Review of Medical Physiology - William F. Ganong 2002

Physiology of Nerve and Muscle Cells
Excitable Tissue: Nerve
Excitation and Conduction

Nerve Cells are characterized by a low threshold of excitation. Stimuli can be electrical, chemical, or mechanical in origin. There are two known types of responses to physicochemical stimuli: a local, non-propagating response—referred to depending on its site of origin as synaptic, generator, or electrotonic potentials; and a propagating response—action potentials, or nerve impulses. Nerves and other excitable tissues exhibit exclusively electrical responses, which serve as the primary "language" of The Nervous system. These responses are driven by changes in Cell membrane permeability to ions, regulated by the state of Ion Channels. An axon transmits a Nerve Impulse to its terminal. Nerves do not transmit impulses passively, as occurs, for example, in a telephone network; the propagation of nerve impulses, even when rapid, is much slower than the flow of electric current through wires. Nervous Tissue is actually a relatively poor passive conductor: to generate a 1 V signal at the far end of a 1-meter axon in the absence of active processes within the nerve, a multivolt potential would be required. The transmission of a nerve impulse along a nerve is an active, self-sustaining process that propagates with constant amplitude and velocity. This process is often compared to the burning of a gunpowder trail: the ignition of each grain triggers the ignition of the immediately adjacent one, causing the flame to spread steadily and uniformly along the trail to its end.

Class="center">

Fig. 2-4. Functional Organization of a neuron. Local potentials accumulate in the receptor zone, whereas the Action Potential originates in the region close to the receptor zone (arrow). The axon propagates the action potential to the nerve terminals, where it triggers the release of synaptic Transmitters.

Electrical processes occurring within a neuron are transient, measured in milliseconds (ms); potential changes are also minute, measured in millivolts (mV). Combining microelectrode techniques—using microelectrodes up to 1 µm in diameter—with electronic amplifiers and a cathode-ray oscilloscope enables detailed investigation of electrical activity in nerves. Modern instruments amplify potential changes 1,000-fold or more, while the cathode-ray oscilloscope provides virtually inertia-free and simultaneous recording of electrical processes in a nerve.

Cathode-ray oscilloscope

The cathode-ray oscilloscope (CRO) is used to measure electrical processes taking place in living tissues. In a CRO, electrons emitted by a cathode are directed as a focused beam onto the screen of a Glass tube housing the cathode (Fig. 2-5). The screen is coated with one of various substances (phosphors) that emit light when struck by electrons. Positioned on either side of the electron beam is a vertical metal plate. When voltage is applied to these plates, the positively charged plate attracts the negatively charged electrons, while the negatively charged plate repels them. As the voltage applied to the vertical plates (X-plates) is gradually increased, then suddenly decreased and increased again, the electron beam sweeps progressively toward the positively charged plate, subsequently returns to its initial position, and is deflected toward the positively charged plate once more. Applying this type of " sawtooth" voltage causes the electron beam to deflect horizontally across the tube screen, with the sweep speed proportional to The rate of increase of the applied voltage.

Fig. 2-5. Cathode-ray oscilloscope. Simplified diagram of the basic setup for recording potential changes in a nerve.

Another pair of plates (Y-plates) is arranged horizontally, one plate positioned above and the other below the path of the electron beam. The voltage applied to these plates deflects the electron beam upward and downward as it sweeps across the tube screen. The magnitude of the vertical deflection is proportional to the potential difference between the horizontally placed plates. When these plates are connected to electrodes attached to a nerve, any changes in nerve potentials can be recorded as vertical deflections of the electron beam as it moves across the screen.

Recording potential changes in isolated axons

Mammalian axons have a small diameter (20 µm or less), making them difficult to isolate from other axons in a nerve, whereas giant unmyelinated nerve cells occur in large numbers in invertebrates and can be separated with relative ease. Such giant cells are found, for example, in crabs (Carcinus) and cuttlefish (Sepia), but the largest axons are discovered in the squid (Loligo). The cervical region of the squid muscular mantle contains single axons up to 1 mm in diameter. The Main Properties of these axons closely resemble those of mammalian axons.

Resting Membrane Potential

If two electrodes placed On the surface of an isolated axon are connected via an amplifier to a CRO, the instrument will record no change in voltage. However, if one of the electrodes is inserted through the membrane into The Cell interior, the instrument will register a constant potential difference between the negatively charged intracellular environment and the positively charged surface. The resting membrane potential is a characteristic of almost all cells. The mechanism generating the resting membrane potential is discussed in Chapter 1. In Neurons, its value is approximately -70 mV.

