In vivo microstimulation with cathodic and anodic asymmetric waveforms modulates spatiotemporal calcium dynamics in cortical neuropil and pyramidal neurons of male mice

Abstract

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.

Systematic Evaluation of DBS Parameters in the Hemi-Parkinsonian Rat Model

“…Neither PW, nor polarity, wave asymmetry or interphase intervals were varied in this study ( Stieger et al, 2020 ). We thus cannot claim our systematic investigation of different STN-DBS parameters in the hemi-parkinsonian rat to be complete, yet we were already able to show that the transiently induced rotation behavior provides a valuable readout to assess DBS parameters in the hemi-PD rat.…”

PEDOT:PSS‐Coated Stimulation Electrodes Attenuate Irreversible Electrochemical Events and Reduce Cell Electropermeabilization

“…Monophasic waveforms are more efficacious than conventional charge-balanced biphasic pulses [53,54] and asymmetric waveforms can be used to modulate the spatial selectivity for neuronal stimulation. [55] However, charge imbalance of monophasic pulses and the long activation phase of asymmetric pulses might result in irreversible Faradaic reactions that can damage the electrode and the tissue. Application of PEDOT:PSS opens the possibility to employ alternative waveforms without adverse effects, which possibly improves desired stimulation effects and therapeutic outcomes.…”

Imaging the Efficiency of Poly(3,4‐ethylenedioxythiophene) Doped with Acid‐Functionalized Carbon Nanotube and Iridium Oxide Electrode Coatings for Microstimulation

“…[ 57 , 58 ] Using in vivo two‐photon calcium imaging in mice, rats, and cat models, Histed et al revealed a sparse, distributed population of cortical neurons by electrical microstimulation via glass pipettes containing tungsten and platinum–iridium microwire electrodes. [ 59 ] In more recent studies, the Kozai and coworkers utilized mesoscale fluorescence microscopy and two‐photon imaging to investigate the calcium responses to prolonged electrical stimulation in Thy1‐GCaMP6s mice and reported the effect of stimulation frequency, [ 60 ] pulse symmetry, and phase order, [ 61 ] using Michigan planar arrays. [ 62 ] These studies demonstrate the capability of fluorescence imaging to characterize the neuronal response to stimulation at cellular and mesoscopic spatial scales in vivo.…”