Section 1 NERVE PHYSIOLOGY 1.1 Membrane Structures All cells are surrounded by membranes, and the membranes for nerve and muscle fibers have unique properties that allow the selective passage of ions that are key elements in the ability of these cells to generate action potentials. The surrounding membrane is composed of lipids and is impenetrable to ions, and thus separates intracellular and extracellular ionic environments. However, the membrane contains protein channels or pores that allow ions to pass across the membrane (Figure 1.01). Channels are complex structures made up of multiple subunits that function together. Membrane channels are selective for which ions can pass through. Some channels are always open, but are selective (Figure 1.02). Selectivity can be based on ion size (which includes the size of the hydration sphere) or ion charge (Figure 1.01). Other channels open after undergoing conformational changes. Conformational changes can occur in response to changes in voltage across the membrane (depolarization or hyperpolarization) – voltage gated channels. Channels can serve as receptors, and change conformation after a neurotransmitter attaches to them – ligand gated channels (Figure 1.02). 1.2 Membrane Biophysics Extracelular and intracellular ionic environments differ. The selective permeability of the channels leads to a potential difference across the membrane, the inside negative with respect to the outside. In the resting state, ions flow down their respective concentration gradients, with positive sodium charges moving in and positive potassium charges moving out through their respective channels. Ionic flow down concentration gradients is impeded by intracellular electrostatic charges due to large negatively charged proteins that can not pass through the channels. Chloride ions flow freely across the membrane (Figure 1.03). Overall, these forces lead to a net distribution of ionic charges across nerve and muscle membranes, and a resting membrane potential that is –70 to 90 mV inside with respect to the outside. The flow of ions across the membrane would, in time, lead to a reduction of charge separation and a lower membrane potential. There is an energydependent (ATP) pump that maintains the concentrations of sodium and potassium (Figure 1.04). Actually, two sodium ions are removed for every potassium ion returned, and the pump contributes to a small degree to the resting membrane potential. 1.3 Passive Membrane Properties Passive membrane properties govern how action potentials are propagated down axons and along muscle fibers. The separation of charges on either side of the membrane also results in positive ions lining the inside and negative changes lining the outside of the membrane. Accordingly, the membrane forms a capacitor (Figure 1.05). Intracellular ions offer resistance or impedence to the flow of additional ions along the length of the fiber. The amount of charge able to flow down a fiber represents current (Figure 1.05). A high fiber resistance will impede current flow, with less charge flowing down the fiber and a short membrane length constant. .As an action potential travels down an axon or muscle fiber, a high membrane capacitance will take time to charge, leading to a long membrane time constant.
Transcript
Section 1
NERVE PHYSIOLOGY
1.1 Membrane Structures
All cells are surrounded by membranes, and the membranes for nerve and muscle fibers have unique properties that allow the selective passage of ions that are key elements in the ability of these cells to generate action potentials. The surrounding membrane is composed of lipids and is impenetrable to ions, and thus separates intracellular and extracellular ionic environments. However, the membrane contains protein channels or pores that allow ions to pass across the membrane (Figure 1.01). Channels are complex structures made up of multiple subunits that function together.
Membrane channels are selective for which ions can pass through. Some channels are always open, but are selective (Figure 1.02). Selectivity can be based on ion size (which includes the size of the hydration sphere) or ion charge (Figure 1.01). Other channels open after undergoing conformational changes. Conformational changes can occur in response to changes in voltage across the membrane (depolarization or hyperpolarization) – voltage gated channels. Channels can serve as receptors, and change conformation after a neurotransmitter attaches to them – ligand gated channels (Figure 1.02).
1.2 Membrane Biophysics
Extracelular and intracellular ionic environments differ. The selective permeability of the channels leads to a potential difference across the membrane, the inside negative with respect to the outside. In the resting state, ions flow down their respective concentration gradients, with positive sodium charges moving in and positive potassium charges moving out through their respective channels. Ionic flow down concentration gradients is impeded by intracellular electrostatic charges due to large negatively charged proteins that can not pass through the channels. Chloride ions flow freely across the membrane (Figure 1.03). Overall, these forces lead to a net distribution of ionic charges across nerve and muscle membranes, and a resting membrane potential that is –70 to 90 mV inside with respect to the outside.
