Peripheral Nerve Physiology, Anatomy, and Pathology

Shikha Sethi

Brian J. Harley

Christian Custodio

Michael Stubblefield

A comprehensive understanding of peripheral nerve anatomy and physiology is essential for understanding peripheral nerve pathophysiology and mechanisms of peripheral nerve injury and regeneration. Understanding peripheral nerve injury and cellular repair is critical to clinical management of operative nerve injury, microsurgical nerve repair, and emerging applications that target intrinsic nerve cell functions to assist in nerve regeneration.

Peripheral Nerve Anatomy

Gross Anatomy

General Organization

31 mixed spinal nerves emerge from the spinal cord:
- 8 cervical
- 12 thoracic
- 5 lumbar
- 5 sacral
- 1 coccygeal
Nerves emerge from the foramen of the vertebral bodies after the union of ventral and dorsal roots.
- Autonomic, sensory, and motor fibers travel together in peripheral nerves to their destinations.
- Nerves branch into dorsal and ventral rami upon exiting the foramen.
- Dorsal rami
  - Small-caliber branches
  - Provide segmental innervation to dorsal paraspinal area
- Ventral rami
  - Large-caliber branches
  - Cervical, lumbar, and sacral roots join together to form nerve plexuses to innervate the extremities.
  - Thoracic spinal nerves (except T1) do not form plexuses but instead provide segmental innervation to large areas of the ventral trunk.

Nerve Plexus

Coalescence of multiple spinal nerve ventral rami
- Fairly consistent anatomic connections and exchanges within plexuses
- Each root level still innervates specific dermatomal and myotomal segments.
At the distal aspect of the plexus, peripheral nerves form with representations from multiple spinal levels.
Four consistent locations
- Cervical plexus
  - First four cervical roots
- Brachial plexus
  - Lower four cervical and first thoracic ventral rami
- Lumbar plexus
  - First three and a part of the fourth lumbar ventral rami
- Sacral plexus
  - All sacral rami along with the fifth and a part of the fourth lumbar ventral rami

Peripheral Nerves

Each nerve may contain any combination of three possible nerve types:
- Motor efferent fibers
  - Cell bodies in the spinal cord
  - Transmit motor information to muscles about when and how to act
  - Motor unit: individual motor neuron and the specific group of muscle fibers it innervates
- Sensory afferent fibers
  - Cell bodies in dorsal root ganglia
  - Convey modality or quality, intensity, duration, and location of a stimulus from the periphery
  - Arise from specialized pain, thermal, tactile, and stretch (proprioceptive) receptors in the periphery
  - Terminal axons and presynaptic terminals for sensory fibers may be at the spinal level of the corresponding dorsal root ganglion or deeper in the central nervous system.
- Sympathetic fibers
  - Originate in the intermediolateral cell column in the thoracic and upper lumbar spinal cord
  - Synapse at variable levels of the paravertebral sympathetic ganglion and then travel as fibers within mixed spinal nerves to end organs such as sweat glands, blood vessels, and erector pili
  - Fibers join the spinal nerve and can then branch into ventral and dorsal primary rami.

Figure 25-1 (A) Arrangement and ensheathment of peripheral, myelinated nerve fibers. All but the smallest peripheral nerves are arranged in bundles (fascicles), and the entire nerve is surrounded by the epineurium, a connective tissue sheath. Each small bundle of nerve fibers is also enclosed by a sheath, the perineurium. Individual nerve fibers have a delicate connective tissue covering, the endoneurium. The myelin sheath is formed by neurolemma (Schwann) cells. (B) Peripheral nerves are structured similarly to tendons, ligaments, and muscles, with long parallel fibers contained in bundles surrounded by connective tissue. (A from Moore KL, Dalley AF. Clinically Oriented Anatomy, 5th ed. Baltimore: Lippincott Williams & Wilkins, 2006. B from Hendrickson T. Massage for Orthopedic Conditions. Baltimore: Lippincott Williams & Wilkins, 2002.)

Microanatomy

Nerves (Fig. 25-1)

The normal peripheral nerve is composed of blood vessels, nerve fibers, and three levels of connective tissue within which the fibers and vessels lie.
- Epineurium
  - Outermost connective tissue layer
  - Represents up to 50% of the cross-sectional area of the nerve trunk
  - Loose meshwork of collagen and elastin fibers and is generally thicker where a nerve crosses a joint
  - Well-developed vascular plexus runs within the epineurium.
  - Functions to protect the nerve fiber bundles, called fascicles, within the nerve
    - Tough external epineurium surrounds periphery of nerve.
    - Loose internal epineurium occupies space between fascicles.
- Perineurium
  - Thin, dense, multilayered connective tissue sheath that surrounds each fascicle
  - Tight basement membranes within the perineurium protect the endoneurial space by serving as a diffusion barrier.
  - Tensile strength of the perineurium helps maintain intrafascicular pressures.
  - Vascular structures traverse the perineurium obliquely to enter the endoneurial space.
- Endoneurium
  - Delicate collagenous matrix with fibroblasts, mast cells, and a capillary network
  - Surrounds individual myelinated nerve fibers or groups of unmyelinated nerve fibers within a fascicle

