Action-potential Propagation In the previous discussion of the ionic basis of the action potential, we were referring to the changes

in Vm occurring at a given region of a neurons axon. In reality, action potentials propagate along the axon at speeds (conduction velocities) ranging between 0.1 and 120 m/sec. How is this accomplished? The figure below shows membrane potentials along a length of axon. Positive and negative potentials are denoted by plus and minus signs (+ and -) inside the axon. Assume that the peak of an action potential is occurring at position x = 0.

At regions nearby the action potential, Vm is positive, but in neighboring regions away from the action potential, Vm is at the resting potential. These differences in potential cause electrotonic currents to flow, which are illustrated by the arrows in the figure. The currents flow axially along the inside of the axon conducted by ions in the intracellular cytosol. They ultimately cross the membrane and flow in the opposite direction in the extracellular solution. When the currents cross the membrane, they depolarize the membrane by an amount equal to the product of the current and the membranes resistance, rm; the membrane resistance is simply equal to the reciprocal of the total membrane conductance (i.e., rm = 1/gT). Given the membrane potential displacement DVm (= Vm - Vrest), one can compute the potential at any distance along the axon using the following equation:
DVm ( x ) = DVm (0) e -|x|/ l ,

where DVm(0) is the membrane potential at x = 0 and l is the termed the length constant. The constant e is simply a positive number (2.71828); it is raised to a power that becomes more negative as x increases in either direction (note the absolute value). Thus, DVm becomes exponentially smaller as x gets larger. Note that l has units of distance (e.g., mm), and for each l mm traveled, DVm decreases by 63%, as shown in the following graph:

40 20 0

Vm (mV)

-20 -40 -60 -80 -4 -3

l (potential by 63%)

Threshold

-2 -1 0 1 2 Distance along axon (mm)

The figure shows Vm plotted as a function of distance from the peak of the action potential (membrane potential is +30 mV). The length constant is 1 mm, and as shown by the cross-hair on the curve, Vm decreases by 63% when one moves away a distance of one length constant. At a distance of four length constants (4 mm), Vm decreases to a potential near the resting potential (-70 mV). The horizontal line shows a typical threshold potential of -50 mV. Recall that when the membrane is depolarized to the threshold potential, inward Na+ current just exceeds outward K+ current, and this triggers activation of the Na+ channels. Action potentials are elicited at all regions of membrane that are depolarized at or above thresholdin the example above, at regions of the axon up to 1.6 mm from the action-potential peak. Thus, the action potential effectively moves down the axon. Similar electrotonic currents flow in this new region of the axon and the process continues, conducting the nerve impulse along the entire length of the axon. Can action potentials conduct in two directions? If one stimulates (with an electrode) a motor neurons axon at a distance halfway between the soma and the nerve terminal (the end of the neuron that makes contact with a muscle) then action potentials will conduct in both directionstoward the muscle as well as toward the neurons soma. However, physiologically this rarely happens. The action potential normally starts in the axon hillock region where the axon begins. As it conducts down the length of axon, retrograde conduction (conduction in the reverse direction, toward the soma) is prevented since the region of membrane just traversed by the action potential is in the refractory-period phase of the action potential. Recall that during the refractory periods, the threshold potential is elevated. The electrotonic currents flowing in the retrograde direction are incapable of overcoming the higher threshold.

Note that orthodromic conduction is the term that refers to the usual uni-direction conduction along an axon. Conduction in an abnormal direction (e.g., from the muscle to the neurons soma) is called antidromic conduction. Antidromic conduction can only be elicited by stimulating the axon using an external electrode. What determines conduction velocity? The conduction velocities in axons are determined by the length constant, l. An axon with a long length constant will conduct faster, since the voltage decrement from the site of an action potential is more gradual, allowing membrane a significant distance away to attain threshold. This is illustrated in the following graph:

40 20 0

Vm (mV)

-20 -40 -60 -80 -4 -3

l = 1 mm

l = 2 mm

-2 -1 0 1 2 Distance along axon (mm)

