Extracellular neural microstimulation may activate much larger regions than expected by simulations: a combined experimental and modeling study

PLoS One. 2012;7(8):e41324. doi: 10.1371/journal.pone.0041324. Epub 2012 Aug 7.

Abstract

Electrical stimulation of the central nervous system has been widely used for decades for either fundamental research purposes or clinical treatment applications. Yet, very little is known regarding the spatial extent of an electrical stimulation. If pioneering experimental studies reported that activation threshold currents (TCs) increase with the square of the neuron-to-electrode distance over a few hundreds of microns, there is no evidence that this quadratic law remains valid for larger distances. Moreover, nowadays, numerical simulation approaches have supplanted experimental studies for estimating TCs. However, model predictions have not yet been validated directly with experiments within a common paradigm. Here, we present a direct comparison between experimental determination and modeling prediction of TCs up to distances of several millimeters. First, we combined patch-clamp recording and microelectrode array stimulation in whole embryonic mouse spinal cords to determine TCs. Experimental thresholds did not follow a quadratic law beyond 1 millimeter, but rather tended to remain constant for distances larger than 1 millimeter. We next built a combined finite element--compartment model of the same experimental paradigm to predict TCs. While theoretical TCs closely matched experimental TCs for distances <250 microns, they were highly overestimated for larger distances. This discrepancy remained even after modifications of the finite element model of the potential field, taking into account anisotropic, heterogeneous or dielectric properties of the tissue. In conclusion, these results show that quadratic evolution of TCs does not always hold for large distances between the electrode and the neuron and that classical models may underestimate volumes of tissue activated by electrical stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Anisotropy
  • Computer Simulation*
  • Electric Conductivity
  • Electric Stimulation
  • Extracellular Space / physiology*
  • Mice
  • Microelectrodes
  • Models, Neurological*
  • Neurons / physiology*

Grants and funding

This work was supported by the French ministry for research and technology (RMNT Neurocom project No 03J489 and ACI Neurosciences Intégratives et Computationnelles No 2003541), the French National Research Agency (ANR – Programme Blanc No ANR06BLAN035601 and Programme TecSan No ANR07TECSAN01404), the Institut pour la Recherche sur la Moelle Epinière et l'Encéphale (IRME), the Région Aquitaine (No 20030301201A and 20040301202A), and the European Union (EU) FP7 program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.