Manos Thanos, Zeitler Magteld, Tass Peter A
Institute of Neuroscience and Medicine (INM-7), Research Centre Jülich, Jülich, Germany.
Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Front Physiol. 2018 Apr 12;9:376. doi: 10.3389/fphys.2018.00376. eCollection 2018.
In 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.
在本文中，我们通过计算为去同步化神经调节技术背景下的剂量探索研究生成假设。异常强烈的神经元同步是几种脑部疾病的一个标志。协调重置（CR）刺激是一种时空模式化的刺激技术，其专门旨在破坏异常的神经元同步。在具有 spike - 时间依赖性可塑性的网络中，CR 刺激最终可能导致抗点燃，即异常突触连接和神经元同步的消退。这种长期的去同步化在理论上已被预测，并在多项临床前和临床研究中得到验证。我们已经表明，使用快速变化序列（RVS）的 CR 刺激在低强度下能有力地诱导抗点燃，例如，如果 CR 刺激频率（即刺激模式重复率）处于神经元振荡频率范围内。相比之下，使用缓慢变化序列（SVS）的 CR 刺激结果显示能更强烈地诱导抗点燃，但相对于 CR 刺激频率的变化，其稳健性较差。受临床限制的推动并受学习理论间隔原则的启发，在这项计算研究中，我们提出了一种短期给药方案，该方案能使 RVS 和 SVS CR 刺激都产生稳健的抗点燃效果，对于那些之前 RVS 和 SVS CR 刺激被证明无效的参数值也是如此。有趣的是，对于绝大多数测试的参数值，具有按需控制的刺激频率和强度变化的间隔多次 CR 刺激会导致稳健且明显的抗点燃。相比之下，具有固定刺激参数的间隔 CR 刺激以及等积分持续时间的单次 CR 刺激未能改善刺激结果。在所考虑的模型网络中，我们的短期给药方案能够在相对较短的刺激持续时间和低积分刺激持续时间下有力地诱导长期去同步化。目前，深部脑 CR 刺激用于帕金森病治疗以及声学 CR 刺激用于耳鸣治疗已有临床概念验证。对于帕金森病治疗的振动触觉 CR 刺激已有有前景的首次人体数据。对于这些治疗方法的临床开发，进行剂量探索研究以揭示最佳刺激参数和给药方案是必不可少的。我们的研究结果可以直接在人体剂量探索研究中进行测试。
