CHAPTER 2 HUMAN NERVOUS SYSTEM ELECTRICAL ACTIVITIES

CHAPTER 2 HUMAN NERVOUS SYSTEM ELECTRICAL ACTIVITIES Behavior of human nervous system is well realized as electrical signal propagation through nerves from different parts of body to the brain. Now, it is also well established that electric conduction in nerve can be realized in the form of an electric circuit which was purposed by Hodgkin and Huxley [1] and they got Nobel Prize for this. This model and its mathematical interpretation are capable to explain the generation and transmission of a stimulus through the human nervous system. Nerve conduction depends upon excitation and de-excitation of electrochemical ions available at inner and outer layer of the nerve [2]. The generation and propagation of electric signal in a nerve is caused due to the variation in concentration of different electrochemical ions (such as Na +, K +, Cl -, proteins etc.). In this Chapter, study and analysis of the chemical and electrical behavior of nerve is done while Hodgkin Huxley model is explained in Chapter 4. For this purpose, the behavior of the nerve conduction is discussed and realized in the form of an electrical signal, basically in the form of electrochemical Transmission. 2.1 ELECTRICAL BEHAVIOUR OF NERVOUS SYSTEM Human nerves, organs, muscles, etc are controlled and operated by the electricity generated inside the body in different forms. For example, electric signal propagation is involved in all kind of functions as well as activities of the human nervous system [2, 3]. Similarly, the attraction of opposite charges is responsible for the forces of muscles. The brain s action for any stimulus is basically in the form of electrical signal. All nerve signals reaching to (or coming from) the brain are actually in the form of flow of electrical currents. The nervous system of a human plays a fundamental role in every function of body. Basically, the brain receives signals in both internal and external information, extracted as stimuli, by different human nerves and then communicates the proper responses. This information is received and transmitted in the form of electrical signals through various nerves. This communication system of human nervous can deal with millions of information at the same

time, analyze them at great speed and generate response simultaneously. These Nerves are made up of large number of nerve fibers (which are known as neurons) which are unidirectional, i.e. can transmit only in one direction. Nerves responsible for the stimuli transmission of the information from muscles/glands to the brain (or spinal cord) are known as afferent nerves and while nerves responsible for the signal transmission from the brain / spinal cord to the appropriate muscles / glands are known as efferent nerves. By selective measurement of the desired signals (without disturbing the human body), such as ECG (Electro Cardiogram), EMG (Electro Myogram), EEG (Electro Encephalogram), etc., useful clinical information can be obtained about a particular body functions. Neuron is the fundamental structural unit of the nervous system. A nerve cell performs reception (acceptance), interpretation (analysis), and transmission of electrical signals to the human brain. A neuron is made up of a cell body which performs reception of electrical stimuli from its neighbouring neurons through its contacts (known as synapses) which are located on the cell body or on the dendrites. The dendrites are the sensitive parts of the neuron which are specialized to receive information from other cells or stimuli. So, the dendrite in neuron can be a compared with transducer in electric circuit (temperature receptor, stretch receptor, etc). If the external stimulus is enough strong to generate a potential difference in the contact nerve that cross a definite barrier of voltage (known as threshold voltage), the neuron transmits its corresponding signal, in electrical form, outward through a fiber type structure known as axon [3]. This nerve fiber or axon is the part of neuron which carries the electrical stimulus to glands, muscles, or other neurons. Length of a neuron can be a metre or more, or example, it could have its extension from the spinal cord to a hand finger or from the brain to a synapse in lower part of the spinal cord. Most of the neurons present in the human nervous systems, their axons are covered by an insulating layer, known as the myelin sheath. This sheath is made up of supporting cells (wrapped around the axon), which are known as Schwann cells. Between Schwann cells, there are small regions of exposed axon called Nodes of Ranvier.

Figure 2.1: Different parts of a human nerve These nodes contain the voltage-gated ion channels which allow the propagation of action potentials through the axon [4]. As result, the electrical signals jump from one node to another node. This mechanism (known as salutatory conduction) shows faster propagation of electrical signals in myelinated neurons with comparison to ummyelinated neurons. The membrane of neuron and myelin sheath forms an insulating layer between the extracellular fluid and conducting axoplasm, as shown in Figure 2.2. Figure 2.2: Axon as an insulated wire The cross section view of an axon is also shown in Figure 2.3. When a sufficient stimulus appears in any part of this axon, a voltage variation occurs there which forces its nearby charges to move either toward it (or attraction) or away from it (or repulsion), as illustrated in Figure 2.4.

