Generation of direct current electrical fields as regenerative therapy for spinal cord injury: A review

Abstract

Electrical stimulation (ES) shows promise as a therapy to promote recovery and regeneration after spinal cord injury. ES therapy establishes beneficial electric fields (EFs) and has been investigated in numerous studies, which date back nearly a century. In this review, we discuss the various engineering approaches available to generate regenerative EFs through direct current electrical stimulation and very low frequency electrical stimulation. We highlight the electrode-tissue interface, which is important for the appropriate choice of electrode material and stimulator circuitry. We discuss how to best estimate and control the generated field, which is an important measure for comparability of studies. Finally, we assess the methods used in these studies to measure functional recovery after the injury and treatment. This work reviews studies in the field of ES therapy with the goal of supporting decisions regarding best stimulation strategy and recovery assessment for future work.

FIG. 1.

(a) The equivalent circuit of a common stimulation setup consists of electrodes [ $R_{EL}(t)$ and $C_{EL}(t)]$ in contact with tissue [ $R_{\mathrm{\text{tissue}}}(t)$]. The stimulating current $I_S$ is generated by an energy source $U_{\mathrm{\text{cell}}}(t)$. The resulting electric field strength depends on the characteristics of the respective tissue layers. (b) Recorded voltage $U_{\mathrm{\text{cell}}}(t)$ of the stimulation experiment. $U_{\mathrm{\text{cell}}}(t)$ increases rapidly, which is typical for capacitive current $I_C(t)$. Afterward the voltage stabilizes, speaking for a predominantly faradaic current $I_R(t)$. The inset shows the estimated time dynamics of capacitive and faradaic current based on the slope of $U_{\mathrm{\text{cell}}}(t)$. (c) Images of 5 cm PtIr wire (0.18 mm diameter) as anode before and after DC stimulation (24 h, 17.5 μA). (d) Comparison between the cyclic voltammograms (CV, 100 mV/s) collected with the wire before and after stimulation reflects the surface change. After stimulation, an oxidation peak at 0.3 V and an increased reduction current at −0.25 V are present. We interpret the former as oxidation peak from Ir, while the latter might speak for a higher density of oxides from PtIr. The changes express that after the stimulation experiment the electrode undergoes reduction and oxidation more effectively as seen in the increased/decreased current for positive/negative peaks. Further experiments are necessary for a precise analysis of the changed composition of the PtIr wire. The applied current was similar to the work of Borgens et al.

FIG. 2.

(a) Simple model of a rat's spinal cord with an implant positioned under the dura (insulation layer), in space filled with cerebrospinal fluid (CSF). The scalebar in the inset represents 150 μm. (b) In FEM, the volume is divided into smaller elements on which the equations describing electric field propagation are solved. (c) The computed field strength on the yz-plane (x = 0) in the middle of the spinal cord reveals that the longitudinal field strength generated by two electrodes (white cross) depends on the tissue type and distance from the electrodes.

FIG. 3.

(a) The electrode position in mammals relative to the injury is shown as deduced from publications in which the placement was described. The model of the spinal cord is dimensionless because various animal models (rats, guinea pigs, dogs, and humans) were considered. In some studies, the resulting field strength was measured by recording electrodes (rectangles). In the work of Shapiro et al. and Borgens et al., three sets of stimulating electrodes were utilized; we only show the approximate placement of one electrode pair. More details on electrode separation are given in Table IV. (b) Estimated field strength vs current as stated in the reviewed literature. Circles for Shapiro et al. and Borgens et al. were shifted for better visuality; in the works, the same values are reported.