteochondrosis doesn’t an isolated problem of the musculoskeletal system, it leads to hypoxia of the brain, the excitement of sub-cortical centers of self-regulation and, as a consequence, in violation of the nervous and endocrine regulation. Treatment by means of phytolaserophoresis method implies soft methods of therapeutic effects on central and peripheral factors to chronic disease. After normalization of the regulatory functions of the body, against the background of recovery of homeostasis and microcirculation in organs, the targeted therapeutic effect at the site of the problem becomes more efficient and can achieve a significant improvement and long-term remission. Advantages of the technique are its non-invasive, absence side effects, available technical and material resources and the possibility of applying the method in medical establishments of any capacity.

Interpretation of clinical studies in electrophysiology: statistical considerations for the clinician

EP Europace ◽  
2020 ◽  
Author(s):  
David Chieng ◽  
Sue Finch ◽  
Hariharan Sugumar ◽  
Andrew J Taylor ◽  
Chris Reid ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Clinical Studies ◽  
Statistical Power ◽  
Sample Size Calculation ◽  
Af Ablation ◽  
Non Invasive ◽  
Intervention Treatment ◽  
Efficient Resource ◽  
Study Designs

Abstract Atrial fibrillation (AF) outcome studies play an essential role in the development of clinical evidence to improve the management of AF patients. Understanding the statistical considerations involved in study design and interpretation is crucial if electrophysiologists are to change practice. In this review, with the guidance of a medical statistician and a clinical trialist we provide an overview of important statistical issues for the clinician, with a focus on clinical studies in AF ablation. Various types of study designs including randomized controlled trials, superiority, and non-inferiority studies are described, along with their implications and limitations. Appropriate sample size calculation is fundamental to ensure statistical power and efficient resource use. Multiplicity in study endpoints is useful to encapsulate the varied effects of an intervention/treatment, although statistical adjustments are required to account for this. Finally, we discuss the limitations with the current primary endpoint used in AF ablation studies, namely, freedom from atrial tachyarrhythmia of >30 seconds, and propose AF burden as a more relevant primary endpoint, based on findings from recent clinical studies. However, technical challenges need to be overcome before AF burden can be routinely adopted, especially the need for non-invasive, long-term monitoring. The emergence of newer technologies, particularly wearable technology, offers significant promise in filling this gap.

scholarly journals Long-Lasting Desynchronization Effects of Coordinated Reset Stimulation Improved by Random Jitters

2021 ◽  
Vol 12 ◽  
Author(s):  
Ali Khaledi-Nasab ◽  
Justus A. Kromer ◽  
Peter A. Tass
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Electrical Current ◽  
Spike Timing ◽  
Stimulation Frequency ◽  
Therapeutic Effects ◽  
Computational Studies ◽  
Synchronous Firing ◽  
Novel Theory ◽  
Coordinated Reset

Abnormally strong synchronized activity is related to several neurological disorders, including essential tremor, epilepsy, and Parkinson's disease. Chronic high-frequency deep brain stimulation (HF DBS) is an established treatment for advanced Parkinson's disease. To reduce the delivered integral electrical current, novel theory-based stimulation techniques such as coordinated reset (CR) stimulation directly counteract the abnormal synchronous firing by delivering phase-shifted stimuli through multiple stimulation sites. In computational studies in neuronal networks with spike-timing-dependent plasticity (STDP), it was shown that CR stimulation down-regulates synaptic weights and drives the network into an attractor of a stable desynchronized state. This led to desynchronization effects that outlasted the stimulation. Corresponding long-lasting therapeutic effects were observed in preclinical and clinical studies. Computational studies suggest that long-lasting effects of CR stimulation depend on the adjustment of the stimulation frequency to the dominant synchronous rhythm. This may limit clinical applicability as different pathological rhythms may coexist. To increase the robustness of the long-lasting effects, we study randomized versions of CR stimulation in networks of leaky integrate-and-fire neurons with STDP. Randomization is obtained by adding random jitters to the stimulation times and by shuffling the sequence of stimulation site activations. We study the corresponding long-lasting effects using analytical calculations and computer simulations. We show that random jitters increase the robustness of long-lasting effects with respect to changes of the number of stimulation sites and the stimulation frequency. In contrast, shuffling does not increase parameter robustness of long-lasting effects. Studying the relation between acute, acute after-, and long-lasting effects of stimulation, we find that both acute after- and long-lasting effects are strongly determined by the stimulation-induced synaptic reshaping, whereas acute effects solely depend on the statistics of administered stimuli. We find that the stimulation duration is another important parameter, as effective stimulation only entails long-lasting effects after a sufficient stimulation duration. Our results show that long-lasting therapeutic effects of CR stimulation with random jitters are more robust than those of regular CR stimulation. This might reduce the parameter adjustment time in future clinical trials and make CR with random jitters more suitable for treating brain disorders with abnormal synchronization in multiple frequency bands.

The Effect of Long-Term Antioxidant Treatments on Redox Homeostasis in Clinical Studies

2007 ◽  
Vol 1 (1) ◽  
pp. 83-95
Author(s):  
Anna Blázovics ◽  
Ágota Kovács ◽  
Andrea Lugasi
Keyword(s):  
Clinical Studies ◽  
Redox Homeostasis

Physical activity and cognitive function in older persons

2016 ◽  
Vol 64 (2) ◽  
Keyword(s):  
Physical Activity ◽  
Cognitive Impairment ◽  
Cognitive Function ◽  
Executive Functions ◽  
Cognitive Aging ◽  
Clinical Studies ◽  
Older Persons ◽  
Positive Effects ◽  
Critical Challenge

Strategies to improve cognitive aging are highly needed. Among those, promotion of exercise and physical activity appears as one of the most attractive and beneficial intervention. Indeed, results from basic and clinical studies suggest that exercise and physical activity have positive effects on cognition in older persons without cognitive impairment, as well as in those with dementia. Despite inconsistent results, aerobic exercise appears to have the strongest potential to enhance cognition. However, even limited periods of walking (45 minutes, three times a week, over a 6-month period) have also been shown to enhance cognition, particularly executive functions. Changing long-term lifestyle habits in these older persons remains a critical challenge and attractive programs susceptible to gain adherence are needed to succeed in achieving improved cognitive aging.

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