Figure 2.3: Axon s cross section The movement of these charges actually decides how fast the action potential will travel along the length of the axon. This current is limited by the electrical resistance and the membrane capacitance (the way they interact with charges across the membrane). Figure 2.4: Movement of charges inside the axon in response to a stimulus 2.1.1 Electric Resistance of Human Neurons There are two substances in the neuron of nervous system, which produce electrical resistance: one is the axoplasm and another is the cell membrane with/without myelin sheath [4,

5]. The electrical resistance R of a neuron, along the length of its axon, can be described with the classical relations (i.e. as a wire) as shown in Figure 2.5. Figure 2.5: A wire with Resistance R, length l and radius r. ρ1 ρ1 R = = (2.1) A πr 2 where the resistivity of the neuron is shown by ρ, (it is a constant but depends on the medium). l and r are the length and radius of the wire, respectively. The resistivity ρ of the axoplasm is 2.0 Ω-m for both myelinated and unmyelinated neurons, i.e., for the average length of an axon in a neuron is 2 mm and readius is 5 µm, then by using Eq. (2.1),the resistance of the axoplasm should be R axoplasm = 5 x 10 7 Ω. Thus, it can be easily understood that axons are actually very poor conductor of electricity. The resistance of cell membrane of is finite. Cell membrane is also permeable to charge. This resistance of the membrane depends on the surface area of the axonal membrane: ρ ρ1 R = = (2.2) A 2π rl surface For example, an unmyelinated axon (UA), ρ UA = 0.20 Ω m. So, again for an average axon 2 mm long with radius of 5 µm, R UA = 3.2x10 6 Ω. Myelinated axons (MA) have a much higher resistivity, ρ MA = 40.0 Ω m, so R MA = 6.4x10 8 Ω. 2.1.2 Electric Capacitance of Human Neurons Capacitor is consist of two conductor surfaces placed side by side and separated by insulating material(s) known as dielectric material. Dielectric materials are used here to enhance the capacitance of the capacitor. Capacitors have ability to store charge and hence electric energy which is generated by the attraction of that charges in one surface experienced due to the charges

in another (this process is known as electric induction). A voltage is applied across the conducting surfaces of a simple conductor, due to which the charges move from one surface to the other. For electrically neutral surfaces, moving positive charges away from a surface itself implies that there should be a net negative charge of identical magnitude is left behind on that surface [4, 5]. The amount of charge Q that can be moved from one to the another surface depends on the voltage V applied across the conductor plates, the separation d between the two plates, and the total surface area A between them: εav Q = (2.3) d Here ε is known as permittivity which is different for different dielectric material filled between the conducting plates/surfaces. The amount of charge stored in capacitor per unit volt applied across it, i.e. Q/V, is known to as capacitance, which is denoted by C. It is basically a measurement of storage capacity of the capacitor. Therefore, capacitance of a parallel plate capacitor is given by: εa C = (2.4) d SI Unit of capacitance is known as Farad, represented as F. Again, the equation (2.4) makes sense because of the following interpretations: 1. If the surface area of the plates is larger than it should store more charge and hence more electric energy. 2. If the separation between the plates is smaller than the attraction between the charges of the plates should be more, causing the increment in the capacity to store the charge. For example, if a dielectric medium is with ε = 2 X 10-11 F/m and d = 100 Ǻ = 1 X 10-8 m, the capacitance per unit area of this capacitor is C ε = = 2x10 3 F/m² (2.5) A d For a neuron, a lipid bilayer has ε = 5 X 10-11 F/m and d = 50 Ǻ = 5 X 10-9 m. Thus, the capacitance per unit area of an unmyelinated axon is C ε = = 10 2 F/m² (2.6) A d