Notice that in an axon with a 2-mm length constant (broken curve), membrane 3.2 mm away from the peak of the action potential is depolarized to threshold. In the axon with a 1-mm length constant (solid curve), only membrane up to 1.6 mm away from the action potential attains threshold. The length constant is determined by the following equation:

l=

rm , ri

where rm is the membrane resistance and ri is the intracellular (axial) resistance; both resistances are normalized to a unit length of axon. Compared to small-diameter axons, large-diameter axons have lower resistances: there is more membrane area (hence rm is lower), and there is a larger intracellular volume for current flow (hence ri is lower). Yet, large diameter axons have longer length constants than small diameter axons. Why is this the case?
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The reason is that rm varies inversely with axon diameter, but ri varies inversely with the square of axon diameter. Stated mathematically,
rm 1 1 and ri 2 , d d

where d is the axon diameter and denotes proportionality. Since with increasing diameter the relative decrease in rm is less than the relative decrease in ri, rm / ri becomes larger, and thus l ( = rm / ri ) becomes larger as well. So to reiterate large-diameter axons conduct faster than small-diameter axons because larg-diameter axons have longer length constants than small-diameter axons. Recall the studies performed using the squid giant axonone of the largest diameter (1 mm) axon found in nature (it was originally thought to be a vessel). Why is the squid giant axon so large? Recall also the function of that axon: to cause contraction of the squids mantle thereby rapidly propelling the animal out of harms way. It is in a squids best interest to have the conduction velocity of that axon as fast as possible, such that the emergency escape reflex is as rapid as possible. A major evolutionary advantage for vertebrates: myelin Invertebrates can only achieve high conduction velocities solely by increasing (through evolution) the diameter of their axons, but this comes with a price: having large-diameter axons limits the number of high-speed axons in a given anatomical space. A major evolutionary advantage occurred with the emergence of vertebrates, which permitted the packaging of literally millions of high-speed axons in a small cross-sectional area (like that of the human spinal cord). The strategy adopted by vertebrates was to increase l by effectively increasing rm, and this is done by glial cells that surround axons. The glial cells wrap several layers of an insulating material called myelin tightly around the axon (this is perfectly analogous to wrapping several layers of electrical tape around a bare copper wire). The following diagram shows a cross section of a so-called myelinated axon:

The concentric layers of myelin effectively increase rm and prevent electrotonic current from flowing across the membrane. Thus, the current must flow axially down the length of the
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axon until it finds a gap between successive glial cells. These gaps along the axon are located at nodes of Ranvier, where the bare (unmyelinated) axon membrane is exposed to extracellular fluid. This is shown in the following diagram:

The Na+ channels are located solely at the nodes of Ranvier. When an action potential occurs at a given node, the intracellular flow of electrotonic current depolarizes the membrane at the next node, which then attains threshold and generates another action potential. Thus, nerve conduction involves the generation of action potentials that jump from node to node. This discontinuous type of nerve conduction is termed saltatory conduction. Although the large increase in l brought about by myelination results in a tremendous increase in conduction velocity, still further speed ups are achieved by increasing axon diameter (thereby reducing ri). Thus, the fastest axons in the body are large-diameter myelinated axonsnotably, motor neurons that innervate skeletal muscles which are termed a motor neurons.

Multiple Sclerosis (MS) MS is caused by scattered, discrete areas of demyelination in different regions of the nervous system. It is notable that the disease appears not to affect the neurons themselves, other than disrupting conduction of their axons. Individuals suffering from MS typically experience recurrent attacks that come and go seemingly randomly over many years; a typical attack lasts several weeks. Symptoms vary depending on the specific locations of the demyelination. They include impaired vision, loss of tactile sensations, weakness or paralysis of the limbs, loss of coordination, tremors, and other varied symptoms. The cause of MS is unknown, although some evidence indicates that it may be an autoimmune disorder whereby something goes awry with the immune system, which then attacks the glial cells. There is no effective treatment of MS, although a number of drugs are useful in ameliorating the acute symptoms.

