The Peripheral Nerve and Reflex: Fibers, Roots and the Segmental Loop

01Crest and neural tube

The peripheral nervous system is built by cells that leave the neural tube and are sorted by the corridor they enter

Most of the peripheral nervous system comes from neural crest cells that detach from the edge of the neural fold under bone morphogenetic protein induction. HNK-1 antibody labeling in the quail embryo mapped three corridors out of the trunk crest Erickson 1988. Cells travel between the ectoderm and the somites, through the intersomitic space, or through the anterior somite along the basal surface of the myotome. Adhesion to laminin and fibronectin carries the cells forward. Chondroitin sulfate walls off the routes they may not take, and contact inhibition supplies the direction.

In the chick trunk, cells taking the ventral path between the neural tube and the somite give rise to the neurons and glia of the peripheral nervous system Erickson 1998. Cells taking the dorsolateral path between the ectoderm and the dermamyotome differentiate into the pigment cells of the skin. The ventral stream branches to build both the dorsal root ganglia and the autonomic ganglia. Melanocyte and neuron are separated by the corridor they take, before any later step of differentiation.

Sonic hedgehog and bone morphogenetic protein sort the neural tube into countable domains

The embryonic neural tube of vertebrates is divided along its dorsoventral axis into eleven molecularly discrete progenitor domains. The ventral six contribute to motor circuits and the dorsal five to sensory circuits Zannino 2015. Two morphogens set that pattern. Sonic hedgehog is released from the notochord and floor plate, bone morphogenetic protein is produced in the roof plate, and each acts as a concentration gradient. A cell reads its position as a signal level and takes an identity from it. The dorsal domains build the cord circuits that peripheral nerve afferents will terminate on, and the ventral domains build the motor neurons whose axons leave through the ventral root.

Signal level decides the outcome, and the gene can be entirely intact. A rare nucleotide variant sitting 460 kb upstream of SHH in a person with holoprosencephaly destroyed the activity of the brain enhancer SBE2 in the hypothalamus of transgenic mouse embryos Jeong 2008. A single base change far outside the gene was enough to break midline forebrain formation.

The somites impose segmentation on an unsegmented crest

Migrating crest cells in the chick trunk stay bound to the anterior half of each somite, and its basal lamina is their migratory substrate Loring 1987. The somite itself splits into a dorsal dermomyotome giving skin and striated muscle and a ventral sclerotome giving vertebrae and meninges. Only after that division does migration proceed, which lets the sensory and motor halves of the peripheral nervous system separate cleanly.

Motor axons are excluded from the caudal half of each sclerotome, the same half that repels crest cells, so both are funneled through the anterior half and the body inherits an orderly metameric plan. That plan is the reason one spinal level maps to a predictable strip of skin and a predictable set of muscles. It is also the reason an examiner can reason backward from a numb patch to a compressed root. The tube stage before the crest departs is set out in embryology and development.

02Findings

What the research shows

03Axon and Schwann cell

One axon paired with one Schwann cell is the working unit of the peripheral nerve, and the Schwann cell selects its partner

Schwann cells select individual axons out of a nerve bundle and build the one to one pairing through radial sorting. The Rho family GTPase Rac1 drives the process extension and lamellipodia formation that sorting requires Chan 2007. In myelinated fibers, serially arranged Schwann cells each wrap one segment of axon in many concentric layers. In unmyelinated fibers, a single Schwann cell holds several axons in shallow troughs with no spiral wrapping at all.

Mice carrying a spontaneous or targeted mutation of Sox10 still form neurons in the dorsal root ganglia, yet generate no Schwann cells and no satellite cells. Their sensory and motor neurons then degenerate severely Britsch 2001. Sox10 acts inside neural crest cells and controls ErbB3 there, which ties the peripheral glial lineage straight back to the ventral crest corridor that built the peripheral nervous system.

Peripheral nerve fiber diameter sets conduction speed, and the spectrum is assembled after birth

Myelinated peripheral nerve fibers span roughly 2 to 20 micrometers, and childhood assembles that distribution. Morphometry of human sural nerve covered 27 controls aged 1 day to 59 years, with total transverse fascicular area measured in 10 of them. The distribution of myelinated fiber diameters was unimodal in the first four months of life, and definitely bimodal by age two. Total transverse fascicular area rose from about 0.25 mm2 in the first week to about 0.82 mm2 at nine years Ouvrier 1987.