The myelin sheath of myelinated axons contains a membrane that is wrapped around the axon hundred times. Due to this multilayer arrangement, thickness of the lipid bilayer increases by a factor of 200, i.e. d = 1 µm. Thus, for a myelinated axon, capacitance per unit area is: C ε = = 5x10 5 F/m² (2.7) A d 2.1.3 Summary of Electrical Properties of Axon The electrical properties of neurons are summarized by the Figure 2.6 and Table 2.1 shown below. IAxon IWall Physical System Physical Model Figure 2.6: The physical model of nerve Electric impulse produced by a stimulus in human nerve imbalances membrane potential and propagates in the form action potential through the nervous system. Current generated due to this potential flows through the axon of the nerve and also through the walls of cell membrane [4]. In Figure 2.6, its equivalent physical model is shown which consists wires, a capacitor and two resistors that approximate the physical flow of charge through the real axons. It is clear here that the behaviour of the functioning of nerve, i.e. nerve conduction can be compared with electrical conduction process which will be discussed in detail in Chapter 4. Dielectric Property / Axon Type Table 2.1: Dielectric Properties of Neurons Unmyelinated Axon (UA) Myelinated Axon (MA) Axoplasm resistivity (ρ axoplasm ) 2.0 Ω m 2.0 Ω m Wall resistivity (ρ UA, ρ MA ) ρ UA = 0.20 Ω m 2 ρ MA = 40.0 Ω m 2

Wall capacitance/area (C/A) 10-2 F/m 2 5 10-5 F/m 2 2.2 ACTIVITIES OF NERVOUS SYSTEM The human nervous system uses complex networks of neurons to receive, process and exchange vast amounts of information in different part of bodies. Basically, Neurons respond to any stimuli by generating and conducting electrical impulses, which are known as action potentials. These electrical signals can then be communicated to other neurons/ neural networks. The cellular membrane of neurons separates its internal environment from the external environment and regulates permeability and flow of ions and molecules. The capability of selectiveness of the membrane allows passage of electrical currents created by the movement of ions through the membrane. The cellular membrane is basically a thin polar membrane made up of two lipid layers with embedded integral proteins. These proteins provide internal structures for essential cellular function, including ion channels, ion transporters, ATP pumps, receptors, enzymes, structural support, etc. Proteins act as pumps, channels or transporters from one side of the impermeable membrane to the other. These proteins regulate the fluctuation of cellular ionic concentration and therefore the conduction of electrical current in and out of the membrane, which is fundamental to in neural communication [3, 4]. Ion channels are basically the intrinsic membrane proteins, which contain aqueous pores which open or close as per the functional requirements. When pores are opened, these ion channels permit selected ions for one way diffusion in the membrane which creates the electrochemical potential gradient. While when pores are closed, they are impermeable for one way flow of these ions. It is important here that ion channels can allow single or multiple types of ions when opened depending upon the size of the ions and the channel, but in all cases, this flow can only be in one way. Flow of ions in these ion channels depends upon the type of stimuli that causes the channel gates to open or close. Out of these, some channels (such as neurotransmitters) can be particular for a chemical inside or outside the cell. Other channels may be sensitive to changes in voltage across the membrane. Still there may be others type of channels which may respond to various kinds of sensory stimuli [1]. Ion channels show selectivity in the ions to which they are permeable. Some are constructed to only permit a specific type of ions, such as sodium, potassium, chloride ions, etc.

Others with fewer restrictions permit broader groups of ions, such as monovalent cations (or may allow all cations to pass through it). These two characteristics of ion channels (sensitivity and ion selectivity) are vastly used for description and classification of ion channels. There is one more specific category of channels (named as leak channels) which are of selective type ion channels. Leak channel always remain open, do not have gates and do not require stimuli for activation of deactivation. In this way, sodium, potassium, chloride ions, etc all have their own individual ion channels throughout the body, which have their specific and important roles in neural functioning, firing and muscle contraction [5]. 2.2.1 Active Transporters Active transporters are a category of intrinsic plasma membrane proteins which selectively transports across the membrane and against their concentration gradient [2]. An active transporter binds with ions and forms complexes, which are then trans-located across the membrane and then released. This procedure takes several milliseconds to complete which makes the movement of ions through these active transporters much slower in comparison to the ion movement through the ion channels. Ions movement through active transporters also requires the consumption of energy. Based on their energy resources, active neural transporters are divided into two classes named as ATPase pumps and ion exchangers. Basic difference between ATPase pumps and ion exchangers is that an ATPase pump receives energy directly from the hydrolysis process of ATPs while an ion exchanger utilizes the concentration gradients of other ions as energy source to move the desired ions across the membrane. This type of transporter carries one ion up its electrochemical gradient while at the same time carrying another ion down its electrochemical gradient [2, 6, 8]. Figure 2.7 includes the Na + /K + pump and the Na + /K + exchanger.

