PHYSIOLOGY OF NERVES

The human nervous system contains more than 100 billion Neurons which are the
basic structural units of the nervous system.

STRUCTURE OF NEURON:
It is formed of:
a. Cell body or the soma is present mainly in CNS but some are present outside
the CNS e.g., in dorsal root ganglia and autonomic ganglia.
b. Cell processes: are of 2 types:
1. Dendrites which are short, branched processes receiving impulses from
other input neurons (receptive zone).
2. Axon or Nerve fibre: is a single elongated branch which arise from an
elevated part of the soma, axon-hillock. It is surrounded by plasma
membrane which is a continuation of the cell membrane.
The terminal end of the axon becomes expanded forming the synaptic knob
which contain vesicles containing the chemical transmitters, e.g., acetyl-
choline vesicles.
There are 2 types of nerve fibres:
1- Myelinated nerve fibres: The axon is surrounded by a myelin sheath which
is formed of lipid - protein complex. Myelin acts as electric and ionic
insulator. It is interrupted at distances of 1 mm apart, at points called nodes
of Ranvier which are devoid of myelin sheath.
2- Unmyelinated nerve fibres which are not surrounded by myelin sheath.
Most of the nerve fibres are myelinated but the postganglionic autonomic
fibres and small fibres having diameter less than one micron are
unmyelinated.

PROPERTIES OF NERVES
The nerves have 2 properties:
1- Excitability: it is a property of all living structures. It is the ability to
respond to an adequate stimulus.
2- Conductivity: the main function of the nerve is to conduct or transmit the
excitation wave (= the nerve impulse) along the nerve fibre till its end.

Nature of Excitability:
Excitability is an electrical phenomenon. All nerves, muscles and cells of the body
are present in a polarized state i.e., having excess positive charges on the outer
surface and excess negative charges on the inner surface of the nerve or the muscle
fiber.
The potential difference between the outer and inner surface of the membrane is
celled Resting Membrane Potential (RMP). The value of RMP in nerve fibers
varies between -70 and -90 mV. The negative sign indicates that the inner surface
of the membrane is negative to the outer surface.

Causes of Resting Membrane Potential:

1- Selective permeability of the membrane of the nerve fibre.

2- Sodium- Potassium pump mechanism.

Selective permeability:
The membrane is much more permeable to K+ than Na+ and is not permeable to
intracellular anions (proteinate and phosphates).

Distribution of ions inside and outside the nerve fibres is as follows:

Intracellular Extracellular
fluid fluid
Na+ concentration (mmol) 14 140
K+ concentration (mmol) 140 4

Ions can move across membrane according to electric and/or concentration

gradients.
Concentration of K+ intracellularly is about 35 times its concentration extracellular,
while concentration of Na+ extracellularly is about 10 times its intracellular
concentration.

Resting membrane potential is generated as follows:

- There are Na+ - K+ leak channels in the membrane of the nerve fibre. These
channels are 100 times more permeable to K+ than Na+. Amount of K+ outflow
is greater than Na+ inflow.
- K+ will move from inside to outside according to concentration gradient. Excess
positive charges accumulate on the outer surface of the membrane.
- Proteinate anions (negative ions) are large and cannot cross the membrane to
follow the positively charged K+ (i.e., the membrane is impermeable to
proteinates).
- Proteinate anions will accumulate on the inner surface of the membrane which
will be negatively charged.
- Polarized state is generated, and an electric gradient starts to develop.
- The newly developed electric potential repels further K+ outflow. However, K+
outflow continues because its concentration gradient is still stronger than the
developing electric gradient. Outflow of K+ adds more positive charges on the
outer surface and leaves more negative charges on the inner surface. The
electric gradient increases gradually.
- When the electric gradient reaches a value sufficient to counterbalance the
concentration gradient, equilibrium in K+ movement across the membrane
occurs (i.e., K+ outflow due to concentration gradient becomes equal to K+
inflow due to electric potential).
- The membrane potential at which this equilibrium occur is called the
“equilibrium potential for K+ (EK+)”.
- The equilibrium potential for K+ (EK+) can be calculated using Nernst equation
as follows:
[K  ]in
EK   - 61  log
[ K  ]out
EK   - 61  log 35
- -

This means that if K+ outflow was the only factor causing the resting
potential, the value of resting membrane potential would be - 94 mV.
- The R.M.P. (-70 to -90 mV) is less negative than the equilibrium potential for
K+ (-94 mV) because during rest small amount of Na+ can diffuse with
difficulty inside the nerve fibre according to concentration gradient.
- Goldman Equation is used to calculate the membrane potential more accurately
because it takes in consideration K+, Na+, and Cl-.
According to Goldman equation the calculated R.M.P. is - 86 mV.

