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My aim is to clarify how the propagation and conduction velocity of action potentials vary between myelinated and non myelinated axons and how it also may be affected by the diameter of axons. After looking at the normal physiology, I will look at the problems regarding action potential conduction in multiple sclerosis
Neurones communicate with each other by producing electrical signals in the form of action potentials, illustrated in fig-1. Action potentials occur when there is enough depolarisation to reach threshold via the influx of sodium into the axon through voltage gated sodium channels (VGSC). At the peak of the action potential VGSC become inactivated, where no further sodium enters the axon. However, voltage gated potassium channels (VGPC) open causing repolarisation via the efflux of potassium out of the axon, bringing the action potential back towards resting membrane potential. Hyperpolarisation follows where action potential travels below the resting membrane due to the slow closing of potassium channels. Via the Na+K+ATPase transporter, the undershoot eventually returns to the resting membrane potential and is maintained until the next action potential. Action potential follows an all or nothing principle in which a stimulus of any strength must reach the threshold to provide a complete response. If it fails to reach threshold there is no response and so an action potential does not occur.
Figure-1: Typical Action potential (, Action_Potential.JPG (JPEG Image, 402x300 pixels) )
Action potentials in unmyelinated axons can be explained by the local current theory.
Before a stimulus is projected, the axon maintains a resting membrane potential where inside the axon has a more negative charge compared to a more positive charged axon on the outside. This difference of electrical charge across the membrane is known as the resting membrane potential. Due to the high permeability of potassium inside the cell, the resting membrane potential tends to be close to the equilibrium potential of potassium. For this to be possible, sodium and potassium gradients are maintained across the membrane via Na+K+ATPase pumps.
Voltages gated channels in the membrane open and close depending on the voltage changes across the membrane. When no nerve impulses are being transmitted these voltage gated channels are closed. When stimuli occur, action potentials travel in a continuous manner because of the relatively even distribution VGSC along the entire length of the axon.
A stimulus depolarises the axon locally allowing VGSC to open causing influx of sodium ions into the cell. The axon at that region now becomes positive on the inside with respect to the outside. As action potentials are generated, local currents tend to depolarize the membrane immediately adjacent to the action potential. See Figure-2. How far along these local currents spread determines the conduction velocity. When depolarization caused by local currents reaches threshold level, a new action potential is produced adjacent to the original one. The recently depolarised area of the membrane has now repolarised due to the inactivation of VGSC and opening of VGPC. The efflux of potassium ions outside the cell restores the negative charge inside the axon.
Figure-2: Local Current Theory Diagram (, non-myelinated-axon-local-circuit.jpeg (JPEG Image, 402x176 pixels) )
Note that the action potential will only occur in one direction because the area that has just fired an action potential is absolute refractory period so cannot generate another action potential until the VGSC have recovered. These sequences of events carry on continuously throughout the axon.
Action potentials in myelinated axons
The role of myelin is important regarding myelinated axons as propagation of action potentials and conduction velocity tends to faster in contrast to unmyelinated axons. (siegel 2010) The myelinated nerve has been designed by evolutionary factors to provide the body with a fast and efficient transfer of information between the central and peripheral nervous systems. (Hildebrand, Mohseni 2005)
Axons are wrapped concentrically of up to 300 layers thick around the circumference of the axon to form a myelin sheath. Two glial cells are involved in the production of myelin sheath; oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Myelination by oligodendroctyes takes less space than myelination by Schwann cells as space limited in the CNS. One oligodendrocyte is able to myelinate approximately 30 to 50 axons. It has been suggested that oligodendroctyes in the CNS developed from selection pressure to economise space and maintain conduction velocity. (Waxman 2002)
The length of the nerve wrapped by myelin sheath with a glial cell is around 1mm in length and is referred to as an internode. The spaces between the internodes are termed the nodes of Ranvier. The nodes are unmyelinated and are approximately 2µm in length. Myelin acts as a good insulator of the axon giving internodal regions increased resistance and decreased capacitance (the ability to store charge), inhibiting the leakage of current. It allows local circuit currents to extend to the adjacent node illustrated in fig-3.