Figure 2.7: ATPase pumps and ion exchangers 2.2.2 Resting Potential Human nerves are excitable cells which generate electrical signals to respond any stimuli. Stimulus is communicated to human brain in the form electrical signal. To achieve this phenomenon, a potential is maintained across the cell membrane. Without this potential, no nerve impulse can occur. A nerve is considered in a rest state or in equilibrium up to when it maintains a consistent membrane potential without any kind of change in it [7]. The electric potential across the membrane during this rest state is known as the resting membrane potential or simply resting potential. 2.2.3 The Intracellular and Extracellular Environments The intracellular and extracellular environments of human s neurons is mostly consists of water, amino acids, proteins, phospholipids, inorganic and organic ions. Proteins, phosphate groups of ATP and other organic molecules available in intracellular environment are negatively charged and impermeable to the membrane. These non-diffusible and negatively charged molecules keep the intracellular environment negatively charged in comparison with its surrounding extracellular environment. Thus, intracellular environment is always negatively charged with respect to extracellular environment for a neuron. At rest state, the intracellular environment contains high concentration of potassium ions along with membrane impermeable anions, while the extracellular environment contains high concentration of sodium ions and chloride anions. These concentrations of Na +, K + and Cl - ions remain consistent at rest state and fluctuate during the excited state which causes the generation of potential difference and hence action potential [4, 9]. Ionic concentration of different ions for intracellular and extracellular environment of human neurons is shown in the Table 2.2.

Table 2.2: Intracellular and extracellular ionic concentrations for human nervous Ion Extracellular (mm) Intracellular (mm) Permeable to Membrane (Yes/No) K + 5 125 YES Na + 120 112 NO Cl - 125 5 YES A - 0 108 NO H 2 O 55,000 55,000 YES 2.3 PHYSICS OF IONS MOVEMENTS The intracellular and extracellular environment of human nervous stays in rest state until a stimulus occurs. If the stimulus is strong enough to cross the threshold voltage then action potential is generated. The movement of ions then takes place due to fluctuation in the concentration of the ions of intracellular and extracellular environments. This movement of ions is caused by many parameters which plays their specific role in this procedure. The factors that move the ions are described below. 2.3.1 Passive Forces There are two passive forces (namely the chemical concentration and electrical gradient) which cause the movement of ions and create influence in ionic equilibrium across the cell membrane without any requirement of the external energy. These two forces results in the form of electrochemical gradient which describes the ability of an ion to move across a membrane [4, 9]. Ionic diffusion is basically a result of electrochemical gradient. Diffusion is defined as the arbitrary movement of ion particles from its area of higher concentration to lower concentration. Cellular environments of neurons are always regulated by the cell membrane and ion channels. If the cellular environment of a neuron could be left unregulated, these chemical concentration gradients of different ions from their intracellular environment to extracellular environment would move sodium as well as chloride ions from extracellular to intracellular environment of membrane cell and potassium ions from intracellular environment to extra cellular environment of the membrane cell. However, the membrane itself repels this diffusive force, by storing energy in the form a chemical potential across the membrane [10]. The ions,

due to their electric nature, exert electrostatic force on one another which generates electrostatic gradient across the membrane. In a neuron s environment there is an excess of positive ions at extracellular surface which is separated from its negatively charged intracellular surface by the cellular membrane. This difference in ion charges across the cellular membrane generates an electrical gradient across the membrane [5]. 2.3.2 Active Forces Transmission of ions in intracellular/extracellular environment depends on to the effective electrochemical gradient s direction due to diffusive and electrostatic forces. However, the capability to move these ions against this gradient is also required to maintain a proper level of resting potential in the membrane. Forces responsible for this transmission against the gradient are known as active forces. In human neurons, Na +, K + and ATPase pumps work for this purpose and actively transport Na + and K + ions against their electrochemical gradient to maintain resting potential [3]. 2.3.3 Sodium Potassium Pump The sodium potassium pump is basically a carrier protein which actively extrudes sodium ions from the cell in ratio of 3:2 with potassium ions which it transports into the cell. Again this pump acts against the sodium and potassium electrochemical gradients so this process is actually energy dependent. This energy is gained from the exergonic hydrolysis of ATP into ADP and Pi by the carrier protein ATPase enzyme [11]. Typically -57kJ/mol energy is released by the hydrolysis of one mole of ATP. ATP + H 2 O ADP + Pi + Free Energy (2.8) Each neuron has passive leak channels which allow sodium or potassium to flow in the direction of their electrochemical gradient. A cell membrane has many such potassium leak channels, which allow potassium ions to leave the cell. This action is counteracted by sodiumpotassium pump by restoring potassium ions again into the cell. This complete procedure keeps intracellular concentration of sodium and potassium ions at a relatively constant level and hence membrane potential remains leveled [2]. This complete process keeps on repeating itself each