The graph on the following page shows typical conduction velocity as a function of neuron diameter in both myelinated and unmyelinated axons.

Notice that for unmyelinated axons, conduction velocity increases as the square-root of the diameter (i.e., a two-fold increase in diameter produces only about a 2 = 1.4 -fold increase in velocity). The conduction velocity of myelinated axons increases almost linearly with diameter. But notice something interesting, as seen in the inset of the figure. At very small axon diameters, unmyelinated axons actually conduct faster than myelinated axons. This is exploited by the body: small neurons with axon diameters less than 2 mm are unmyelinated, whereas larger neurons are invariably always found to be myelinated.

100
8 m/sec 6 4 2 0 0.0 0.4 0.8 1.2

80

Conduction Velocity (m/sec)

mm

60 Myelinated 40 Unmyelinated 20

0 0 2 4 6 8 Neuron Diameter (mm) 10 12

Homework: Using the data in the above graph, estimate the conduction velocity of an unmyelinated squid giant axon. Assume that the diameter of the giant axon is 1 mm (1000 mm). (Answer: about 90 m/sec.) Roughly how many mammalian axons of similar speed could be placed within a 1 mm2 cross-sectional area (the area occupied by one squid giant axon)? (Answer: about 400.)
White matter versus gray matter

Myelin is a fatty substance (like pig fat) and is white in appearance. Neurons composed of myelinated axons therefore appear white. Neurons lacking myelin appear gray. This has lead to the common differentiation of nervous tissue as being either white matter or gray matter. When you see white matter, think of large myelinated high-speed axons that are carrying information (nerve impulses) long distances. When you see gray matter, think of smalldiameter short neurons that are involved in processing the information.

Measuring neuron conduction velocities

In the laboratory, the conduction velocity of a neurons axon can be measured quite simply by using two microelectrodes inserted into the axon at a known distance apart. This, however, is not feasible in the clinical setting. Neurologists measure the conduction velocity of, say, the ulnar nerve of the arm, by measuring the so-called compound action potential.

The compound action potential differs from a neurons action potential in two ways. First, it is an extracellular potential that does not reflect the axons true membrane potential. And second, the compound action potential reflects the electrical response of the entire nerve. As such, it reflects the average response of all the neurons comprising the nerve.

mV

time

The figure (above) shows how a compound action potential is recorded. The gray tube depicts a nerve comprising a number of different axons (small ovals). A differential voltmeter is attached to two electrodes placed on the skin (black rectangles). The voltmeter measures the difference in the voltage between the two electrodes; if the left electrode is at a potential negative to that of the right electrode, then a negative deflection will appear on the meter (and vice versa). Now, assume action potentials were elicited in the nerve axons at time t = 0 msec by stimulating the nerve with an electric shock at the point indicated by the black arrow; also assume that this triggers a recording device (typically an oscilloscope or a personal computer) that starts to plot the meters voltage as a function of time (graph). As the action potentials propagate down the nerve axons (white arrow), the extracellular voltage starts off positive at rest (+s on the right of the figure), briefly becomes negative where the action potentials are occurring (-s in the center of the figure), and returns to positive values after the nerve axons repolarize (+s on the left of the figure). This is due to the electrotonic currents that flow across the axons and through the extracellular solution as the action potential conducts. But, prior to the arrival of action potentials at the recording (skin) electrodes, the voltmeter will record no voltage change, since the two electrodes are over regions measuring the same potential (recall, the voltmeter measures the difference in the voltage between the two electrodes). This is depicted as no potential change in the recording (horizontal black line at 0 mV).

mV

time

As the action potentials propagate under the recording electrodes (above), one starts to observe a voltage difference. Namely, the left electrode is over the region of depolarized axons while the right electrode is over a region of resting axons. This produces the negative deflection shown in the graph. Notice, however, the size of the deflectionit is only a few microvolts (mV) in amplitude, not the tens-of-millivolts typical of an action potential! The voltage simply
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reflects the small extracellular currents flowing through the low resistance extracellular fluid (i.e., by Ohms Law, DV = ire ).