The flow of ions across the membrane would, in time, lead to a reduction of charge separation and a lower membrane potential. There is an energydependent (ATP) pump that maintains the concentrations of sodium and potassium (Figure 1.04). Actually, two sodium ions are removed for every potassium ion returned, and the pump contributes to a small degree to the resting membrane potential.
1.3 Passive Membrane Properties
Passive membrane properties govern how action potentials are propagated down axons and along muscle fibers. The separation of charges on either side of the membrane also results in positive ions lining the inside and negative changes lining the outside of the membrane. Accordingly, the membrane forms a capacitor (Figure 1.05). Intracellular ions offer resistance or impedence to the flow of additional ions along the length of the fiber. The amount of charge able to flow down a fiber represents current (Figure 1.05). A high fiber resistance will impede current flow, with less charge flowing down the fiber and a short membrane length constant. .As an action potential travels down an axon or muscle fiber, a high membrane capacitance will take time to charge, leading to a long membrane time constant.
1.4 Ionic and Capacitive Currents
Ionic currents represent the flow of ions across a membrane or down a fiber. Current can cross a membrane by two mechanisms, capacitive and resistive flow. Capacitive currents represent the accumulation of ions along one side of a membrane and release of similar ions from the other side of the membrane, and thus no ions actually flow across the membrane (Figure 1.05). Resistive flow of ionic current across the membrane occurs through voltagegated channels. Both types of current flow across a membrane are important, and are usually interconnected during the generation of action potentials.
Ion flow down a fiber meets resistance from intracellular ions (Figure 1.05). As ions flow, those near the inner side of the membrane also participate in charging the capacitor, further reducing the number able to move down the fiber.
It can be useful to view resistance and capacitance as equivalent electronic circuits (Figure 1.05). The potential flow of ions from an action potential can be viewed as a battery. Flow of positive sodium ions is resisted by flow through channels and the need to charge the membrane’s capacitance. Internal flow is resisted by intracellular ions.
1.5 Physiologic Adaptations to Enhance Current Flow
It is clear that current flow can be “used up” by high membrane capacitance and high internal resistance. It also takes time to add charge to the membrane capacitor. These factors can lead to insufficient flow of ions down the fiber. However, there are several of physiological adaptations that have evolved that reduce capacitance and resistance and lead to reliable and rapid conduction along fibers.
Capacitance can be reduced by increasing the thickness of the membrane. This has been accomplished by adding myelin wrappings to axons, thus reducing capacitance 100 fold (Figure 1.6). This in turn increases conduction velocity along myelinated fibers 50 fold (~50 m/s) compared to unmyelinated fibers (~ 1 m/s).
Resistance can be reduced by increasing fiber diameter. Myelinated axons are larger (up to 12 microns) compared to unmyelinated axons (up to 1 micron) (Figure 1.6).
1.6 Action Potentials
Action potentials are the basic bioelectric signals recorded in electrodiagnostic studies. Nerve fiber action potentials are directly recorded in sensory nerve conduction studies. Muscle fiber action potentials are directly recorded in motor nerve conduction studies and the needle EMG, but are initiated by nerve fiber action potentials.
1.7 Nerve Fiber Action Potentials
Action potentials represent transient reversals of the voltage across the membrane (transmembrane potential). Action potentials are initiated by an intracellular depolarization that opens voltagegated ion channels. The rapid opening of sodium channels allows sodium to flow down its concentration gradient, causing a reversal of the transmembrane potential with the inside of the fiber becoming positive (Figure 1.07). There is also a rapid opening of potassium channels that allows potassium to leave the fiber, thus returning the transmembrane potential so that the inside becoming negative. However, the potassium channels remain open longer, resulting in a transient greater degree of intracellular negativity (hyperpolarization). Even though an action potential results in a reversal of the membrane potential, this is accomplished by relatively few ions moving back and forth across the membrane.
1.8 Continuous Conduction Along Unmyelinated Fibers
There is an even distribution of voltagegated sodium and potassium channels along the fiber in unmyelinated nerve fibers. The action potential travels down the fiber in a selfregenerating manner by continuously depolarizing the membrane ahead. Similarly, there is a following repolarizating process. The distance along the nerve between the leading depolarization that initiates the action potential and the following repolarization depends upon the passive membrane properties, with fiber diameter being the largest determinant. In unmyelinated fibers, the distance is approximately 20 mm long. Conduction in unmyelinated fibers is slow, < 1 m/sec because of the time needed to charge the membrane capacitance and depolarize the membrane (Figure 1.08).
