Neuron as an Electrical Circuit

Ana Boka Drmi*, Kristina Frii** , Tomislav Vojvodi***, Marija Jankovi****1

XV. Gimnazija, Zagreb, Croatia Prva gimnazija Varadin, Varadin, Croatia *** TS-SMSI Dante Alighieri Pula-Pola, Pula, Croatia **** University of Belgrade, Belgrade, Serbia
** *

Abstract - The main goal of this project was to simulate a nerve conduction block with a high-frequency sinusoidal current. We used Hodgkin-Huxley and McNeals models to simulate the signal which is conducted through an axon. We have succeeded in this and we have found values of block current amplitude for certain frequencies, at which conduction block occurs. We have also examined other numerous properties of axons.

(around -60 mV), as the ratio of the expelled-sodium-ions and the intaken-potassium-ions is three to two. The second ones open only when a certain voltage is reached and for a brief period. Then the ions flow through the channels down the concentration gradient. B. The Physical Background When a certain electrical stimulus is applied outside the axon, depending on the stimuluss intensity and duration, either a passive or an action potential can be triggered. If the stimulus is too weak and/or short, the passive potential occurs. The potential outside the axon is either risen or diminished, which contributes to a change in the membranes voltage, but not enough, so that the voltagegated ion channels could be opened. In order to open these channels, either the positive (around +12 mV) or the negative threshold must be reached. Then the action potential occurs. When the voltage-gated ion channels open, the sodium ions start flowing into the cell down the concentration gradient, until the channels close again. This results in a greater voltage change, which always reaches a certain maximum (around +105 mV), and therefore the action potential is an all-or-nothing event. Then the pump restores the original conditions, decreasing the voltage even a little below the resting potential (overshoot), before the resting potential is reached again. In other parts of the axon the same process occurs, activated by ions that flow to those parts through the axon itself. At one part of the axon, an another action potential cannot occur for a short time interval (the absolute refractory period) after the previous action potential was triggered. The goal of this project was to simulate a nerve conduction block, in which we blocked the impulse, using an external electrode, at some point of the axon, so it cannot be conducted to the spinal cord, and thusly to the brain, were it would be perceived as pain. We also measured the threshold and the ratio of the minimal current intensity and duration necessary for activating the action potential, using both positive and negative current, the conductance dependences of time, some refractory period values, an axons diameter and signals velocity ratios, sinusoidal stimuluss effects, temperature dependence and dependence of the block effect on frequency and amplitude of the block electrodes stimulus. Simpler of these phenomena are described in [3], [4].

I.

INTRODUCTION

An important part of a nervous system are long cables through which electrical impulses are conducted, the nerves, which again are formed of very specialized and evolutionary-advanced cells the neurons. Pathological pain or nociception occurs if a tissue is being damaged. However, some muscle inflammations or other types of irritations in our body could lead to a compression or irritation of some nerves, causing a perception of very high and/or long-lasting pain or other problems, as incontinency. Some of these problems could be resolved by taking medicines, but sometimes medicines arent enough or the body could get used to them; medicines or neurotoxins can destroy neurons. A. The Biological Background The nerve cell is a highly specialized cell that contains specific structures that are important for receiving, in a chemical way (synapse), the signal from the other cell in the dendrites; or transmitting the signal to the other cell (electrically, through the axon). A cell membrane is formed of phospholipids, which dont allow the diffusion of ions through them, and proteins, which serve as matter transporters. Proteins are crucial for altering the concentration of specific ions. Ions are important, specifically sodium and potassium cations, since they define the cell voltage. In neurons, resting potential is the voltage which the cell endeavours to keep constant at normal conditions. The cell membrane voltage is measured by subtracting the potential outside the cell from the potential inside the cell. At normal conditions the concentration of the sodium cations is bigger outside the cell, while the concentration of the potassium cations is bigger inside the cell. The most important ion transporters across the membrane are the sodium-potassium pumps and the voltage-gated ion channels. The first ones expel three sodium ions and intake two potassium ions (against the concentration gradient), by using energy (ATP). That explains why the axons resting potential is negative

All authors contributed equally.

II.

MODEL time. The equations are a system of differential equations, where the unknowns are functions and equations contain their derivatives. Solution of the set of equations describes how voltage and ion currents change during time. Scaled value of voltage is used here (resting potential is at zero). Values that we used for membrane properties involved in (1) are given in table 1.

