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The Safe Delivery of Electrical Currents and Neuromodulation
Introduction
When considering the safety requirements for electrical stimulation–based neuromodulation, a common misconception is that the US Food and Drug Administration (FDA) or the European Union notified bodies require that an implantable medical device be 100% safe and cause no damage to tissue. Holding device manufacturers to such a strict standard would be disadvantageous to patients for a variety of reasons. Implantation of the cardiac pacemaker/defibrillator, arguably the most successful implantable stimulation therapy with a history dating back to the 1930s and more than 900,000 patients implanted each year worldwide, still has a 2.2% risk of inducing a pneumothorax and a 0.4%–1% risk of damaging cardiac structures ( ). However, cardiac pacemakers/defibrillators decrease morbidity and mortality rates and improve quality of life sufficiently to offset these surgical risks for certain patients.
For this reason, regulatory bodies typically require only that the potential risks and benefits to the use of an implantable device be well defined and that the potential benefits outweigh the risks. The implantation of a deep brain stimulator (DBS), for example, requires both the temporary insertion of a guide cannula into the brain and long-term placement of an indwelling electrode, resulting in known complications that include infection, hemorrhage, and seizures ( ). However, the benefits of DBS for patients with Parkinson disease and essential tremor have been sufficiently defined in a phase 3 double-blinded randomized sham-controlled clinical study. Likewise, the risks have been sufficiently defined via a progression from preclinical benchtop testing and good laboratory practice (GLP) large animal studies to phase 1, 2, and 3 clinical studies, to support an approval by the FDA for sale and distribution.
Delivering electrical current to tissue via an implanted electrode introduces both direct and indirect risks to the patient that must be quantified and mitigated. Electrical stimulation can create electrochemical reactions at the surface of the electrode that may generate byproducts that are toxic to nearby tissue. Moreover, electrical stimulation of nerves beyond the norms of physiological activation can cause “excitotoxicity,” which can lead to neural dysfunction or death. In addition, unintended activation of nerves other than the intended therapeutic target can cause a myriad of issues, including pain, seizures, movement abnormalities, suicidality, impulsivity, and even sudden death. In clinical practice, minor stimulation damage to local neural or nonneural tissue beyond the damage caused by the implant itself or activation of off-target nerves that leads to side effects may be acceptable if the functional consequences to the patient are minimal. On the contrary, these adverse effects may indirectly limit the benefit of the implant procedure to the patient to the point where the inherent surgical risks are no longer offset by the benefits.
In this chapter, we summarize the mechanisms by which electrical stimulation through an electrode may directly or indirectly affect the risks and benefits associated with an implanted neuromodulation device. Based on these mechanisms, we also describe the theories behind common stimulation practices to mitigate these risks and provide the basis for testing strategies commonly performed to quantify the extent of these risks. More-detailed discussions of the subject matter can be found in many reviews, including those by , and . Other damaging mechanisms, such as insertion trauma, micromotion, and the normal foreign body response (FBR), are discussed elsewhere ( ).
Mechanisms of Stimulation-Induced Tissue Damage
Electrode Reactions and Excitotoxicity
Although the mechanisms by which electrical stimulation can damage neural tissue are not fully understood, they have been categorized into two groups: undesirable electrochemical reactions at the electrode and excitotoxicity (“mass action”). Ideally, electrodes inject charge via reversible electrochemical processes that do not damage tissue. However, charge injection may also initiate reactions at the electrode that produce byproducts that are harmful to tissue. In contrast, damage due to mass action arises as a direct result of the induced hyperactivity of neurons and, therefore, may occur even without the production of harmful byproducts. Both of these classes of mechanisms must be considered and accounted for when determining appropriate stimulation parameters. A brief discussion of these classes of mechanisms is provided here. For a more-detailed discussion, the reader is directed to the works of Agnew et al. ( ), , , and . An additional consideration for determining appropriate stimulation parameters is the onset of off-target stimulation side effects. Although off-target stimulation is not often discussed in the literature and is not technically a mechanism of stimulation-induced tissue damage, it is a critical factor that can limit stimulation intensities and safety.