Sodium-Potassium Pump Mechanism:

The main function of Na+ - K+ pump mechanism is to keep high concentration of
Na+ outside and high concentration of K+ inside the nerve fibre. It is an active
process which needs energy derived from ATP.
During rest some Na+ diffuse inside the nerve, and with activity Na+ entry will
increase. Na+ ions are not allowed to accumulate inside but will be actively
pumped out against concentration and electric gradients.
The outward pumping of 3 Na+ is coupled with inward pumping of 2 K+ ions. This
will create more positive charges on the outer surface of the nerve fibre. This pump
will contribute to the cause of R.M.P. by - 4 mv.
Stimulation of the nerve fiber:
A stimulus is any change in the environment.
Stimuli may be chemical, electric, thermal, or mechanical stimuli. When we study
the function of the nerve fiber in the laboratory, we usually use electric stimuli to
stimulate the nerve.

Factors affecting effectiveness of a stimulus:

1- Intensity or strength of the stimulus: stimuli may be:
a. Threshold stimulus: which is the minimal strength of current needed to
excite the nerve and produce a nerve impulse.
b. Sub-threshold stimuli which cannot produce a nerve impulse but produce
local changes in the nerve which cannot be propagated and are called local
excitatory state (see later).
c. Supra- threshold stimuli produce the same effect as the threshold stimuli (a
nerve impulse).
2- Duration of application of a stimulus: each stimulus needs a certain time of
application to be effective.
3- Rate of application of the stimulus: If the stimulus is applied rapidly, it will be
more effective than if its intensity is slowly increased.
There is relation between the strength and duration of stimuli, as shown in
Strength- Duration Curve:
It is noticed that the more is the strength of the current, the shorter will be the
required duration of application of the stimulus, within limits.
From the curve we can notice the following measurements:
1- “t” time: is the minimal time needed to excite the nerve, below which whatever
strong the stimulus is, there is no response. This is used in diathermy in which we
use strong current of very short duration below “t” time. So, it produces heat but do
not excite the tissues.
2 - Rheobase: is the minimal strength of current needed to excite the tissues, below
which whatever long the duration there is no response. The time needed for
rheobase to excite is called "Utilization time". Rheobase is called also threshold
stimulus.
3 - Chronaxie: It is a time factor. It is the minimal time needed by double rheobase
strength of current to excite the tissue. It is a measure of excitability i.e. If the
chronaxie is long, excitability is low and if it is short excitability is high.
ACTION POTENTIAL (AP)
It is the changes of electric potential between the outer and inner surfaces of
membrane at one point of the nerve fibre. These changes result from application of
single adequate stimulus to the nerve fibre.

How do we record action potential?

Action potential can be recorded by placing one microelectrode on the outer
surface of the nerve fibre and insert the other microelectrode inside the nerve fibre
and connecting the two microelectrodes to a suitable recorder (e.g., cathode ray
oscilloscope or a digital recorder). Under resting condition, the recorder shows the
resting membrane potential.

