Tissue damage thresholds during therapeutic electrical stimulation

Abstract

Objective: Recent initiatives in bioelectronic modulation of the nervous system by the NIH (SPARC), DARPA (ElectRx, SUBNETS) and the GlaxoSmithKline Bioelectronic Medicines effort are ushering in a new era of therapeutic electrical stimulation. These novel therapies are prompting a re-evaluation of established electrical thresholds for stimulation-induced tissue damage.

Approach: In this review, we explore what is known and unknown in published literature regarding tissue damage from electrical stimulation.

Main results: For macroelectrodes, the potential for tissue damage is often assessed by comparing the intensity of stimulation, characterized by the charge density and charge per phase of a stimulus pulse, with a damage threshold identified through histological evidence from in vivo experiments as described by the Shannon equation. While the Shannon equation has proved useful in assessing the likely occurrence of tissue damage, the analysis is limited by the experimental parameters of the original studies. Tissue damage is influenced by factors not explicitly incorporated into the Shannon equation, including pulse frequency, duty cycle, current density, and electrode size. Microelectrodes in particular do not follow the charge per phase and charge density co-dependence reflected in the Shannon equation. The relevance of these factors to tissue damage is framed in the context of available reports from modeling and in vivo studies.

Significance: It is apparent that emerging applications, especially with microelectrodes, will require clinical charge densities that exceed traditional damage thresholds. Experimental data show that stimulation at higher charge densities can be achieved without causing tissue damage, suggesting that safety parameters for microelectrodes might be distinct from those defined for macroelectrodes. However, these increased charge densities may need to be justified by bench, non-clinical or clinical testing to provide evidence of device safety.

Figures

Figure 1

Damaging and non-damaging levels of electrical stimulation of non-human brain with planar macroelectrodes using k = 1.85 in the Shannon equation to delineate the boundary between damaging and non-damaging stimulation. Black and gray solid symbols = tissue damage; open symbols = no damage. Studies referenced (Gilman et al 1975, Pudenz et al 1975, Brown et al 1977, Yuen et al 1981, 1984, Agnew et al 1983, McCreery et al 1988, 1990).

Figure 2

The three scenarios outlined by Shannon for electrode–tissue interaction as a function of distance between a disk electrode and excitable tissue, relative to the electrode diameter. In the near-field case (A), non-uniform current density at the electrode circumference is postulated to contribute to tissue damage; in the mid-field case (B) the current density is lower and more uniform; and, in the far-field case (C) the electrode acts as a point source in which the current uniformity and density at the electrode are not factors affecting tissue damage.

Figure 3

Levels of neural stimulation for clinical devices in humans as reported in published literature or manufacturer device labeling. Vagus Nerve Stimulation (VNS) data from Cyberonics (The Vagus Nerve Stimulation Study Group 1995) assumes a GSA = 0.1 cm2, which was estimated from Terry et al (1990) and Bullara (1990) for a 2 mm inside diameter helix. SCS—spinal cord stimulation, CS—cortical surface stimulation, DBS—deep brain stimulation. DBS charge values are calculated from stimulation voltage levels using an impedance of 1100 Ω. The solid lines for the VNS Study Group and Medtronic DBS data reflect the wide range of possible stimulation intensities available with these treatments. Filled symbols are damaging stimulation levels from figure 1. Studies referenced (Shannon 1992, Haberler et al 2000, Burbaud et al 2002, Herzog et al 2003, Kinoshita et al 2004, Schrader et al 2006, Abejon and Feler 2007, Peyron et al 2007, Medtronic 2010).

Figure 4

Levels of neural stimulation for clinical devices with electrodes having a GSA 2 (region above and to the left of the dotted line as indicated by the arrows). See figures 1 and 3 for symbols not in the legend. Stimulation targets: ER—epi-retinal surface, ON—optic nerve surface, ABI—auditory brain stem surface, CI—cochlear implant, SCR- suprachoroidal placement targeting the retina. Studies referenced (Shannon 1992, Veraart et al 1998, Huang et al 2001, Mahadevappa et al 2005, McCreery and Shepherd 2006, Balthasar et al 2008, Fujikado et al 2011).

Figure 5

Levels of neural stimulation in animal and human studies involving penetrating microelectrodes (geometric area μm2) showing an approximate damage threshold of 4 nC/ph. Filled symbols indicate histological damage; open symbols no damage; partially filled symbols damage but compromised physiological response. The data point (▷), for which no histological damage was observed, employed a pulse frequency of 20 Hz compared with 50 Hz or greater for the other studies. FCN—feline cochlear nucleus, HVC—human visual cortex, CC—cerebral cortex, STN—subthalamic nucleus, ABI—auditory brain stem. Studies referenced (Hambrecht 1995, McCreery et al 2006, 2010, 1986, 1992, 1994, 1997, 2000, McCreery and Shepherd 2006).

Figure 6

Reversible electrochemical limits of charge injection for SIROF (Cogan et al 2009, Kane et al 2013), porous platinum (Terasawa et al 2013) and titanium nitride (Weiland et al 2002) electrodes overlying functional and tissue damage thresholds for micro and macroelectrodes. The difference between saline and in vivo measurements of maximum charge injection capacity are shown for SIROF and porous platinum and the range indicated by arrows. See figures 1 and 3–5 for an explanation of the shaded symbols.