Electrode Reactions
Depending on the electrode material and the chosen stimulation parameters, charge can be injected into tissue either capacitively (through non-faradaic processes in which no species are oxidized or reduced) or through reactions in which charge transfer occurs between the electrode and the surrounding environment through reduction and oxidation (redox) reactions (faradaic processes). Capacitive charge injection occurs through the charging and discharge of the electrode double layer that forms at the interface between the electronically conducting electrode and the ionically conducting electrolyte. The charge carriers in the double layer are electrons in the electrode and a combination of solvated anions and cations in the electrolyte. The double layer is often modeled as a capacitor for smooth electrodes. Faradaic charge injection requires reduction or oxidation and a corresponding change in valance of species at the electrode–tissue interface. Most commonly, the redox reactions are confined to the electrode surface, and charge neutrality is maintained by counterion transport to the electrode. Oxidation or reduction of molecular species from the physiological environment is almost always irreversible. Both capacitive and faradaic mechanisms cause the electrode potential to polarize from equilibrium over the course of the stimulation pulse. If the polarization is large enough, it can induce reactions at the electrode surface that can be damaging to tissue. The reactions that can occur depend on the intensity of the stimulation pulse and its waveform, the electrode material, and the composition of the surrounding environment.
Regardless of the dominant mode of charge injection, the presumed maximum charge injection is considered the point at which the electrode polarizes sufficiently to initiate the electrolysis of water. The water molecules at the surface of the electrode are either oxidized (reaction 1) or reduced (reaction 2), depending on whether polarization is in the positive or negative direction, respectively. At the positive electrode (the anode), hydrogen ions are generated and oxygen gas is evolved ( Eq. 7.1 ), and at the negative electrode (the cathode), hydroxyl ions are generated and hydrogen gas produced ( Eq. 7.2 ).
Water electrolysis is potentially damaging to tissue because of the localized pH changes accompanying the water reduction and oxidation reactions. Nucleation of gas bubbles is possible if the polarization is sustained at electrolysis limits for a sufficiently long time. Furthermore, electrolysis can be damaging to the electrodes themselves as it may lead to delamination of insulation or dissolution of electrode material ( ). Other harmful chemical reactions can occur before the onset of electrolysis. The presence of oxygen in tissue allows for the reduction of oxygen that may produce reactive oxygen species ( ). These reactive oxygen species can disrupt normal chemical signaling in tissue.
Last, reactions at the electrode may result in the dissolution of the electrode material itself, allowing the dissolved products to diffuse into the tissue. Previous studies have established the toxicity of dissolution products of platinum, the most common electrode material for stimulation ( ). Other electrode materials such as titanium nitride ( ) have also been shown to adversely affect neural cell survivability, and it should be recognized that electrode materials may cause neurotoxicity even in the absence of dissolution.
Excitotoxicity and “Mass Action” Damage to Neurons
Observations that neural tissue damage occurs equally with capacitive or faradic charge injection at stimulation intensities that would be considered insufficient to oxidize or reduce water suggest that it is not the generation of noxious products at an electrode that initiates stimulation-induced tissue damage ( ). Equally, when action potentials in peripheral nerve are suppressed with anesthetics, electrical stimulation delivered to the silenced nerve produces little to no damage at intensities that would otherwise be expected to cause axonal degradation ( ). Further studies by implicated glutamate-induced excitotoxic damage via the N -methyl- d -aspartate receptor concurrent with an increase in intracellular calcium ( ). Examples of histology demonstrating excitotoxicity and the absence of neural damage when action potentials are silenced are shown in Fig. 7.1 . In addition, many studies have shown that neural damage is encountered at intensities and frequencies of stimulation that are lower than accepted maximum electrode charge densities for avoiding water electrolysis ( ). These observations, however, do not preclude neural damage from noxious species generated at electrodes via metal dissolution, oxygen reduction, or pH changes.
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