time and with each nerve cell whenever a stimulus of sufficient energy (to cross the threshold voltage) occurs on human body. 2.3.4 Resting Membrane Permeability The differences of ion concentrations between the intracellular and extracellular environments of the nerve cell generate electrochemical potential across the cell membrane and influence the directions of the flow of ions. However, permeability of the cell membrane limits ionic mobility of specific ionic species. Combined effect of the electrochemical gradient and membrane permeability results as fluctuation in ions and hence potential is imbalanced across the boundaries of cell membrane. Na + and K + are the most influential (and membrane permeable) ions in human nervous communication system. Because of the highest quantity of K + ion channels in comparison of any other ion channels, cellular membrane becomes the most permeable for potassium [4, 9]. Na + and K + ion channels are highly selective for the ions which can pass through these channels. Each ion channel spans the lipid membrane with a purely aqueous pore in it. This pore connects the external environment to the internal environment (cytoplasm) [12]. 2.3.5 Membrane Conductance Membrane conductance for a particular ion simply depends on that specific type of ion s ability to move across the membrane as a membrane show resistive nature for flow of ions in itself. Conductance is described as the easiness with which an ion responses for the change in membrane electrochemical potential [13]. Mathematically, Conductance is the reciprocal of the resistance of flow of current in any electrical circuit. Conductance of K + ions is represented by following equation: i k = G k (E m - E k ) (2.9) Here G k is the conductance of the membrane to potassium ions (in Siemens). (E m - E k ) is the driving force (it is basically the electrochemical potential difference) which causes actual movement of K + ions across the membrane (in Volts) and i k is the membrane current flowing outward (in Amperes). Similar equations can be written for Na + and Cl - ions.

and i Na = G Na (E m - E Na ) (2.10) i Cl = G Cl (E m - E Cl ) (2.11) Thus, the membrane conductance for a specific ion is closely related to membrane permeability, but is not identical. Conductance is proportional to the flow of current, i.e. the rate the specific ions at which ions are crossing the cell membrane and this flow rate depend on permeability of cell membrane as well as the number of available ions to flow through it [4]. So conductance varies according to the concentration of available permeable ions. A specific type of ion s Concentration gradient causes an unequal distribution of that ionic charge which creates a bio-electrochemical potential across the cell membrane. It is similar to a tiny battery which has its positive pole at outer side of its cell and the negative pole inside. Concentration gradients are rebalanced by homeostatic processes in cell membrane such as the sodium-potassium pump [4, 12]. 2.4 MATHEMATICAL EQUATIONS FOR EXPLANATION OF NERVE BEHAVIOUR To analyze further the behavior of human nervous system, mathematical modeling of nerve behavior is developed by the researchers [12, 13]. Nernst equation and Goldmann equation are the most significant equations that explain the nerve behaviour. Based on these equations, equivalent electrical model of the nerve conduction is developed by Hodkin and Huxcley (Explained in detail in Chapter 4). This model is able to describe the complete dynamical behaviour of flow of electrical signal generated by any stimuli through the human nerve. Summarized study of Nernst and Goldmann equations is as follows: 2.4.1 Nernst Equation A Cell membrane has two environments (intracellular and extracellular) which are separated to each other by it. This membrane has such kind of channels which allow the flow of only one type of (Let us say K + ions). The charge separation across the membrane builds up a voltage (V=Q/C) which continuously increases until the bidirectional flow of ions becomes leveled. When it occurs, ions that flow in one direction is now counterbalanced by some another

