Calcium activation of cortical neurons by continuous electrical stimulation: Frequency dependence, temporal fidelity, and activation density

Abstract

Electrical stimulation of the brain has become a mainstay of fundamental neuroscience research and an increasingly prevalent clinical therapy. Despite decades of use in basic neuroscience research and the growing prevalence of neuromodulation therapies, gaps in knowledge regarding activation or inactivation of neural elements over time have limited its ability to adequately interpret evoked downstream responses or fine-tune stimulation parameters to focus on desired responses. In this work, in vivo two-photon microscopy was used to image neuronal calcium activity in layer 2/3 neurons of somatosensory cortex (S1) in male C57BL/6J-Tg(Thy1-GCaMP6s)GP4.3Dkim/J mice during 30 s of continuous electrical stimulation at varying frequencies. We show frequency-dependent differences in spatial and temporal somatic responses during continuous stimulation . Our results elucidate conflicting results from prior studies reporting either dense spherical activation of somas biased towards those near the electrode, or sparse activation of somas at a distance via axons near the electrode. These findings indicate that the neural element specific temporal response local to the stimulating electrode changes as a function of applied charge density and frequency. These temporal responses need to be considered to properly interpret downstream circuit responses or determining mechanisms of action in basic science experiments or clinical therapeutic applications.

Cortical Plasticity Induced by Anodal Transcranial Pulsed Current Stimulation Investigated by Combining Two-Photon Imaging and Electrophysiological Recording

“…Our results also showed that the neurogliopil always had significant Ca 2+ response to 2 s a-tPCS when the current intensity was ranged from 0.1 to 0.35 mA. Some studies using electrical microstimulation also showed the activation of neurogliopil (Histed et al, 2009; Michelson et al, 2019). Another important finding in our results is that 2 s a-tPCS cannot induce calcium response in astrocytes.…”

Tissue Response to Neural Implants: The Use of Model Systems Toward New Design Solutions of Implantable Microelectrodes

“…However, it should be also taken into account that mechanical strain from the motion artifacts, such as bending of conducting material, can cause changes in resistance or capacitance of materials. As a result, this can affect the electrical signals of the electrode and can result in unintended performance (Michelson et al, 2019). Thus, the balance between Young’s modulus and the electrical properties need to be carefully considered in designing microelectrodes for neural stimulation.…”

The frequency of cortical microstimulation shapes artificial touch

“…Any proposed neural code to explain the discrimination behavior must account for the animals' ability to distinguish increases in frequency from increases in amplitude despite the fact that both stimulation parameters affect the firing rate of neural populations near the electrode tip. While higher amplitudes lead to the recruitment of a larger volume of neurons (Tehovnik, 1996;Tolias et al, 2005) and to changes in the spatial distribution of neuronal activity (Histed et al, 2009), the precise shape of recruitment is frequency dependent (Michelson et al, 2018). In principle, then, the spatial pattern of neuronal activation may have shaped the resulting percept and mediated the animals' frequency discrimination behavior.…”