Conduction velocity scales with total fiber diameter at a measured rate. In cat hind limb muscle nerves, that scaling factor was 5.7 m/s per micrometer for group I afferent fibers Boyd 1979. For myelinated fibers in group II and group III it was 4.6 m/s per micrometer. The factor was not constant across sizes and did not rise progressively with size. Boyd concluded that a logarithmic relation between velocity and diameter is not appropriate, and attributed the discontinuity to relative myelin thickness.

Inside a peripheral axon the supply runs both ways, and the rate is adjustable

Cargo rides directionally oriented microtubules inside every peripheral nerve axon. Anterograde transport away from the cell body is plus end directed and uses kinesin ATPase motors for fast traffic. In cultured neurons lacking the adaptor protein JIP1, fast anterograde transport of amyloid precursor protein fell from 2.7 to 1.8 micrometers per second. The share of tracked particles moving anterogradely fell from 66 to 45 percent Chiba 2014. One missing adaptor cost a third of the speed and a third of the traffic without stopping it.

Retrograde transport runs the other way. It is minus end directed and driven by dynein, carrying organelles, aggregated proteins for clearance, and neurotrophin signals. Photolytic inactivation of dynein in living lamprey Mauthner axons abolished retrograde bead movement and left anterograde movement untouched Wang 1995. The same retrograde stream carries injury news back, using locally synthesized importins and vimentin to link signaling molecules to the dynein motor Hanz 2006.

04Roots, rami and the disc

Each spinal nerve splits into two rami and sends a recurrent branch back into the canal, which is why deep spinal pain refuses to localize

The third branch of a spinal nerve turns around and re-enters the canal it just left. The sinuvertebral nerve, also called the recurrent nerve of Luschka, was first described by Luschka in 1850 Raoul 2003. It passes back through the intervertebral foramen to supply the dura, the posterior longitudinal ligament, and the outer annulus. Each one is formed by a somatic root from a ventral ramus and an autonomic root from a gray ramus communicans, and the nerves are mixed, polysegmental and plexiform Faustmann 2004. Markers for pain-leading fibers stain positive in the dorsal region of the annulus and especially in the posterior longitudinal ligament.

Two features of that wiring make discogenic pain diffuse. One disc reports to several levels at once through a plexus. And in the lumbar spine the sinuvertebral nerve cannot reach a somatic element at every level between L3 and L5, so its traffic must first reach the L2 spinal ganglion Raoul 2003. Resecting the sympathetic trunks lowered the number of nerve bundles supplying these structures Faustmann 2004, so this somatic sensory route is wired through autonomic supply.

Dermatome maps are a coarse rendering of the peripheral nerve's segmental plan

Adjacent dermatomes overlap so heavily that anesthetizing one lumbosacral root numbs a mean of 2.7 dermatomes on the standard map. A double-blind study of 40 single-root blocks at L2 to S1 in 29 patients measured that overlap directly, and the same hypesthesia spanned 3.6 dermatomes on an overlap-adjusted map. Paresthesias fell in the expected dermatome 80 percent of the time on the standard map and 98 percent on the adjusted one Wolff 2001.

A systematic review of the studies behind the printed charts found current dermatome maps inaccurate and based on flawed work, and built a new evidence-based map from the best available data Lee 2008. The segmental plan the somite laid down for the peripheral nerve is orderly and real. The chart of it is low resolution, and overlap and variability are part of the anatomy.

Root compression depresses the reflex, dermatomal sensation and myotomal strength together

Nerve root compression produces pain and paresthesia along the nerve distribution, weakness in every muscle the root innervates, and depression of the deep tendon reflex at that segment. Facet arthrosis usually produces axial and referred pain with no radicular sensory or motor loss. A disc lesion compressing a root produces dermatomal sensory change, myotomal weakness and reflex depression together, so the segmental map becomes a diagnostic instrument. Lesions of the cord itself follow different rules, and those patterns are set out in the cord and nerve root.