When formulating the model, the conductances of the ion channels can be observed individually for sodium ions and potassium ions, since these conductances depend only on the membranes voltage. The phospholipid bilayer, which forms the cell membrane, does not allow sodium and potassium ions to pass through it, hence it is a kind of a capacitor (an electrical circuit element which accumulates charges on both of its sides, not allowing them to pass through it) [Fig. 1 C m ]. The ion channels and pumps through which ions flow can be represented as resistors (circuit elements which offer some resistance to the passage of the current) with variable resistance [Fig. 1 R Na , R K ]. It is necessary to include the leakage current, too, that occurs due to the constant flow (conductance) of some other, less important ions [Fig. 1 - R l ]. These elements are connected in parallel, since they are under the same membrane voltage [Fig. 1 V m ]. This model represents just a small piece of an axon membrane, described by the Hodgkin-Huxley equations [1]. The McNeals model (if adapted for unmyelinated axons) [2] is a refrigeration of the entire axon, which combines a big number of Hodgkin-Huxley circuits (separated by x the length of one piece) into one single circuit, including the resistance of the axoplasm [Figure 2 - R a ]. Protein channel activation and inactivation parameters m, h and n were built up by Hodgkin and Huxley based on some fundamental knowledge, but mostly to fit experimental data. Hodgkin-Huxley equations (1) describe how the resistors conductances change depending on voltage and

(1)

For solving the system of these differential equations, numerical methods have to be used. That means that we are not able to find an analytical, exact form of the solution. Instead, as a result we get a set of values of great resolution, i.e. great precision. Adapted McNeals model is therefore described by a set of Hodgkin-Huxley system of equations, with one system per an axon piece. The first equation for a simple circuit is replaced by: (2) where V e represents the external voltage, caused by an electrode producing a current I test (t), e is external resistivity, d is an axon diameter, i axoplasm resistivity, x length of the small piece. Formula (2) is derived using model from Fig. 2, using Ohms and Kirchhoffs laws. The following formula is used to calculate external potential coming from a monopolar electrode at position x 1 , z 1 . The rest of an axon properties is given in table 2. The same approach was used in [7]. (3) III. SIMULATION

Figure 1. An electric circuit representing a small piece of axon membrane

Figure 2. Model of an unmyelinated axon 40mm long, source: [6]

We used programming language Mathematica to perform simulations of the model. With simulations, we imitated the real-world processes of how the change and addition of certain parameters influence the conduction of the signal traveling along the axon. The first version of the simulation simulated non-propagating membrane potential change, i.e. the basic Hodgkin-Huxley model. Stimulus was a rectangular current pulse. With this simulation we estimated membrane voltage threshold for the action potential, by changing stimulus between currents which cause passive and action potential. Then we examined a relationship between stimulus intensity and duration for stimuli that hits as near to the threshold as possible. The second version of the simulation was an extension to the full axon model. Amongst other phenomena, we examined relationship between axon diameter and the velocity of signal propagation. The

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simulation was run for a certain diameter value and the velocity was calculated as a ratio of distance between two chosen nodes and difference in time at which action potential is fired at those nodes. We examined how a change in temperature affects action potential threshold, which we did by altering Hodgkin-Huxley equations as described in []. The most important part of our project was simulating the nerve conduction block by adding a sinusoidal high frequency current throughout the block electrode. In the third, final version of our simulation, there were two electrodes: external potential along the axon, coming from the block electrode, was calculated by the same (3) formula, so that total external potential was a sum of potentials caused by both (a test and the block) electrode. Test electrode at the beginning of an axon was causing initial action potential, which would be conducted through the axon, to be blocked (under certain conditions) when it comes under the block electrode. These conditions were also examined simply by rerunning the simulation for different sets of values.
Table 1. Membrane properties
capacity per area unit sodium conductance per area unit potassium conductance per area unit leaking current conductance equilibrium (reductioned) voltage for Na equilibrium (reductioned) voltage for K equilibrium (reductioned) voltage for leaking current initial value for m initial value for h initial value for n0 Cm gNa gK gL VNa VK VL m0 h0 n0 1 F/cm2 120 1/k cm2 36 1/k cm2 0.3 1/k cm2 115 mV -12 mV 10.589 mV 0.053 0.596 0.318