Phases of action potential:

Application of threshold stimulus results in AP which shows the following phases:
1- Slow gradual depolarization:
Membrane potential decreases below - 70-90 mv. This is due to slight
increase of the permeability of the membrane to Na+.
2- Firing level: when the membrane potential reach - 55 to -65 mV (i.e., 15 to
25 mV depolarization) the firing level is reached. At the firing level, the rate
of depolarization increases.
3- Rapid depolarization: membrane potential changes rapidly from the firing
level to reach zero potential (iso-potential).
4- Reversal of polarity (overshoot): the inner surface of the membrane
becomes positive, and the outer surface negative. Membrane potential
reaches +35 mV.
5- Rapid repolarization: membrane potential return rapidly towards the
resting value.
 6- After-depolarization: when repolarization is 70% completed, the rate of
repolarization slows down, and the resting membrane potential is reached
slowly.
7- After-hyperpolarization: the membrane will become hyperpolarized i.e.,
the membrane potential will be more negative than-70 or -90 mV before it
gradually reaches the resting level.
So, action potential is simply formed of ascending limb (depolarization and
reversal of polarity) followed by descending limb (repolarization). Ascending and
descending limbs are sometimes called “spike potential”. The duration of AP is
very short: Duration of spike is 1-2 msec and the duration of the whole AP is
normally less than 10 msec. The magnitude of the action potential will be + 35- (-
70) = 105 mV, or +35-(-90) = 125 mV.

Ionic basis of action potential:

The changes of membrane potential that occur during action potential are caused
by movement of Na+ and K+ across the membrane through voltage-gated Na+
channels and voltage-gated K+ channels.
Na+ voltage-gated channels:
These channels have two gates:
- Outer (activation) gate.
- Inner (inactivation) gate.
voltage-gated K+ channels:
These channels have only one gate.
These voltage-gated channels are closed during rest but they orderly open and
close during AP as follows:
 At resting membrane potential: the outer (activation) gate of Na+ voltage-
gated channels are closed, and the inner (inactivation) gate is open. The
channel is therefore closed. Voltage-gated K+ channels are closed.
 During slow depolarization, increasing number of Na+ voltage-gated
channels open by opening of outer (activation) gates. The open channels
allow Na+ inflow that causes more depolarization which opens more Na+
channels. Positive feedback occurs that leads to progressive depolarization
till the firing level is reached.
 At the firing level, all voltage-gated Na+ channels become open.
 During rapid depolarization, massive inflow of Na+ occurs through the open
voltage-gated Na+ channels. This continues till depolarization is complete
(iso-potential). Na+ inflow is caused by both concentration and electric
gradients
 Reversal of polarity is caused by Na+ inflow through voltage-gated channels
which remain open during this phase. Na+ inflow during this phase is caused
by concentration gradient alone. At +35 mV, reversal of polarity ends due to
closure of inner (inactivation) gates of Na+ voltage-gated channels. These
gates remain closed until complete membrane repolarization occurs.
 During repolarization K+ voltage-gated are open allowing K+ outflow that
causes repolarization. These channels are slow to open and slow to close
compared to Na+ voltage-gated channels.
 Afterhyperpolarization is due to continuing K+ outflow through K+ voltage-
gated channels which remain open during this phase. K+ voltage-gated
channels close slowly at the end of this phase. When K+ voltage-gated
channels close, the membrane potential come back to the resting value and
remains stable at -90 mV.

All or None law:

When all the conditions affecting the nerve are not changed, the threshold stimulus
will produce a maximum action potential. In other words, the nerve fibre will
respond maximally to a threshold stimulus. Sub-threshold stimuli will not produce
AP at all. Increasing the intensity of the stimulus more than the threshold will not
produce change in the shape or magnitude of the action potential.

Excitability changes during the action potential:

During the action potential, excitability of the nerve changes as follows:

1- Absolute Refractory Period (ARP):
During this period the excitability of the nerve is lost. No stimulus, however
strong it is, can stimulate the nerve. ARP coincides with the rapid ascending
limb of the spike and the first third of the descending limb. The reason for ARP
is that the Na+ channels are inactivated by closure of their inner inactivation
gates which are irresponsive to stimuli. Any stimulus applied to these channels
at this point will not open the inactivation gates.
2- Relative Refractory Period (R.R.P.):
It is the period during which we need a stronger stimulus to produce a response
i.e., the excitability returns gradually but is still below normal. It coincides with
the rest of the rapid descending limb of the spike. During this RRP some Na+
channels have been recovered from their inactivation state and others are not
recovered.
3- Supernormal phase of excitability:
It is the period during which, a sub-threshold stimulus can produce a response
i.e., excitability is above normal. It coincides with the period of after
depolarization or negative after potential. During after depolarization the
membrane potential is nearer to its firing level and many Na+ voltage-gated
channels have recovered and returned to the resting responsive state. So, nerve
fiber will be more excitable.
4- Subnormal phase of excitability:
It is the period during which the excitability is below normal, and it coincides
with the after hyperpolarization. Supra-threshold stimulus is needed to produce
a response. The membrane potential is far away from its firing level, so it will
be less excitable. Excitability will return to normal by the end of
afterhyperpolarization.