Conduction speed can be increased by reducing the internal resistance of the nerve fiber. Low resistance allows greater ionic current to reach resting membrane along the fiber. This can be accomplished by increasing the diameter of the nerve fiber. However, there are limitations on the size of an axon. Another approach is to reduce membrane capacitance. Low capacitance allows less ionic current to be used to charge the capacitor and more charge can be used to depolarize the membrane.
1.9 Saltatory Conduction Along Myelinated Fibers
Both approaches are used in myelinated fibers were axon diameters are up to 10x larger than unmyelinated fibers (Figure 1.06). However, the greatest increase in action potential conduction velocity is achieved by decreasing capacitance through increasing the effective membrane thickness with layers of myelin. Myelin wrappings are elongations of Schwann cell membrane and are arranged in segments along the nerve fiber. The myelin wrappings of Schwann cells do not abut against each other, and there is are spaces between them called nodes of Ranvier. Internode lengths vary in a linear fashion with the diameter of the fiber, and range between 0.5 and 1.0 mm long. There is a high concentration of voltagegated sodium channels under the nodes of Ranvier (Figure 1.09). Since capacitance is low along the internode region, very little ionic current generated by an action potential is lost charging the capacitance, and the ionic current travels quickly to the next nodal region. At the node, the degree of depolarization is sufficient to open the sodium channels and slightly later the potassium channels, and the action potential is regenerated. Thus, the action potential currents “jump” from node to node at conduction velocities of 5060 m/s, in contrast to continuous conduction of the action potential along unmyelinated fibers at conduction velocities up to 1 m/s. However, it should be understood that although the action potential ionic currents are regenerated at the internodes, the total wave of depolarization and repolarization moves down the fiber in a continuous manner. The wave length includes the time sodium and potassium channels remain open, and spans the length of 3060 internodes (Figure 1.10).
1.10 Conduction Along Whole Nerves
Thus far, the propagation of action potentials considered above represents conduction in single unmyelinated and myelinated nerve fibers. Routine nerve conduction studies involve the summated potential from all fibers of a whole nerve. Unmyelinated fibers are much more numerous than myelinated fibers (Figure 1.06), but they contribute little to the compound action potential. This is due to their very small individual fiber action potential amplitudes and the fact that very slow conduction velocities places them behind the arrival of the high amplitude myelinated fiber action potentials.
1.11 Sensory Nerve Action Potential
With sensory nerve recordings, the whole nerve is electrically activated and the compound action potential represents the sum of 2000+ nerve fiber action potentials, and is called the
sensory nerve action potential (SNAP) (Figure 1.12). Since each nerve fiber potential is small in amplitude, the sum is in the microvolt (µV) range.
1.12 Compound Muscle Action Potential
With motor nerve recordings, the whole motor nerve is also electrically activated, but the recorded response represents the muscle fiber action potentials. There are 100+ nerve fibers innervating a muscle, and each motor axon branches within muscle and innervates 100 to 1000+ muscle fibers. Thus, the compound action potential represents the sum of 10,000 to 100,000+ muscle fibers action potentials, and is called the compound muscle action potential (CMAP) (Figure 1.13). Action potentials from muscle fibers are larger in amplitude, and the sum is in the millivolt (mV) range.
1.13 Temporal Dispersion
Myelinated fibers have a range of fiber diameters reflected in a range of conduction velocities, and hence the arrival of individual nerve fiber action potentials at the recording electrode will be spread over time. This is represented in nerve conduction studies as temporal dispersion of the SNAP and CMAP waveforms. A helpful analogy is to consider action potentials as a group of runners that includes fast 6minute milers, slow 7 minute milers, and a range of runner running at speeds in between. Thus, in a 1mile race there will be a 1minute temporal dispersion of the group crossing the finish line, and in a 10mile race there will be a 10minute dispersion at the finish line.