pushes the sodium ions outside and the potassium inside the cell (Figure 6). Figure 7 shows the pairs of values of minimum stimulus current intensity and stimulus duration that fire the action potential. Membrane voltage threshold is found to be around 12mV. Action potential can also be fired by a negative current pulse, causing hyperpolarization (Figure 8). If stimulus is strong enough, this can lead to the same type of action potential as usual depolarization of the membrane. We also found the value of refractory period, time needed so that the same stimulus repeated after that period can cause another action potential: around 10ms. Cable theory predicts that conduction speed is proportional to square root of axon diameter. Results presented at Figure 9 agree with this prediction. Linearized data was fit and we have got a following linear function for the dependence of the speed on the square root of the diameter. Temperature dependance of voltage threshold is shown in the table 3. Axon diameter was set to 100 m. We compared our results with experimental results from [5]. Results agree in a way that relationship seems to be linear and that voltage threshold increases with temperature and our results are inside the intervals of their measurements.
Table 3. Temperature dependance

Temperature (C) Voltage treshold (mV)

5 11

10 12

15 13

20 14

Table 2. Axon properties

number of pieces piece length axon diameter axoplasm resistivity extracellular resistivity distance between the test electrode and axon distance between the block electrode and axon number x d a e ztest zblock / 0.05 cm 30106 m 34.5 m 300 cm 0.01 cm 0.01 cm

Figure 10 shows what happens when the test electrode gives out sinusoidal current instead of rectangular pulse. Our main goal was to observe a nerve conduction block and to examine parameters on which this effect depends. Nerve cnduction block was successfully simulated, an example of it being shown in Figures 11a, 11b, 11c and 11d. Nerve conduction block occurrs as described in Simulation section. High frequency sinusoidal block current blocks the propagating action potential only at certain values of current frequency and amplitude, or, to be more precise, inside a certain interval of amplitude for each given frequency. This results is shown in Figure 12.

IV.

RESULTS AND DISCUSSION

Figure 3 shows a passive potential which is caused by a small current stimulus. Figure 4 shows what happens when a strong enough stimulus fires an action potential. There is a very short time of depolarization when treshold is reached at 2 ms, when sodium ions enter the cell (also shown on Figure 5). After the voltage has reached 100 mV at 3 ms, sodium channels close and the potential decreases. At that point the sodium-potasium pump [Type text]

Figure 3. Passive potential

Figure 4. Action potential Figure 8. Action potential after hyperpolarization-voltage

Figure 5. Conductance for sodium during action potential

Figure 9. Conduction speed dependance on axon diameter

Figure 6. Conductance for potassium during action potential Figure 10. Sinusoidal stimulus

Figure 7. Stimulus intensity-duration relation for the treshold

Figure 11a. Nerve conduction block, x=0.1cm

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V.

CONLUSION

Figure 11b. Nerve conduction block, x=0.45cm

Figure 11c. Nerve conduction block, x=0.5cm

We have determined the action potential thresholds at different temperatures (the default temperature is 6.3 C), the change of the sodium and potassium conductances during action potential, the dependence of the signals speed on the axons diameter, the minimal current intensity and duration pairs for firing the action potential, and the refractory period using a sinusoidal current. The simulation was successful: the signal was blocked by a high frequency sinusoidal current. We found that it is important to match the correct block current frequency and amplitude combinations. Therefore we found the limits of amplitude (using two significant figures), for certain frequencies, needed to block the signal. We have also discussed why it is not possible to use any amplitude with a specific frequency. The results given in this project could be applied, after some experiments were done, in medicinal use to stop the axon signals such as those originating from pathological pain.

REFERENCES
[1] A. L. Hodgkin and A. F. Huxley, A quantitative description of membrane current and its application to conduction and excitation in nerve, J. Physiol., vol. 117, pp. 500544, 1952 Functional electric stimulation, available at http://www.bem.fi/book/21/21.htm J. A. Bednar, Practical: The Hodgkin-Huxley model, 2010, available at http://www.inf.ed.ac.uk/teaching/courses/nc/mvrlab2.pdf Evyatar Av-Ron et al., Teaching Basic Principles of Neuroscience with Computer Simulations, 2006, available at http://www.funjournal.org/downloads/avronetal.pdf R. Guttman and R. Barnhiel, Temperature characteristics of excitation in space-clamped squid axon., 1965 C. Tai, W. C. de Groat and J. R. Roppolo, Simulation analysis of conduction block in unmyelinated axons induced by high frequency biphasic electrical currents, IEEE Trans Biomed Eng., 2005

[2] [3]

[4]

Figure 11d. Nerve conduction block, x=0.55cm

[5] [6]

Figure 12. Conditions in which nerve conduction block occurs for 30m axon (intervals of amplitude for 6, 7, 8, 9 and 10kHz)

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