same kind of ions crossing in the opposite direction to maintain an equilibrium condition. This potential difference is this situation is known as the Nernst potential or equilibrium potential. The quantitative terms of Nernst potential can be expressed by the net ion flow j in the terms of its chemical and electrical gradients: (2.12) Here D is known as diffusion coefficient, V is the potential difference, R is the gas constant, F is the Faraday constant, z is the valence, n is the ion concentration and T is the temperature. When j = 0 (no net flow), integration of above equation gives the equilibrium potential of an ion which is known as Nernst Equation: V = RT zf ln (2.13) Here n o is extracellular ions concentration and n i is intracellular ions concentration This equation shows relation between the equilibrium potential V across the cell membrane and the concentration gradient of ions. It can be tabularized as follows: Ion Table 2.3: Axon ion concentration and their Nernst s potentials External Concentration (mm) Internal Concentration (mm) Nernst Potential (mv) K + 20 400-75 Na + 440 50 55 Cl - 560 40-66 2.4.2 Goldmann Equation As we know, there are several types of ion channels available in the cell membrane; each one of them selects and transmits a specific type of ions, such as Sodium or Potassium. Therefore the condition discussed here, i.e. zero net flow of ions, across the cell membrane is not dependent on any single specific type of ion concentration gradient [4]. It basically involves the concentrations (and hence concentration gradient) of all type of ions channel species and relative permeability of these ion channels for cell membrane. The solution in this condition, when the

algebraic sum of all the current flows becomes zero, can be given by Goldman-Hodgkin-Katz equation: V = RT F ln P kk 0 P Na Na 0 P Cl Cl i P k K i P Na Na i P Cl Cl 0 (2.14) Here P Na, P k and P Cl are known as the membrane permeability to Na +, K + and Cl - ions respectively. Combination of Goldmann and Nernst equations serve as important tool in determination nerve conduction s behaviour and characteristics. 2.5 ACTION POTENTIAL We know that human neurons are electrically excitable cells. Due to this specific characteristic, neurons respond to any stimulus by generating and conducting electrical impulse, which is known as action potential. This generation of action potential facilitates the propagation of the electrical signal from one neuron to other neurons. This procedure is the basic phenomena for working of human nervous and its communication system [8]. The dendrites in cell body are common post-synaptic site for coupled pre-synaptic neurons. Pre-synaptic neurons provide incoming information which is either excitatory or inhibitory in nature. The dendrites pass this information to the cell body in the form of electrical impulses where, if sufficient stimulation occurs (i.e. if information signal has enough energy to cross the threshold potential), then only the action potential formation takes place. Action potential is transmitted from the trigger zone (which is in the cell body down the axon) to the ending terminal of axon. An action potential at axon s end releases chemical or electrical signals into the synaptic gap. The neuron releases these signals from the pre-synaptic side of the synaptic gap. These signals now travel across the synapse and couple with another neuron s post-synaptic site, which restarts this entire process again. 2.5.1 Generation of an Action Potential Human nervous system responds to every stimulus which has sufficient energy to cross threshold potential. This stimulus current is passed through cell membrane which produces a variation in rest membrane potential. This is the procedure of generation of action potential. Sometimes, the stimulus current is not enough to cross the threshold barrier and generate action

potential. In this situation, a smaller change in membrane potential is generated which is known as Graded Potential. Therefore, a nerve may generate either action potential or graded potential depending on the magnitude of the stimulus current [4, 5]. The mechanisms of generation of action potential and grade potential are also different. Graded potentials allow continuous relationship between magnitude of stimulus and membrane potential as these potentials are not able to activate the voltage gated channels. On the other hand, action potentials allow discontinuous relationship between stimulus magnitude and membrane potential because these potentials activate voltage-gated channels which actively change the membrane permeability. 2.5.2 Voltage-Gated Ion Channels The ion channels which open or close with changes in trans-membrane potential are known as Voltage-gated ion channels. Voltage-gated sodium channels respond to stimulus currents to initiate an action potential; once an action potential appears voltage-gated sodium and potassium channels continue these changes in ion permeability until the membrane is repolarized back to resting potential [3, 4]. These channels have gates which regulate ions flow. Voltage-gated sodium channels have two independent gates, which are known as the m and h gate. The m gate (also known as sodium activation gate) is located at the extracellular side of the membrane protein and is closed at resting potential. The h gate (or sodium inactivation gate) is located at the intracellular side of the membrane protein and is open at resting potential. The n gate (or potassium activation gate) is located on extracellular side of the membrane protein and is closed at resting potential. These gates respond to particular changes in membrane voltage and open or close at different rates [4, 7]. The response of these channels and their gates during different phases of an action potential in a human neuron is briefed below. 2.5.3 Different Phases of an Action Potential During the onward move of an action potential, the distribution of Na + and K + ions across the cell membrane varies, which creates change in trans-membrane voltage as described in Figure 2.8. This fluctuation occurs due to the shifts in ionic permeability and results in movement of ions. Intervals of membrane permeability change can be divided into four basic