1.14 SNAP Temporal Dispersion
The duration of a single nerve fiber action potential is short (approximately 1 msec) and the range of conduction velocities is fairly broad (approximately 25 m/s). The negative peak voltage of late arriving action potentials will occur well after the negative peak of the early arriving action potentials, and phase cancellation will reduce the amplitude of the summed SNAP (Figure 1.14). The effects of temporal dispersion will be magnified with conduction over greater distances. For the SNAP, the effects of temporal dispersion over routine distances will reduce the amplitude by 50% or more.
1.15 CMAP Temporal Dispersion
In motor nerve conduction studies, the duration of a motor unit action potential is long (approximately 4 ms) and the range of conduction velocities of the nerve fibers is short (approximately 13 m/s). The negative peak voltage of the late arriving action potentials will occur close to the negative peak of the early arriving action potentials, and phase cancellation will reduce the amplitude of the summated CMAP to a relatively little degree (Figure 1.15). The effects of temporal dispersion will be relatively little affected by conduction over greater distances. For the CMAP, the effects of temporal dispersion over routine distances will reduce the amplitude by less than 10%.
Section 1
NERVE PHYSIOLOGY (Figures)
Figure 1.01 Composite figure illustrating several aspects of membrane function. A: Representation of lipid bilayer membrane with ion channels piercing membrane. B: Protein subunits that make up ion channel and aspects of pore selectively based on hydrated ion size. C: Effect of membrane impermeability separating ionic charges, with inside negative.
Figure 1.02 Mechanisms of altering ion channel permeability. A: Permeability based on hydrated ion size. B: Permeability based on change in transmembrane potential leading to change in conformation or charge within the channel (voltagegated channel). C: Permeability based on ligand interaction causing conformational change within the channel (ligandgated channel).
Figure 1.03 Diagram showing effects of selective membrane ion permeability and distribution of ions influenced by their concentration gradients and electrostatic forces. Outward potassium (K + ) ion movement down its concentration gradient countered by electrostatic forces from large impermeable protein cations (A + ). Sodium (Na + ) ions restricted by size. Membrane freely permeable to chloride (Cl + ) ions. Net effect is intracellular negativity.
Figure 1.04 Equivalent membrane circuit. Top: Ion channels and sodiumpotassium pump. Bottom: Driving force (battery) and channel permeability (resistance) for sodium, chloride and potassium, and the pump.
Figure 1.05 Composite figure showing passive membrane properties and equivalent membrane circuit. Top: Injection of current at left depolarizes inside of nerve fiber. There is a distribution of positive charges along the inner membrane surface due to capacitance, liberating positive charges along the outer membrane surface (capacitive current). Positive charges used locally for capacitive current results in fewer charges available farther along the fiber. There is resistance to flow of charge down the middle of the fiber (axial resistance). Bottom: Equivalent circuit showing parallel membrane resistance and capacitance and series axial resistance.
Figure 1.06 Composite figure showing photomicrograph of myelinated fibers and clusters of unmyelinated fibers, and histogram of the relative numbers and diameter distributions of myelinated (dark lines) and unmyelinated fibers (lighter lines).
Figure 1.07 Ionic currents and membrane potential changes during the action potential. A: Top curves show initial inward depolarizing sodium current and later outward repolarizing potassium current. Bottom shows opening of individual channels and summed opening of several channels that lead to the net inward currents. B: Net sodium and potassium currents as they produce the action potential (dashed lines).
Figure 1.08 Action potential waveform propagating along unmyelinated fiber showing long wavelength. DIFFERENT LABEL
Figure 1.09 Distribution of sodium channels (gNa) which are high at nodes of Ranvies and potassium (gK) channels which are high at internodes and sodium currents along a myelinated axon.
Figure 1.10 Action potential waveform propagating along a myelinated fiber showing long wavelength.
Figure 1.11 Montague showing how a single nerve fiber action potentials (A) can be modeled to form the compound nerve action potential. A: Single action potential. B: Nerve fiber diameter histogram. C: Model of single fiber action potentials (inset) summed based on their conduction velocities.
Figure 1.12 Model of individual sensory nerve fiber action potentials summating to form sensory nerve action potential (SNAP).
Figure 1.13 Model of individual muscle nerve fiber action potentials activating muscle fiber action potentials summating to form compound motor action potential (CMAP).