05The segmental loop

The deep tendon reflex reads the condition of a whole pathway, and what returns is a population rather than a single impulse

A deep tendon reflex tests the shortest circuit in the nervous system, and what comes back is never one impulse. The arc leaves a peripheral receptor, passes through one segment of the cord, and ends on a muscle. A peripheral receptor transduces a stimulus into a sensory nerve action potential. The afferent fiber carrying it belongs to a pseudounipolar neuron whose cell body waits in the dorsal root ganglion, outside the conducting pathway, with a single protoplasmic process capable of bidirectional signaling. That signal enters the dorsal horn, synapses within the segment, and drives an efferent motor fiber out the ventral root to muscle.

Human microneurography shows what actually arrives. Percussing the soleus tendon produced a dispersed afferent volley starting 3.5 to 7.0 ms after the tap Burke 1983. It rose to a peak over 6.5 to 11.0 ms and lasted 25 to 30 ms, depending on the strength of percussion. Burke concluded that neither the H reflex nor the tendon jerk is purely monosynaptic. The visible twitch is the summed arrival of a graded population, and the receptor feeding it is set out in muscle spindles and proprioception.

The ganglion filters the traffic before the cord ever sees it

The T junction, where the single process of a pseudounipolar neuron splits, works as an active gate. In rat dorsal root ganglion recordings, all 20 action potentials in a train transited that junction only up to a maximal rate. That rate was lower than the dorsal root axon or the soma could each sustain alone Gemes 2013. The junction acts as a low pass filter for propagation. The failure builds up over the train, since that maximal rate was lower for a train of 20 impulses than for two. Propagation failure came with a fall in somatic membrane input resistance, and it worsened when calcium sensitive potassium currents were augmented.

Injury moves the setting of that gate. After painful peripheral nerve injury in the rat, following frequencies rose in axotomized C type neurons and fell in axotomized A type neurons Gemes 2013. One peripheral event reset the gain of the segment instead of adding or subtracting signal. Traffic that is triggered ectopically in a neuroma or in the cell body itself then reaches the cord more easily than it did before.

No single sign reads the whole pathway

One probe samples one slice of that pathway. Measured against imaging in 116 patients with chronic lumbar radiculopathy, no individual test of strength, dermatomal sensation, reflex or straight leg raise reached a positive likelihood ratio above 4.0 or a negative ratio below 0.4. The examiner's overall clinical evaluation did better, with a positive likelihood ratio of 6.28 for L4, 1.74 for L5 and 1.29 for S1 Iversen 2013. Disc herniation prevalence was 77.8 percent in this highly selected specialist population. The afferent limb also thins with age. An absent ankle jerk at seventy can report attrition of the afferent population and no root lesion at all, and that count is set out in muscle spindles and proprioception. The summed pattern carries information that no single sign holds.

06Loading one vertebral segment

A mechanical input at one vertebra does not enter at one segment, because the tissue that reports it is supplied by a plexus

What reaches an axon is graded mechanical and sensory information, and at a vertebra the tissue that first receives it is supplied by a plexus. The sinuvertebral nerves that serve the dura, the posterior longitudinal ligament and the outer annulus are polysegmental, so one loaded segment reports to several levels at once Faustmann 2004. In the lumbar spine the nerve cannot reach a somatic element at every level between L3 and L5, and its traffic must first reach the L2 spinal ganglion Raoul 2003. A thrust delivered low in the lumbar spine is therefore read at a ganglion sitting well above the hand that delivered it. The segment that receives an input and the segment that reports it need not be the same segment.

What arrives is spread in time as well as across levels. Electrical stimulation of the human sciatic nerve at H reflex threshold produced a comparatively synchronized volley Burke 1983. Its fastest fibers conducted at 62 to 67 m/s and its slowest conducted at 36 to 45 m/s. Even that volley is a smear, because a nerve carries a spectrum of diameters and each diameter has its own arrival time. A tap on a tendon is more dispersed still and takes 25 to 30 ms to finish. No input to a peripheral nerve reaches the cord as a single event.

A matched spinal input shifts the responsiveness of the loop

The Unified Model of Tone reads a reflex as a loop with a responsiveness of its own, sharp or sluggish, and much of disease as that responsiveness stuck. Health in a segmental loop is the freedom to change its own amplitude and return to where it was. Illness is a loop parked at one following frequency, handing back the same answer whatever arrives. The target of a matched input is that adjustability and not the height of any single twitch.

