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Fig. 6.4 Strength–duration graph illustrating threshold current required to elicit response at different pulse durations. Rheobase current = b; chronaxie = c. Modified from [23]
Fig. 6.5 Representative graph illustrating the gradual increase in response amplitude as the stimulus strength is increased. The amplitude of response is usually measured in microvolts (mV) while the applied stimulus amplitude is usually in microamps (mA)
6.6 Safe Stimulation of Tissue
A neural stimulation system that is not properly designed can cause damage to the tissue or to the electrode itself. For any neural stimulation system to be successful, it must elicit the required neuronal excitation without causing any damage to the
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biological system. Electrode shape, size and material along with stimulus pulse parameters need to be carefully chosen to meet the requirements of the system. Extensive work has been done in defining the role of all the different parameters that determine the safety limit of the tissue and electrode.
6.6.1 Mechanisms of Neural Injury
There are several mechanisms that may cause neural injury; they are broadly categorized into two main classes. The first mechanism of damage is associated with the electrochemical processes through which the stimulus current is injected into the target tissue. Damage is induced due to formation of toxic electrochemical reaction products during stimulation at a rate greater than what can be tolerated by the physiological system. These damaging processes have been well characterized using electrochemical methods as discussed in Sects. 6.2 and 6.3. A second mechanism of neural injury is associated with the flow of current through the target tissue [35]. This involves the metabolic stresses induced on the tissue causing a transient or permanent elevation of neurotransmitter release (excitotoxic effect). It may also include large depolarizations and hyperpolarizations induced by the voltage gradient (membrane electroporation). This second mechanism is multi-factorial and complex.
6.6.2 Parameters for Safe Stimulation
One of the well-established principles of neural stimulation is to achieve charge balancing during stimulation between the different phases of the stimulus pulse. This was first reported by Lilly in 1961 and ensures that the total net charge during stimulation at the electrode–tissue interface is zero [34]. If charge balancing is not accomplished, then a net accumulation of charge will ultimately lead to the rise of electrode potentials to levels where water hydrolysis will start. For monophasic stimulation, charge balancing is accomplished by the use of a blocking capacitor that slowly discharges after the application of the pulse. Although charge – balancing ensures that there is no net accumulation of charge, it does not guarantee safety. Such stimulus waveforms may momentarily exceed the established safety limits of total charge, charge density or electrode potential. Classically, safety limits for neural stimulation have been divided into two broad categories:
1. Neural damage limits dictated by the ability of biological tissue to withstand electric current without any degradation.
2. Electrochemical limits based on the ability of the electrode to store or dissipate electric charge without exceeding the water window, outside of which formation of harmful products start.
While neural injury limits are defined in terms of both charge density and charge per phase, electrochemical limits are defined in terms of charge density only. Charge
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density is simply the total charge per unit area of electrode and determines the magnitude of the depolarization or hyperpolarization induced in the neurons and axons close to the electrode. Charge per phase is the amount of charge injected during each phase of the stimulus pulse and determines the distance over which the applied stimulation can activate the neurons, i.e. the number of neurons activated. McCreery et al. [37] have shown that charge density and charge per phase act synergistically to determine the safe or unsafe levels of stimulation. They showed that neural damage is induced with low charge per phase but high charge density, as is often the case for microelectrodes. Based on these data delineating the boundary between safe and unsafe charge injection for different charge and charge density levels, Shannon et al. [51] developed the following empirical relationship:
log(D) = k −log(Q) |
(6.10) |
where, D is the charge density in mC/cm2/phase and Q is the charge per phase in mC/phase. The equation describes a family of lines for different values of k. The line for which k = 1.5 describes combinations of charge density and charge per phase values for which no damage was observed. Merrill et al. have graphically summarized the work of both studies and also included results of other studies assessing safety of neural stimulation (Fig. 6.6).
Along with charge density and charge per phase, other stimulus parameters such as frequency of stimulation, duration, etc. have been found to play an important role in determining the presence or absence of neural damage. McCreery et al. [38] demonstrated the effect of stimulus frequency as a parameter in causing injury during peripheral nerve stimulation. Their study showed that continuous stimulation of the cat sciatic nerve for 8 h over 3 days causes the myelin sheath to collapse into the axonal space leading to early axonal degeneration (EAD). The threshold of neural injury decreased with increasing stimulus pulse frequency (Fig. 6.7).
Fig. 6.6 Charge (Q) vs. charge density (Q/A) for safe stimulation. Different symbols indicate results of different studies. Reprinted from [39], with permission
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Fig. 6.7 Percentage of myelinated axons undergoing degeneration 7 days after undergoing 8 h of continuous stimulation. At higher stimulus frequency, the percentage of axons undergoing EAD can be substantial even at low stimulus current. Reprinted from [38], with permission
Most of the aforementioned studies have employed single electrode stimulation. However, a recent study [36] found that in the case of multi-electrode stimulation, both sequential and simultaneous stimulation at levels previously found to be safe create transient depression in the resulting neural response. One theory put forward by the authors is the creation of overlapping electric fields that cause certain neurons to be driven at rates higher than what is actually being delivered. The authors dubbed the observed effect “SIDNE” (stimulation induced depression in neuronal excitability).
6.6.3 Stimulation Induced Injury in the Retina
To date, most safety studies have been carried out in structures such as the cortex, muscle, etc. With increasing efforts towards developing retinal implants [20, 56, 59], extensive studies are being done to understand the response of the visual system to artificial stimuli [2, 29, 49, 50]. However, only a few studies so far have been dedicated towards understanding the consequences of long-term stimulation. Güven et al. [27] carried out chronic stimulation studies in dogs and found that the retina is able to tolerate chronic stimulation at 0.1 mC/cm2 without any histological detectable damage or change in the electroretinograms (ERGs). Another study investigated chronic stimulation effects through suprachoroidal-transretinal stimulation [40]. The results of the study showed that threshold for safe charge increased logarithmically or almost linearly with increasing stimulus duration but the threshold