Fascicles

All neurons within a peripheral nerve are bundled together into structures termed fascicles.
- Fascicles are located within the internal epineurium.
- Bounded by the perineurium
Fascicles are often grouped together into a larger unit.
- Inner interfascicular epineurium bounds grouped fascicles.
- Grouped fascicles can be easily divided along internal epineurial planes.
Major peripheral nerves will contain many grouped fascicles.
- There is constant redistribution of fascicular organization along a peripheral nerve.
  - Interfascicular plexuses allow for interconnections.
- Fascicles are more numerous and smaller where a nerve crosses a joint.
  - Smaller fascicles and more internal epineurium between them allows for increased protection of nerve fibers from external trauma and deformation.
As the nerve gives off branches along its course, the fascicles divide (see Fig. 25-1).
- Small terminal nerves contain only one or two fascicles.
  - Example: digital nerve

Figure 25-2 Neuron showing cell body, axon, dendrites, Schwann cells, myelin sheath, and nodes of Ranvier. (From Werner R, Benjamin BE. A Massage Therapist’s Guide to Pathology, 2nd ed. Baltimore: Lippincott Williams & Wilkins.)

Cellular Anatomy and Physiology

Neurons (Fig. 25-2)

Individual nerve fibers within the endoneurium of a peripheral nerve are termed neurons.
- Neurons are extensions of a single nerve cell body.
Neurons are broken down into four distinct regions:
- Cell body
  - Contains the nucleus of the nerve cell
  - Metabolic center of the nerve cell
  - Dorsal root ganglion contains the cell body for sensory nerve fibers.
  - Motor nerve cell bodies are found in the anterior horn cells of the spinal cord.
- Dendrites
  - Thin processes that branch off the cell body
  - Receive inhibitory or stimulatory synaptic input from other cells
    - Synapse with both central and peripheral nervous systems
    - This input allows modulation of peripheral nerve function.
- Axons
  - Each cell body gives rise to a single axon at its axon hillock.
  - Propagate electrical signals known as action potentials
    - Convey information over distances from cell bodies to nerve terminus
  - Axons may act at great distances from their cell bodies.
    - Example: Signal to extend great toe is generated in the motor cell bodies of the anterior horn cells of spinal nerve roots L5 and S1 and runs to the distal portion of the lower leg to innervate the extensor hallucis.
- Presynaptic nerve terminal
  - Located at the distal end of the axon
  - Action potential causes changes in ion exchange at terminus.
    - Release of neurotransmitter at the synaptic cleft or neuromuscular junction results.

Schwann Cells and Myelin Sheaths

Specialized macroglial cells are called Schwann cells.
Surround peripheral nerve axons and produce myelin
- 70% lipid
- 30% protein
- High concentration of cholesterol and phospholipids
Myelin provides electrical insulation for the electrical impulse.
- Allows propagation of electrical impulses at faster speeds and at higher frequencies

Myelinated Axons

Wrapped throughout their length by concentric, tight spirals of layers of the Schwann cell membrane
Schwann cells line up end to end along the course of a single axon.
- Entire length of the axon is surrounded.
- Small spaces (up to 1.0 mm) between adjacent Schwann cells called nodes of Ranvier
- Up to 500 Schwann cells may myelinate a single axon.

Unmyelinated Axons

Surrounded as a group by processes of a single Schwann cell
Conduction through these axons is comparatively slower.

Peripheral Nerves

Contain both myelinated and unmyelinated fibers in an average ratio of 4:1 traveling within each fascicle
- Pathologic processes that disrupt the myelin sheath can slow conduction or cause focal conduction block.

Axoplasmic Transport

Specialized transport processes within a nerve cell
- All cellular proteins and neurotransmitters are produced in cell body.
- Cell body may be at a significant distance from the terminal axon.
- Multiple transport mechanisms
  - Fast and slow anterograde transport
    - Move cellular proteins from the cell body to the axon
  - Fast retrograde transport
    - Removes debris and breakdown products from the distal axon back to the cell body
- Mechanisms proposed consist of carrier proteins binding to microtubules within the nerve cell.

Electrophysiology of Peripheral Nerves

Nerve cells communicate via electrical and chemical impulses. Ion exchanges between the microenvironment inside and around a nerve fiber create electrical potential differences in the nerve cell. When certain threshold levels are reached, events such as release of neurotransmitter vesicles, or initiation of an action potential, occur.

Resting Cell Membrane and Electrical State

Neurons at rest have a negative potential within the cell between -50 and -80 mV.
- Na⁺ and Cl^– are concentrated on the outside of the neuron.
- K⁺ and organic anions are concentrated on the inside.
Cell membrane is essentially impermeable to charged ions, except where specialized ion channels allow transit of charged ions.
Net ion flux across the membrane at rest is zero.
- Actively maintained by the Na ⁺/K⁺ pump
Excitatory and inhibitory neurons induce graded potentials in the nerve cell.
- Act at cell body and dendrites
- Membrane potential can become more or less negative as a result.
- If sum of electrical activity received and processed reaches threshold, nerve depolarizes.