mV

time

As the action potentials continue to propagate, the voltages under the electrodes briefly reverse polarity (see above), where the right electrode measures the voltage of the depolarized axons, while the left electrode measures the voltage adjacent to repolarized axons.

mV

time

Finally, after the action potentials have conducted past the recording electrodes, the measured voltage returns to zero, reflecting the fact that the entire nerve has repolarized (or returned to resting), thereby producing the characteristic biphasic tracing seen in the graph. The conduction velocity of the compound action potential is computed by simply dividing the distance between the stimulation electrode (black arrow in first figure, above) by the time of the first deflection seen in the tracing. The figure on the right shows the actual setup for measuring nerve conduction in the hand, in this case, to aid in the diagnosis of carpal tunnel syndrome (a syndrome resulting in poor nerve conduction in the wrist). The recording electrodes are taped on the skin at the base of the thumb. The two-pointed device placed over the wrist is the stimulating electrodea device (similar to a Taser) that delivers a highvoltage, but brief, shock, thereby eliciting action potentials in the underlying nerves. When the clinician triggers the shock (switch on stimulating electrode), this triggers the collection (by a personal computer) of the voltages measured by the recording electrodes as a function of time.

The figure on the next page shows an actual recording displayed on the computers monitor. In this example, the recording was done from recording electrodes placed over the ulnar nerve at the wrist, with the stimulating electrode positioned at the upper forearm. Disregard the voltage scale, which shows units of volts! It reflects the gain of an amplifier (typically >1000) needed to amplify the tiny extracellular voltage to levels suitable for the computer. The initial brief voltage deflection (seen at 0 msec) is the so-called stimulus artifacta signal produced by the stimulus electrode and conducted to the recording electrodes by the resistive properties of the skin. The stimulus artifact does not reflect nerve conduction (albeit, it does provide a useful index of when the stimulus was applied). The dark region of the tracing indicates the time period (4.6 msec) for the arrival of action potentials at the recording electrode. In this example, the distance between the stimulus and recording electrodes was 30 cm, resulting in a ulnar nerve conduction velocity of 0.3 m/0.0046 sec = 65 m/sec (a typical value). But, notice something odd in the recording. The first deflection in voltage occurs at 4.6 msec, yet the compound action potential is >15 msec in duration. Arent action potentials rapid events, with duration of 1-2 msec? The resolution of this apparent paradox is obvious when one remembers the fact that compound action potentials reflect the response in an entire nerve as opposed to a single neuron. The nerve contains the axons of thousands of different neurons, with differing conduction velocities. All these axons are being stimulated simultaneously, with the fastest conducting action potentials arriving at the recording electrodes at 4.6 msec, but others taking substantially longer. This results in the somewhat complicated (bumpy) waveform seen in the figure, with a duration far longer than that of a single action potential. What is the clinical utility of measuring a compound action potential? The progression of (or recovery from) demyelinating diseases like multiple sclerosis and ALS (amyotrophic lateral sclerosis, or Lou Gehrigs disease) can be monitored by monitoring nerve conduction velocity, since demyelination causes a reduction in conduction velocity. Also, the anatomical site of a nerve injury can often be precisely located by measuring a compound action potential. This is done by positioning the recording electrodes at, say, the site of a denervated (paralyzed) muscle, then positioning the stimulating electrode at different distances along the nerve looking for the point at which it is capable of eliciting a compound action potentiali.e., at distances along the nerve just distal to the injury. And, the total amplitude of the compound action potential is useful in assessing reinnervation of peripheral nerves following a nerve injury. Since the amplitude is proportional to the number of conducting axons within the nerve, the neurologist can follow the gradual reinnervation process as more and more of the nerves axons start to conduct.