Conduction of action potential:

When a nerve is stimulated with an adequate stimulus, an action potential or "nerve
impulse" will be produced and will be propagated over the surface of the nerve till
its end. Conduction is a self-propagating process that occurs as follows.

1. Conduction in unmyelinated nerve fibre:

If we stimulate unmyelinated nerve fibre by a threshold stimulus an action
potential is generated during which reversal of polarity occurs, i.e., the outside will
become negative in relation to the inside which will be positive. This area of
negativity on the outer surface of the membrane is known as area of "Current Sink"
because positive charges present on the adjacent area of the membrane will flow
into the “current sink”. The flow of positive charges will decrease the membrane
potential in the adjacent area (electrotonic depolarization) till it reaches the firing
level. All Na+ voltage-gated channels in the adjacent area will open and an action
potential is produced. By a similar process, action potential in the adjacent area
will be conducted to the next adjacent area leading to generation of action
potential. This process is repeated leading to propagation of action potential along
the nerve fiber till its end.

2. Conduction in myelinated nerve fibre:

The myelin sheath acts as electric and ionic insulator i.e., current cannot pass
through it. It is interrupted at Nodes of Ranvier which are devoid of myelin sheath.
Thus, the stimulus applied will activate the near node of Ranvier in which there
will be reversal of polarity and will act as the area of “current sink”. The positive
charges will jump from the adjacent resting node of Ranvier to the activated node
producing electrotonic depolarization and when reaching the firing level an action
potential is produced and so on. This means that the impulses will jump from one
node of Ranvier to the other till the end of the nerve fibre. This is called Jumping
or Saltatory conduction. It is a rapid process and conduction in myelinated nerve
fibre will be 50 times or more faster than unmyelinated nerve fibre. Saltatory
conduction also, saves energy for the axon, because Na+-K+ pump will occur only
at the nodes of Ranvier. This requires less extra metabolism for the axon.

Normally, action potentials inside our bodies pass in either one of two directions
depending on the type of nerve fiber whether sensory or motor:
- In the sensory nerve: action potential pass from the receptors (present e.g. in
skin) to CNS.
- In the motor nerve: action potential passes from CNS to the organs.
Conduction in these normal directions is called Orthodromic conduction. If the
nerve fibres transmit impulses in opposite direction, this is called antidromic
conduction.

Types of nerve fibers:

Nerve fibres in our body, are classified according to diameter and conduction
velocity into 3 main types:
1- Type “A”, which is further divided into A, A, A, and A.
2- Type “B” fibers.
3- Type “C” fibers.
The following table summarizes the main characteristics of the three fiber types.

Fiber type Diameter Conduction velocity Spike duration

(m) (m/sec) (msec)
A 3-20 15-120 0.5-1
 B 1-3 3-15 1-1.5
C 0.5 0.5-2 2
The bigger the diameter of the nerve fibre, the more will be the velocity of
conduction, the shorter will be the duration of the spike, and the higher will be the
excitability.

Compound action potential of nerve trunk:

If we stimulate a nerve trunk by increasing intensity of current and record the
action potentials at a distance from the stimulator, we will obtain a compound
action potential having different peaks. This is because each nerve trunk contains
many nerve fibres having different diameters, thresholds, and rates of conduction.

Effects of minimal and Subminimal Stimuli:

A- Threshold or minimal stimuli applied to the nerve will produce an action
potential, which can be transmitted as a nerve impulse all over the nerve fibre.
Nerve impulse produced has the following properties:
1- obeys all on non- rule,
2- can be conducted over the nerve.
3- is followed by an absolute refractory period.
4- cannot be summated.

Effect of subthreshold stimuli:

Subthreshold stimuli can produce either “local electrotonic potential changes” or
“local response” depending on the intensity of the stimulus.