Latent period

When a stimulus is applied and nerve impulses are propagated along the axon, characteristic short-lived potential changes occur, known as the action potential, which are recorded when the impulses reach the surface electrode.

Immediately following stimulation, a brief, biphasic deflection from the baseline occurs—the stimulus artifact. This artifact is caused by the spread of electrical current from the stimulating electrode to the recording electrode. Such a phenomenon is typically observed despite careful shielding, yet it holds significant practical value because its appearance on the cathode-ray tube screen allows the exact time of stimulation to be determined. The stimulus artifact is followed by an isopotential interval (the latent period), which terminates at the onset of the action potential and corresponds to the time required for the impulse to travel along the axon from the site of stimulation to the recording electrode. The duration of this period is proportional to the distance between the stimulating and recording electrodes, and inversely proportional to the conduction velocity. If the duration of the latent period and the distance between electrodes are known, the conduction velocity in the axon can be calculated. For instance, suppose the distance between the cathode stimulating electrode and the surface electrode (Fig. 2-6) is 4 cm. The constant electrical current serving as the stimulus is typically delivered from the cathode. If the latent period lasts 2 ms, the conduction velocity is 4 cm per 2 ms, or 20 m/s.

Fig. 2-6. Action potential in a neuron. One of the electrodes is located inside the cell.

Action potential

The initial manifestation of an action potential is membrane depolarization. After the first 15 mV, the rate of depolarization increases. The point at which this rate change begins is called the critical level of depolarization, or threshold. From this point onward, the curve traced by the oscilloscope rapidly reaches and surpasses the isopotential line (zero potential), peaking at approximately +35 mV (overshoot). Subsequently, the potential rapidly declines toward the Resting Potential level. Once repolarization reaches about 70%, the rate of repolarization slows down, and the curve approaches the resting potential level more gradually. The rapid rise and subsequent abrupt fall of the potential are termed the spike potential of the axon, while the slow decline at the end of the process is referred to as after-depolarization. Upon returning to the initial resting potential level, the curve deflects upward once again toward hyperpolarization, albeit slightly, recording The phenomenon of after-hyperpolarization. An action potential recorded with one electrode inside the cell is called monophasic because the process predominantly unfolds in a single direction.

The Proportions of the curve shown in Fig. 2-6 have been intentionally distorted to better illustrate the Phases of the action potential. A curve whose components accurately reflect the temporal characteristics and potential values in a mammalian neuron is shown in Fig. 2-7. Note that the rise in potential is extremely rapid, precluding a clear observation of the depolarization changes and the critical threshold level, while the after-hyperpolarization value amounts to only 1–2 mV, even though this period lasts nearly 40 ms. The duration of after-depolarization in this case is approximately 4 ms. In many neurons, it is even briefer and of smaller magnitude. Variations in after-polarization values can occur without significant Changes in the remaining phases of the action potential. For instance, if a nerve transmits impulses for an extended period, the magnitude of after-hyperpolarization typically increases.

The "all-or-none" law

If the action potential is recorded under conditions as depicted in Fig. 2-6—with recording electrodes placed at a considerable distance from the stimulating electrodes—the minimum value of direct current (threshold intensity) that, acting for a given duration, triggers an action potential can be determined. There is a reciprocal relationship between current intensity and its duration of action. Weaker currents require a longer duration of action, whereas stronger currents require a shorter duration. The relationship between current intensity and duration is described by a strength-duration curve. A slow increase in current does not elicit excitation in a nerve because the nerve adapts to this type of stimulus; this process is called accommodation. A stimulus of threshold intensity elicits an action potential. Any further increase in stimulus intensity does not result in an increased magnitude or other parameters of the action potential, provided that other experimental conditions remain constant. A subthreshold (inadequate) stimulus fails to elicit an action potential. An action potential of constant amplitude and waveform is generated regardless of stimulus strength, provided the stimulus reaches or exceeds the threshold. Consequently, the action potential obeys the "all-or-none" law.

Fig. 2-7. Recording of an action potential in a large myelinated mammalian nerve fiber, reflecting the true proportions of its phases.

