Fundamentals of Electrical Stimulation

Overview

When electrical currents are delivered to the nervous system to elicit or inhibit neural activity, two things can happen. First, the current creates a potential field that can alter the state of the voltage-gated ion channels, proteins that are embedded in the membranes of neural elements. Second, electrochemical reactions can occur at the electrode–tissue interface. Altering the state of voltage-gated ion channels can initiate or suppress a propagated action potential, which, in turn, effects the release of neurotransmitter at the terminal end of the axons. Uncontrolled electrochemical reactions, at the electrode–tissue interface, can cause damage to the electrode or injury to target tissues.

There are three primary ideas that one must keep in their mind when thinking about neuromodulation. The science behind clinical applications such as effecting movement or sensation has been well developed, and these principles are essential to understand for safe and effective delivery of electrical stimulation to neural tissue.

• First , electrical activation of the nervous system is more than causing paralyzed limbs to move, sound sensations in the deaf individual, and visual sensations in a blind person. It is about controlling and targeting release of neurotransmitters.

• Second , the science underpinning electrical activation technology is the knowledge of voltage-gated ion channels, particularly the voltage-gated Na ⁺ channel.

• Third , the electrode is the business end of any neural prostheses. What happens at the electrode–tissue interface can determine the long-term viability of a device.

Using these three concepts as a foundation, one can more easily understand the rationale for making decisions about choices for stimulation parameters and how these choices affect the utility and longevity of a device intended to modulate the behavior of neural circuits or activate the nervous system to restore function.

Some Basic Concepts

An electrode forms the interface between the neuromodulation hardware and the targeted nervous tissue. Electrical stimulation is achieved by connecting two opposite poles of a stimulus source to the tissue. Conventional current flows from the positive pole of a stimulus source to the negative pole, while electrons (negative charges) flow in the opposite direction.

Anode and Cathode : The electrode at which oxidation reactions occur (increased positive valence or electron removal) is defined as the anode, and the electrode at which reduction occurs (decreased positive valence or electron gain) is defined as the cathode.

Voltage and Current : Neuromodulation is effected by application of electrical charge to the tissues. Voltage is a measure of the energy carried by the charge, being the “energy per unit charge” (volts), while current is the rate of flow of charge (amperes).

Stimulus Characteristics : Electrical charge applied to effect stimulation of neural tissue can be characterized temporally by its voltage or current. The basic element of applied charge, a voltage or current pulse, is defined by its duration (pulse width), amplitude (volts or amperes), and shape (rectangular, triangular, or sinusoidal). The repetition rate of individual pulses is the stimulus frequency or pulse rate. Sets of pulses followed by silent intervals can provide patterned temporal stimulation, and may also be modulated by frequency or amplitude.

Electrode Characteristics : The size (area) of the electrode tissue interface determines the charge and current density of the applied stimulus, which decrease with increasing electrode area. The current intensity varies inversely with the square of the distance from the electrode.

Effect of Axon Diameter : The effects of an applied electrical field are greater on larger diameter axons because they have a longer separation between nodes of Ranvieŕ. The effect can be either depolarization or hyperpolarization. Smaller-diameter axons require higher stimulus amplitudes for the generation of action potentials than do larger-diameter axons.

Nerve Depolarization/Excitation : When the transmembrane potential of an axon is decreased to a level where sufficient numbers of voltage-gated Na ⁺ channels are switched from the resting excitable state to an active state, it causes a propagated action potential to be initiated. This state change occurs when a net transmembrane current occurs, flowing from the inside to the outside of the axon and is usually caused by the application of a cathodic stimulus applied near the site of excitation.

Nerve Hyperpolarization : When the transmembrane potential is increased from the resting state (becoming more negative), the voltage-gated Na ⁺ channels are less likely to be gated into the active state. This state change occurs when the net transmembrane current is negative, flowing from the outside of the cell to the inside of the cell, and is usually caused by the application of an anodic stimulus applied near the site of hyperpolarization.

Resting Potential Across the Axon Membrane

Three major ions are separated across an axon membrane at rest. ¹

1 Calcium, Ca ²⁺ , is also a major ion that is in higher concentration outside the neuron. It will not be considered for the purposes of this discussion.

The concentrations of Na ⁺ and Cl ⁻ are much higher in the extracellular space than in the intracellular space, while K ⁺ is higher on the inside compared with the extracellular space. The resting potential of the membrane is about −70 mV, inside with respect to the outside, which is close to the Nernst potential ²

2 Equilibrium potential of the ionic electrochemical gradient across the membrane.

for both K ⁺ and Cl ⁻ , a value determined by the difference in ion concentration between the two sides of the membrane. K ⁺ and Cl ⁻ concentrations determine resting potential across the nerve membrane. The resting nerve membrane is poorly permeable to Na ⁺ . The Na ⁺ Nernst potential is about +55 mV, which drives an inward current flow during an action potential.

Voltage-Gated Ion Channels

Voltage-gated ion channels are a class of transmembrane proteins that are activated by changes in electrical potential difference across the cell membrane ( ). Voltage-gated sodium ion channels (Na _v ) can have three possible states: closed-activatable, activated (open and conducting), and closed-inactivatable. Na _v channels are made up of 1800 to 4000 amino acids with four transmembrane repeat domains. The molecules of the protein interact with each other and surrounding molecules to form a structure that defines its function. Each of the four transmembrane domains contains a voltage-sensitive α helix that is displaced in the open or conduction state ( ). The linker between the III and IV repeat domains acts as a ball and chain to fold up into the channel opening to block Na ⁺ from moving through the channel in the inactivatable state. When a channel opens, Na ⁺ moves from outside the membrane, through the channel, to the inside following both a concentration gradient and a voltage gradient. Shortly after the channel opens, it becomes energetically favorable for the linker between the III and IV repeats to move into the opening and block further Na ⁺ movement ( ).

The opening of Na _v is a stochastic process that is potential dependent, meaning that as the transmembrane potential increases, the probability increases for a resting channel to transition to a conduction state. In the conduction state, each Na _v channel acts as a current source when the channel opens, permitting Na ⁺ to move from the outside to the inside and depolarize the membrane. The Na _v channel density is about 2000 channels/μm ² in the nodes of Ranvieŕ. By convention, the potential across a membrane is defined as inside with respect to outside, giving rise to the resting potential, which is about −70 mV. Also, positive current flow is defined as positive charge moving from inside to outside; therefore, Na ⁺ moving from outside to inside is a negative current.

At resting membrane potentials, some channels are opening and closing, and about 75% of the Na _v are in an activatable state, meaning they can be opened, and 25% are in the inactivatable state, with the linker between the III and IV repeat blocking Na ⁺ flow through the channel. K ⁺ outflow keeps the membrane potential from drifting, and a Na ⁺ -K ⁺ pump maintains equilibrium concentrations and membrane potentials. If the membrane potential were to be hyperpolarized, made more negative, the fraction of channels in the activatable state would increase, approaching 100% at −100 mV.