Electrical stimulation has been critical in the development of an understanding of brain function and disease. Despite its widespread use and obvious clinical potential, the mechanisms governing stimulation in the cortex remain largely unexplored in the context of pulse parameters. Modeling studies have suggested that modulation of stimulation pulse waveform may be able to control the probability of neuronal activation to selectively stimulate either cell bodies or passing fibers depending on the leading polarity. Thus, asymmetric waveforms with equal charge per phase (i.e., increasing the leading phase duration and proportionately decreasing the amplitude) may be able to activate a more spatially localized or distributed population of neurons if the leading phase is cathodic or anodic, respectively. Here, we use two‐photon and mesoscale calcium imaging of GCaMP6s expressed in excitatory pyramidal neurons of male mice to investigate the role of pulse polarity and waveform asymmetry on the spatiotemporal properties of direct neuronal activation with 10‐Hz electrical stimulation. We demonstrate that increasing cathodic asymmetry effectively reduces neuronal activation and results in a more spatially localized subpopulation of activated neurons without sacrificing the density of activated neurons around the electrode. Conversely, increasing anodic asymmetry increases the spatial spread of activation and highly resembles spatiotemporal calcium activity induced by conventional symmetric cathodic stimulation. These results suggest that stimulation polarity and asymmetry can be used to modulate the spatiotemporal dynamics of neuronal activity thus increasing the effective parameter space of electrical stimulation to restore sensation and study circuit dynamics.

中文翻译：

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具有阴极和阳极不对称波形的体内微刺激调节雄性小鼠皮层神经元和锥体神经元的时空钙动力学。

电刺激对于理解大脑功能和疾病至关重要。尽管其广泛使用且具有明显的临床潜力，但在脉冲参数的背景下，控制皮层刺激的机制在很大程度上仍未得到探索。建模研究表明，刺激脉冲波形的调制可能能够控制神经元激活的概率，以根据引导极性选择性地刺激细胞体或通过的纤维。因此，如果超前相位分别是阴极或阳极，则每相具有相等电荷的不对称波形（即，增加超前相位持续时间并按比例减小幅度）可能能够激活更多空间局部化或分布的神经元群。这里，我们使用雄性小鼠兴奋性锥体神经元中表达的 GCaMP6 的双光子和中尺度钙成像来研究脉冲极性和波形不对称性对 10Hz 电刺激直接神经元激活的时空特性的作用。我们证明，增加阴极不对称性有效地减少了神经元激活，并在不牺牲电极周围激活神经元密度的情况下产生了更多空间局部化的激活神经元亚群。相反，增加阳极不对称性会增加活化的空间扩散，并且非常类似于由传统对称阴极刺激引起的时空钙活性。