Electrotonic Potentials, Local Response, and Critical Level of Depolarization

Although subthreshold stimuli do not trigger an action potential, they do affect the membrane potential. This effect can be observed by placing recording electrodes a few millimeters away from the stimulating electrode and applying a subthreshold stimulus for a certain duration. Applying a subthreshold cathodal current induces a local depolarizing shift in potential, the value of which increases sharply and then decays exponentially over time. The recovery curve of this response drops off more rapidly as the distance between the stimulating and recording electrodes is increased. An anodal current produces a potential change of equal duration in the hyperpolarizing direction. Such potential changes are referred to as electrotonic potentials, and depending on the direction of the current (i.e., whether induced by a cathode or an anode), they are termed katelectrotonic or anelectrotonic potentials, respectively. These potential changes are essentially passive alterations in membrane polarization caused by the addition or subtraction of charge resulting from the application of a specific electrode. At low current intensities that produce a depolarization or hyperpolarization of approximately 7 mV, the magnitude of these changes is proportional to the stimulus strength. With stronger stimuli, this proportional relationship holds true for anelectrotonic potential changes, but fails to apply to cathodal stimulation; in the latter case, the potential shift is greater than would be expected based solely on the stimulus strength. Ultimately, if the cathodal stimulus is strong enough to cause a 15 mV depolarization, assuming a resting membrane potential of -55 mV, the membrane potential abruptly drops, and the propagation of an action potential is initiated.

The disproportionately large potential changes produced by a sufficiently strong cathodal stimulus—resulting in 7-15 mV of depolarization—occur due to the opening of voltage-gated Na⁺ channels (see below) and are known as the local response (Fig. 2-8). The point at which a steep upstroke toward the peak potential is triggered represents the critical level of depolarization. Thus, a cathodal current that causes a 7 mV depolarization elicits a purely passive membrane response resulting from the accumulation of negative charges. A cathodal current causing a 7-15 mV depolarization also has a relatively minor effect on the depolarization process itself. Repolarizing forces still outweigh depolarizing forces, and the potential decays. However, at a depolarization level of 15 mV, the depolarizing forces become sufficient to overcome the repolarizing forces, thereby generating an action potential.

Stimulation is typically delivered via the cathode because cathodal stimuli exert a depolarizing effect. Conversely, anodal currents shift the membrane potential further away from the critical level of depolarization, thereby suppressing impulse generation. However, the cessation of an anodal current can cause the membrane potential to overshoot in the depolarizing direction. This rebound effect is sometimes strong enough to directly trigger excitation in the nerve immediately following the Termination of the anodal stimulus.

Fig. 2-8. Electrotonic potentials and local response. Curves showing changes in the neuronal membrane potential following the application of stimuli corresponding to 0.2, 0.4, 0.8, and 1.0 times the threshold current, plotted on a time scale. Response curves located below the horizontal line represent processes occurring during anodal current flow, while those above represent cathodal current flow. The threshold stimulus was applied twice: the first time it triggered an action potential, whereas the second time it did not.

Changes in Excitability During Electrotonic Potentials and Action Potentials

Just as with the action potential, katelectrotonic and anelectrotonic potentials, and the local response, the threshold level for neuronal excitation also changes. Hyperpolarizing anelectrotonic responses raise the threshold, whereas depolarizing katelectrotonic responses lower it by bringing the membrane potential closer to the critical level of depolarization.

During the local response, the threshold level decreases; however, throughout the upstroke phase and the phases following the peak potential, the neuron becomes refractory to stimulation. This refractory period is divided into the absolute refractory period—which corresponds to the time it takes for the potential to rise from the critical level of depolarization to the point where one-third of repolarization is complete—and the relative refractory period, which extends from that point until the onset of the after-depolarization.

During the absolute refractory period, no stimulus, regardless of its strength, can excite the nerve; however, during the relative refractory period, a stimulus stronger than the initial one can do so. During after-depolarization, the threshold stimulus intensity decreases again, whereas during after-hyperpolarization, it increases. The dependence of the threshold level on the phases of the action potential is illustrated in Fig. 2-9.