A train of 20 action potentials passes or fails at the T junction according to the following frequency that junction can support at that moment. Painful axotomy raised following frequency in C type units of the rat and lowered it in A type units Gemes 2013. The same afferent traffic reaches the cord or does not, and the variable that decides belongs to the neuron. How fast a load has to be applied before paraspinal spindles answer it is set out in muscle spindles and proprioception. What the motor pool downstream does with the result is set out in the spinal cord.

Read this way, the peripheral nerve is where a mechanical event becomes traffic and where that traffic is edited before the cord ever sees it. Afferent filtering at the T junction, the excitability of the motor pool that junction feeds and the mechanical state of the tissue the nerve runs through are not three separate findings. The model reads them together, as the organization that segment is holding. What a radicular pattern looks like once that organization fails, and what moves it, is set out on the research page on sciatica.

07Axon injury and degeneration

A cut axon runs a self-destruct program on a clock, and the cell body remodels because transport backs up behind the hillock

Peripheral nerve injury announces itself at both ends of the neuron. Within days of axonal damage the dorsal root ganglion or gray matter neuron undergoes retrograde chromatolysis Hanz 2006. That suite of structural changes runs to swelling, shifting of the nucleus and dispersal of the Nissl bodies. Motor neurons lose their synaptic contacts, ATP production falls, ion pumps fail, and the resting membrane potential drifts toward threshold.

The displaced nucleus has a proposed physical cause. Axotomy adds protein to the cytoskeleton and enlarges nucleolus, nucleus and cell body together. In axotomized frog spinal motor neurons, cytoskeletal elements that can no longer enter the shortened axon dam up between the nucleus and the axon hillock, pushing the nucleus off center McIlwain 2005.

Wallerian degeneration in a cut peripheral nerve is executed rather than suffered

The severed distal segment of a peripheral nerve does not simply starve. Loss of the transported enzyme NMNAT2 raises the ratio of NMN to NAD+, and SARM1 is activated by that increased ratio. Both metabolites compete for binding to its auto-inhibitory armadillo repeat domain, and SARM1 then cleaves the remaining NAD+ in a feedforward metabolic catastrophe Figley 2021. Raising expression of the mouse WldS protein inside the axon after axotomy halts the process, and in cultured neurons that rescue still works up to 4 to 5 hours after the injury Wang 2015.

Delivery from the cell body holds the distal axon alive continuously, and the threshold for destruction can be raised or lowered. Wallerian degeneration is the program that runs when that delivery stops.

Electrodiagnosis converts an invisible injury into coordinates

Nerve conduction studies and needle electromyography record sensory and motor responses separately by electrode placement, the sensory nerve action potential over a sensory nerve and the motor response over a muscle. Slowed conduction points to demyelination of the Schwann sheath. Reduced response amplitude points to axonal loss.

Suggested guidelines built from 572 peer reviewed electrodiagnostic examinations across six European countries use two plots Tankisi 2005. One sets change in amplitude against change in conduction velocity or distal latency. The other sets change in F-wave frequency against change in F-wave latency. The boundaries on those two plots delimit normal, axonal, demyelinated and neuropathic nerve segments. Read together with the segmental map of dermatomes, myotomes and reflexes, they let an examiner say where along a nerve the trouble sits and which fiber class carries it.

08Tone

How this system expresses tone

In the peripheral nerve the organization is held by a supply line. A fiber stays alive only while delivery from the cell body continues, and once the axon is cut, raising axonal WldS still halts the destruction program for another 4 to 5 hours.

Set point: an axotomized neuron loses its pumps and its resting membrane potential drifts toward threshold, so the cell defends a value it can no longer hold. Prediction: the cell body commits protein to a length of axon it cannot sense, which is why a shortened axon dams that shipment behind the hillock. Oscillation: a tap delivers a wave rather than an impulse, rising to a peak over 6.5 to 11.0 ms in the human soleus and gone by 30 ms. Time course: the fiber spectrum is assembled after birth and is bimodal by age two, and the rescue window after axotomy closes at 4 to 5 hours. Constraint: crest cells and the nerves that follow them are confined to the anterior half of each somite, and that corridor fixes the segmental plan for life. Coupling: the sinuvertebral nerve is built from a somatic root and an autonomic root, so disc sensation and sympathetic supply travel one branch.

09Across the library

How this page relates to the rest of the library

10Frequently asked

Questions about this topic

11The sources

References

Sources: primary literature, linked inline.