Figure-3: Myelinated Axon (, myelinated-axon-local-circuits.jpeg (JPEG Image, 386x226 pixels) )
The distribution of VGSC in a myelinated axon is concentrated at the nodes of Ranvier approximately 10000 per node; therefore action potentials are exclusively generated in these regions. With a stimulus, action potential conduction occurs in a salutatory manner (jumping from node to node). Depolarisation of node of Ranvier to threshold allowing for action potential to occur in this region will allow for depolarisation at the adjacent node and so on. These sequences of events allow for increased conduction velocity. The concept of salutatory conduction was first defined more that 50 yeas ago by Tasaki in 1942 and Stampfli in 1949. By various experiments it was established that that there were a high density of VGSC in the nodes of Ranvier. (Shrager, Simon et al. 2005)
VGPC are located at the juxtaparanode allowing for repolarisation to occur in the region that has previously fired and action potential. However in some myelinated axons, repolarisation may not necessarily involve VGPC because the resting potassium permeability is sufficient enough to restore the resting membrane potential of the axon.
As well as increasing the conduction velocity and reducing current leakage, the myelin sheath reduces the length and surface area in which depolarisation occurs. This helps to conserve energy expenditure as excitation is restricted to nodal regions and reduces amount of ions needed to maintain electrochemical gradient. This all helps to increase action potential conduction (assuming that the time constants for activation of VGSC are equal along axons). (Giuliodori 2004) The conduction velocity is given by the comparison between the diameter of the axon (d) with the diameter of the axon covered in myelin (D), i.e. d/D. The optimum conduction velocity occurs when d/D is 0.7. This is illustrated in fig-4.
Figure 4 (Leicester Medical School 2010)
The conduction velocity between myelinated and unmyelinated axons also depends on the diameter of the axon. Large diameter axons such as motor neurones tend to be myelinated and small diameter axons i.e. sensory fibres such as c-fibres tend not to be. The faster conduction velocity of myelinated axons is only valid is the diameter of the axon is more than 1µm. Unmyelinated axons of diameter less than 1µm have a faster conduction velocity compared to myelinated axon of the same diameter. Local current spread in unmyelinated axons depends on membrane capacitance (ability to store charge) and resistance. The membrane resistance depends on the number of ion channels open so higher the resistance the more ions channels are closed.
The problems with capacitance and resistance effect unmyelinated axons when axon diameter is more than 1µm. With increase diameter the capacitance increases with time so it becomes harder along the axon to depolarise neighbouring regions to threshold and resistance increases along the length of the axons. These factors lead decreased conduction velocity. For ideal spread of local currents along the axon, capacitance should be low and resistance should be high which is achieved by unmyelinated axons with diameter less than 1µm. Because conduction velocity in myelinated axons is proportional to the diameter while conduction velocity in unmyelinated axons is proportional to the square root of the diameter, saltatory conduction can significantly increase the speed of an action potential and conserve space allowing for smaller diameter unmyelinated axons with rapid conduction illustrated in fig-5. (Raine, Mcfarland et al. 2008)
Figure-5: Comparison between conduction velocity and fibre diameter in myelinated and unmyelinated axons (Leicester Medical School 2010)
Temperature also has a profound effect on action potential conduction. With increased temperature, the rate at which ion channels are activated increases. This causes a decrease in action potential conduction.
Overview of Multiple Sclerosis
Multiple Sclerosis is a debilitating neurological disease of demyelination that is thought to be caused by an autoimmune attack of the myelin sheath that affects nerves of the central nervous system. Symptoms include muscle weakness, loss of sensation, visual disturbances, fatigue, dizziness and many more. Antibodies attack of myelin causes them to swell and then detach from the axon. A scar or plaque develops on the nerve fibres which can delay or block nerve impulses. Often these plaques are located within the optic nerves, spinal cord and in the sub-cortical white matter of the cerebral hemispheres. (Perkin, Wolinsky 2000) The presence of lesions differ significantly from patient to patient therefore producing varied clinical manifestations of disease.
Problems with action potential conduction in multiple sclerosis
During attacks of MS, active demyelination is associated with conduction block and conduction slowing, leading to failure of impulse transmission across the demyelinated areas, causing the associated symptoms. When an action potential is generated, the current in demyelinated areas dissipate longitudinally resulting in resistive and capacitive shunting. The current density at the adjacent node will be reduced therefore action potentials fail to reach threshold level.(Waxman, Brill 1978) Sodium channels are redistributed and even new sodium channels are inserted in the internodal regions which may restore some excitability of the demyelinated region however conduction velocity is still significantly slowed.