Electrogenesis of the Action Potential

At rest, the nerve cell membrane is polarized. Its outer surface carries a positive charge, while the inner surface is negative. During the generation of an action potential, this polarity is reversed and briefly becomes inverted (Fig. 2-10). Ahead of and behind the action potential, positive recharging of the membrane extends into the region carrying the negative charges generated by the action potential. The movement of these positive charges reduces the membrane polarity immediately ahead of the action potential. This electrotonic depolarization triggers a local response, and once the critical level of depolarization is reached, excitation propagates, which in turn electrotonically depolarizes the membrane further ahead. Through this sequence of events, excitation propagates uniformly along an unmyelinated axon to its very end. Thus, the self-propagating capability of a nerve impulse is driven by local current circuits that successively depolarize the membrane up to the critical level ahead of the action potential. As it propagates, the nerve impulse does not depolarize the region behind it to the critical level because that region remains in a refractory state.

Action potentials generated at synaptic contacts and sensory endings also rely on the electrotonic depolarization of the nerve cell membrane to the critical level (see Chapters 4 and 5).

Mechanism of Saltatory Conduction

Conduction in a myelinated axon relies on similar current-spread processes. However, myelin acts as an effective insulator, meaning that current Circulation through it is negligible.

Fig. 2-9. Changes in neuronal cell membrane excitability during the propagation of a nerve impulse. As shown, excitability is inversely proportional to the threshold level (modified diagram, reproduced with permission from Morgan CT. Physiological Psychology. McGraw-Hill, 1943).

Fig. 2-10. Local current in axons / movement of positive charges around the impulse. Top: unmyelinated axon. Bottom: myelinated axon; ISF - interstitial fluid (extracellular fluid).

This is why depolarization in a myelinated axon propagates in a saltatory manner—leaping from one node of the nerve fiber (node of Ranvier) to the next. The current flowing through an active node causes electrotonic depolarization that reaches the critical level at the adjacent node located ahead of the action potential (see Fig. 2-10). This node-to-node propagation of depolarization is termed saltatory conduction. It is a rapid process, with conduction velocity in a myelinated axon being up to 50 times faster than in the fastest unmyelinated fiber.

Orthodromic and Antidromic Conduction

An axon is capable of transmitting excitation in both directions. If an action potential is initiated in the middle of an axon, impulses propagate in opposite directions driven by electrotonic depolarization on either side of the stimulation site.

In a living Organism, however, impulses normally travel in only one direction—that is, from the synaptic contact or receptors along the axon toward its terminal. This type of conduction is called orthodromic. Conduction in the opposite direction is termed antidromic. Because synapses, unlike axons, allow signal transmission in only one direction, any antidromic impulses that arise are unable to pass through the very first synapse they encounter and consequently die out.

Biphasic Nature of the Action Potential

The differences between the resting membrane potential and the action potential described earlier are based on potential recordings using two electrodes: one placed on The surface of the axon and the other inserted inside. If both recording electrodes are placed on the axon surface, the oscilloscope will register no potential difference between them at rest. When the nerve is stimulated, an impulse passes these two electrodes, producing a characteristic sequence of potential changes. As the wave of depolarization reaches the first electrode (the one closer to the stimulation site), this electrode registers a negative charge relative to the second electrode (Fig. 2-11). When the impulse is located in the region of the nerve between the two electrodes, the oscilloscope records zero potential, appearing as an isoelectric line. As the impulse reaches the second electrode, it records the second potential change, while the first electrode becomes positively charged relative to the second. Conventionally, electrodes are connected to the amplifier such that the first is negative relative to the second, resulting in an upward deflection on the recording. This is followed by an isoelectric interval, after which the curve deflects downward. This sequence is known as a biphasic action potential (see Fig. 2-11). The duration of the isoelectric interval is proportional to the nerve conduction velocity and the distance between the two recording electrodes.

Conduction in a Volume Conductor

Since Body Fluids contain a significant amount of electrolytes, nerves function within a highly conductive environment known as a volume conductor. The mono- and biphasic action potentials described above were studied in a non-conductive environment outside the organism. Potential changes recorded during extracellular studies within a volume conductor—that is, in an intact organism—are largely consistent with those described above; however, complications arise due to current spread through the volume conductor. These interferences are caused by factors related to the orientation of the electrodes relative to the direction of action potential propagation, as well as the distance between the recording electrode placed over the active tissue and the indifferent electrode. In general, when recording an action potential in a volume conductor environment, electropositive deflections are observed on both sides of the electronegative peak.

Fig. 2-11. Biphasic action potential. Both recording electrodes are placed on the surface of the neuron membrane.