Electrotonic potential changes:

1- Catelectrotonus:
It is a state of partial depolarization that does not exceed 7 mV, produced at the
region of the cathode of the electric stimulator.
It is due to passive additions of negative charges from the cathode which
neutralize positive charges present on the outer surface of the membrane. The
excitability at the region of the cathode will be increased because membrane
potential becomes nearer to the firing level.
2- Anelectrotonus:
It is a state of hyperpolarization at the region of the anode due to addition of
positive charges from the anode to the outer surface of the membrane increasing
the membrane potential above the resting value. The excitability of the nerve at
the region of the anode will be decreased.

Local Response (Local excitatory state LES):

 When the subthreshold stimulus is strong enough to cause depolarization that
exceeds 7 mV, slight active changes occur. Some Na+ voltage-gated channels
will open, Na+ inflow will produce further depolarization. However, the
magnitude of depolarization does not reach the firing level. An action potential
cannot be produced.
Properties of local response (LES):
1- It is localized to the point of stimulation i.e., it cannot propagate.
2- It does not obey all or none rule.
3- It can be graded according to the strength of the stimulus.
4- It is not followed by absolute refractory period.
5- During local response excitability is increased.
6- Local responses can be summated together. This means that if the sub-
threshold stimulus is repeated within very short time, local response may
reach the firing level, and an action potential is produced.

In contrast, action potential has the following different properties:

1- obeys all on none rule.
2- can be conducted over the nerve (i.e., can propagate).
3- is followed by an absolute refractory period.
4- cannot be summated.

Factors affecting excitability of the nerve:

1- Increased permeability of the membrane to Na+ (e.g., by drug veratridine and
low Ca++ in extra cellular fluid) increases excitability of the nerve.
2- Decreased permeability of the membrane to Na+ (e.g., by high Ca++
concentration, tetrodotoxin, and local anesthesia as cocaine) decreases
excitability of the nerve. These are called “Membrane Stabilizers”.
3- Hyponatremia (decrease extracellular Na+) decreases the size of the action
potential but does not significantly affect excitability.
4- Hypokalemia (low extracellular K+) increases the concentration gradient for K+
leading to greater outflow of K+. This leads to membrane hyperpolarization and
decreased excitability.
5- Hyperkalemia (high extracellular K+) decreases the concentration gradient for
K+ leading to some degree of membrane depolarization. We have two
possibilities:
a. If the degree of hyperkalemia is small, the degree of depolarization will be
small. Membrane potential will be closer to the firing level and excitability
is increased.
 b. If the degree of hyperkalemia great causing the membrane potential to
depolarize from -90 mV to -60 mV, Na+ voltage-gated channels become
inactivated, and excitability will decrease.
Familial periodic paralysis:
It is a rare hereditary disease characterized by severe weakness of skeletal muscles,
with attacks of paralysis at intervals. It is more common in females than males.
Cause: It is due to deficiency or decrease of extracellular K+ concentration. This
causes hyperpolarization as explained before. The excitability of nerves and
muscles will be decreased and will become less responsive to stimuli. This will
result in severe weakness or even paralysis of skeletal muscles.
Treatment: by intravenous administration of potassium to increase extracellular K+
concentration, so that the membrane potential return to the normal resting value
and the excitability of nerves and muscles returns to normal level.

How can you block a nerve impulse?

This can be done by:
1- severe mechanical pressure.
2- severe cold.
3- strong anelectrotonus.
4- alcohol.
5- local anesthetics as cocaine.
6- severe O2 lack and prolonged ischemia (decrease blood supply).

Accommodation of the membrane of the nerve fibre:

If we apply a subthreshold stimulus to the nerve and its intensity is gradually
increased (over many milliseconds instead of fraction of millisecond), the nerve
will not respond i.e., an action potential will not be produced. The nerve is said to
accommodate itself to the passage of the current. During accommodation, there
will be enough time for the inactivating gates of Na+ channels to close at the same
time that the activating gates are opened. The inward flow of Na+ will not be
enough to produce action potential. Also, slow and prolonged opening of K+
channels will balance the gradual opening of Na+ channels.