It is a possibility to partially restore action potential conduction via remyelination, which may re-establish near normal myelin architecture. This usually occurs in the early stages of MS. However as the myelin sheath cannot be completely restored, subsequent attacks may lead to regression in remyelination therefore leading to plaque formation in irreversibly damaged axons.(, Pathophysiology of Multiple Sclerosis) This is highly correlated to non reversible neurological impairment due to the limited capacity of CNS to regenerate axons; this tends to occur in the later stages of MS. The reorganisation of sodium channels along demyelinated nodes may also account for the return of function of some axons. All these events lead to the clinical relapsing-remitting appearance of MS.
Axon demyelination also cause an increased refractory period, increasing the time for the propagation of new action potentials. This is due to the reduced repolarisation caused by the conduction delay for depolarisation at the adjacent node in the demyelinated region causing the reduced rate of recovery. VGSC are inactivated for longer and VGPC close slower than normal. This leads to overall slowing of action potential conduction.
Separate to demyelination factors, the inflammatory feature regarding plaques in MS is also a cause of partial nerve conduction. This is due to the infiltration of macrophages producing pro inflammatory cytokines such as IFN-γ and TNF-α.(Korn 2008) They are suggested to cause possible inflammatory effects of ion channels in axons leading to problems in neurological function. Also these inflammatory mediators may also encourage the production of nitric oxide synthase, causing nitric oxide formation. This effectively damages nerve fibres in the CNS permitting reduced nerve conductance. (Liu, Zhao et al. 2001)
Many classes of conduction abnormalities can occur in demyelinated axons illustrated below in fig-6 (Raine, Mcfarland et al. 2008). These include decreased conduction velocity, reduced ability to transmit high frequency action potentials and conduction block. Conduction time from node to node can increase to half second compared to a 20µs of a normal nerve axon. If many regions of an axon are demyelinated there is a considerable reduction in action potential conduction. If a number of axons are demyelinated within a tract for instance the spinothalamic tract, loss of function occurs via temporal dispersion of impulses (shown by C in the diagram).
Figure-6: Classes of conduction abnormalities (Raine, Mcfarland et al. 2008)
Many types of conduction block can occur i.e. high frequency conduction block (D) or complete conduction block (E). High frequency impulses may be a result of hyperpolarisation due to the activity of Na+K+ATPase pumps. Increased sodium inside the axon at the node that has just fired an action potential and accumulation of potassium outside the cell in the demyelinated region has suggested possible inactivation of VGSC, therefore reducing the ability to fire anymore action potential i.e. conduction block. (MCDONALD, SEARS 1970)
It important to note the different accommodative properties of demyelinated sensory and motor nerves. Accommodation states that the longer the stimulus, the larger the depolarization necessary to initiate an action potential. This is demonstrated clearly by MS patients as presentations concerning loss of sensation are more compared to problems with motor activity.(Rasminsky 1981) Increased mechano-sensitivity amongst demyelinated axons (G) is a possible class of conduction abnormality that may account for the clinical manifestation of the Lhermitte's Sign associated with MS. This sign describes electrical sensations in the neck radiating to the back. It is a big indicator of plaques in the cervical spine. Sensations are brought by movement of the neck which causes stretching of the demyelinated fibres and contribute to hyper-excitability of axons. (Rasminsky 1981)
Although multiple sclerosis is a common neurological disease, during my research, many reviews and articles I read were very old (up to 40 year old). Some of the studies regarding conduction abnormalities in axons were not studied on humans but on animals. Though they explain valid conclusions, it may be a possible limitation of studies as animal and human axons may not be entirely comparable. It was very interesting to investigate the different conduction abnormalities regarding demyelination referring to particular problems in regards to MS. Understanding the possible problems regarding action potential conduction opens the possibilities of pharmacological interventions to overcome conduction block. For example the use of 4-aminopyridine (4-AP) is a fast potassium channel blocker which causes prolonged action potential duration by slowing repolarisation. This will enhance depolarisation currents at demyelinated regions and increase the probability of action potential reaching threshold. This is one possible method to overcome conduction block.
Local current theory
Na+ channels concentrated at nodes of Ranvier
Even distribution of Na+ channels along the axon
Faster conduction is diameter of axon above 1µm
Faster conduction if diameter of axon less than 1µm
Only the nodes of Ranvier are unmyelinated
Whole axon is unmyelinated
Formation of plaques and subsequent MS attacks will reduce excitation of successive nodes due to an increase in membrane capacitance; leading to local current dissipation therefore action potential conduction ultimately fails or is delayed.