phases: rest, depolarization, repolarizaton, and hyper-polarization explained later in this chapter). The variations in ion permeability during these phases are the effective results of activation and deactivation of voltage-gated ion channels [5, 10]. Different phases of membrane potential are shown in Figure 2.8. Figure-2.8: Action Potential: Phases 2.5.3.1 Resting Phase The resting phase occurs when the nerve cell is in a steady state. It maintains resting membrane potential. In this state, the cell has the capacity to respond to sufficient stimulus current and generate an action potential. The resting potential of a human neuron nerve cell exists between the Nernst potential for potassium (-80mV) and the Nernst potential for sodium (+58mV). Potassium s potential has a significant influence on resting potential because of its dominance in membrane permeability over sodium. During this phase, the m gate and n gate are closed while the slow h gate is open [4]. 2.5.3.2 Depolarization Phase The depolarization phase (or rising phase) occurs once when a stimulus current of sufficient magnitude flows through the cellular membrane of a nerve cell in resting state. This stimulus current increases the value of membrane potential above the required threshold value

(The threshold is the value of the minimum membrane potential which generates an action potential). Once threshold is reached, the fast acting m gate rapidly opens, the slow acting n gate begins to open and slow acting h gate start to close. This change in membrane sodium permeability allows extracellular sodium to flow down its electrostatic gradient, into the negative intracellular environment of the neuron. This massive sodium influx increases the membrane potential to a peak near sodium s Nernst potential, marking the end of the depolarization phase [5, 7]. 2.5.3.3 Repolarization (Refractory) Phase As the membrane potential reaches its maximum, the repolarization phase, or falling phase, begins. The slow acting h gate closes, inactivating the inward flux of sodium ions into the cell and ceasing the increase in membrane potential. Now the potassium channels slow n gate is fully open, which allows potassium ions to flow down their electrostatic gradient from the newly positive intracellular environment of the neuron and into the more negative extracellular environment. The potassium n gate repolarizes the cell membrane potential, remaining open until resting potential is reached [4]. 2.5.3.4 Hyperpolarization Phase During the repolarization, phase the value of membrane potential becomes more negative because of the efflux of intracellular K + ions. The membrane potential continues to decrease and undershoots resting potential while the n gate fully closes and h gate beings to open again [4]. 2.6 PROPERTIES OF AN ACTION POTENTIAL Generation of action potential and its transmission is the key phenomena for communication system of human nervous. Only those information (Stimuli) are analyzed and responded by human brain which are communicated to it, which is the function of action potential. Properties of this action potential are described as follows:

2.6.1 Threshold To generate an action potential, a stimulus current must have sufficient strength to elevate membrane potential from resting potential to threshold potential. A nerve cell s threshold potential is the minimum value of membrane potential that will produce an action potential. In case if a stimulus current is not of sufficient magnitude to reach the threshold potential then a graded potential is generated [5]. Graded potentials open a small portion of voltage-gated sodium channels, slightly increasing sodium permeability. However, the resulting influx of sodium ions due to gradded potential cannot overcome the opposing efflux of potassium ions. A net outward membrane current is produced, ceasing further depolarization and possible formation of an action potential. At threshold potential, the minimum amount of voltage-gated sodium channels becomes open in order to overcome the efflux of potassium ions and produce a net inward current. This permits further depolarization causing sodium influx to dominate, resulting in an action potential [5]. The value of threshold potential for a particular neuron is influenced by the density of voltage gated sodium channels in the plasma membrane and the sensitivity of those channels. A high density of voltage-gated sodium channels will surely require a smaller portion of channels to open to generate an influx of sodium which overcomes potassium efflux. An increased sensitivity in voltage-gated sodium channels will also requires a smaller portion of channels to open to generate an influx of sodium which overcomes potassium efflux. The lower the threshold potential, the more excitable a neuron is to incoming nerve impulses and the more actively it propagates signals to other neurons [3]. 2.6.2 Summation Neurons receive postsynaptic potentials from many other neurons, located at the synapse sites. To generate an action potential, these signals must generate a resultant potential exceeding the threshold potential when reaching the neuron s triggering zone. These individual postsynaptic potentials decay with time and space when traveling from the synapse sites to trigger zone. However, in certain conditions, postsynaptic potentials can summate spatially or temporally to combine potential and combat decay [12, 13]. Spatial summation occurs when graded postsynaptic potentials, generated at different synapse locations, occur within a single space constant of another (The space constant is the distance a particular potential will occupy before it decays). Similarly temporal summation takes

place when graded postsynaptic potentials occur within a single time constant of another (The time constant is the amount of time a particular potential will take to decay). Potentials which summate combine amplitudes to form a single impulse with an elevated magnitude. This elevation expands the distance postsynaptic potentials can occupy before decaying to zero. Summation of postsynaptic potentials increases the ability of a neuron to produce a resultant potential which exceeds threshold at the trigger zone and generate an action potential [12]. 2.6.3 The Refractory Period Immediately following the occurrence of an action potential, a nerve cell has a reduced ability to generate a second action potential and is said to be refractory. For a brief interval, known as the absolute refractory period, a second action potential cannot be generated by any magnitude of stimulus. For intervals which are greater than the absolute refractory period, there is the relative refractory period in which a second action potential can be produced, but the threshold potential is elevated. Threshold elevation is dependent on a complex history of previous stimulation and also on response cycles of the axon. Absolute refractory periods occur on the order of a few milliseconds, while relative refractory periods have shown lasting effects, up to many minutes [5]. Together absolute and relative refractory periods limit the maximum frequency at which neurons can conduct information. 2.7 CONCLUSION In this chapter, the working o human nervous system is summarized and behaviour and properties of the nervous system are discussed. It can now be understood that the human nerve has electrochemical mechanism which imparts proper information for any stimulus through the generation and propagation of action potential in nerves. Human nerves has specially designed ion channels and gates to make the communication possible and to maintain the reset membrane potential. This all communication from different parts of the nervous system to the brain and vice versa is purely in the form of electrical signals. This signal propagates through the nerves and hence our brain is informed about the occurrence of the stimulus/stimuli. The electrical analogy of the nerve system is discussed in detail in Chapter 4.

Due to the electrical nature of the nerve communication, our interest is now focused on the impact of electromagnetic signals on the nerve conduction. In present work, we have focused on noo-ionizind radiations (NIR), specifically on mobile phone radiations. Details of these radiations and their interaction with human body are discussed in Chapter 3.

REFERENCES 1. A. L. Hodgkin, and A. F. Huxley, The dual effect of membrane potential on sodium conductance in the giant axon of Loligo J. Physiol, vol. 116, no. 4, pp. 497-506, Apr. 1952. 2. S.I. Fox,, Human physiology, 5th ed. Boston, Mass: Wm. C. Brown Publishers. 1996. 3. S.G. Waxman, Clinical neuroanatomy, 26th ed. San Francisco: McGraw Hill Medical, 2010. 4. M K Gupta, R. K. Khanna and K. J. Rangra, Study and analysis of human nervous system and effects of external em signals on conduction in human nerves, Intl. Jour. on Rec. and Inno. Tren. in Comp. and Comm., Vol. 4, No. 4, PP: 448 458, 2016. 5. D.J. Aidley, The physiology of excitable cells, 4th ed. Cambridge, UK: Cambridge University Press, 1998. 6. Matthews, G. Gary, Cellular physiology of nerve and muscle, 4th ed. Boston: Blackwell Scientific Publications, 2001. 7. M. Cholette, Membrane channel properties, California Polytechnic State University- San Luis Obispo, BMED 450: Neuroengineering Lecture Slides. Fall 2011. 8. M. Cholette, Membrane potential California Polytechnic State University- San Luis Obispo, BMED 450: Neuroengineering Lecture Slides. Fall 2011. 9. M. Cholette, The action potential California Polytechnic State University- San Luis Obispo, BMED 450: Neuroengineering Lecture Slides. Fall 2011. 10. D. Purves, G.J. Augustine and D. Fitzpatrick, Neuroscience, 2nd ed. Sunderland, Mass: Sinauer Associates; 2001. 11. Z.J. Xu and D.J. Adams, Resting membrane potential and potassium currents in cultured parasympathetic neurons from rate intracardiac ganglia, J. Physiol.,no. 456, pp. 405-424. October, 1992. 12. A. L. Hodgkin, A. F. Huxley, and B. Katz, Measurement of current-voltage relations in the membrane of the giant axon of Loligo, J. Physiol, vol. 116, no. 4, pp. 424-448, Apr. 1952. 13. A. L. Hodgkin and A. F. Huxley, Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo, J. Physiol, vol. 116, no. 4, pp. 449-472, Apr. 1952.