Preferential motor reinnervation

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Preferential motor reinnervation (PMR) refers to the tendency of a regenerating axon in the peripheral nervous system (PNS) to reinnervate a motor pathway as opposed to a somatosensory pathway. [1] [2] [3] PMR affects how nerves regenerate and reinnervate within the PNS after surgical procedures or traumatic injuries. It is important to understand in order to further develop axonal regrowth surgical techniques. Further research of preferential motor reinnervation will lead to a better understanding of peripheral nervous system function in the human body regarding cell roles and abilities.

Contents

Summary

Motor vs sensory nerve reinnervation

Nervous System Organization - The Motor and Sensory Systems Nervous system organization en.svg
Nervous System Organization - The Motor and Sensory Systems

The peripheral nervous system has the ability to regrow cut nerves. Motor axons preferentially reinnervate motor pathways. The tendency of motor axons to reinnervate motor pathways instead of cutaneous pathways is influenced by a number of factors in the PNS system. Some factors include Schwann cell characteristics, neurotrophic factors, and nerve branch size. These factors influence the pathway preference of the motor neuron. [2] [3] [4] The different nervous systems are illustrated in the image displayed on the right. Preferential motor reinnervation is a tendency that is specifically seen in the peripheral nervous system, which is illustrated in the photos of the bottom of the system shown.

Regeneration vs reinnervation

When peripheral axons are severed, the distal part of the cut axon degenerates. The only remaining distal parts from the original nerve are the Schwann cells which myelinate the peripheral axons. The basal lamina components that the Schwann cells secrete help to guide axon regeneration. The more precisely the axon stump is able to regrow along its original path, the better the recovery of function – especially when it comes to experiencing fine touch and movements. The growth of the axon stump to its original target is regeneration. [5] Reinnervation on the other hand, is the recovery of function through reestablishing synaptic connections. Even though the original axon degenerates, the Schwann cells and acetylcholine receptors remain in place, allowing for the junction to reestablish the original synapses once the axon stump regenerates. [6] In medical jargon, regeneration and reinnervation are not commonly distinguished. Regardless of the fact that there is a technical difference, many professionals use the terms interchangeably. This is because without regeneration, there would not be a nerve to innervate, but without reinnervation, the nerve would not function.

PMR relevancy

Knowledge of preferential motor reinnervation is necessary because of how it affects the regeneration of nerves. When a patient loses nerve function, PMR can interfere with (or help) the different methods of repair that physicians use. Physicians understanding of natural nerve repair processes will allow for overall improvement in surgery, because they will be able to better interface their repair efforts with natural ones. Axon reinnervation is greatly affected by the pathway the regenerated nerve has chosen to grow along. The nerves' ability to properly function after damage is very dependent on successful reinnervation, which is why the effects of PMR are so relevant. The success of nerve reinnervation after different grafting attempts is a current research area. Grafting aims to solve the problem of incorrect targeting of regenerating axons, resulting in less-than-perfect reinnervation. PMR effects are being investigated to see how they can help grafting, and ultimately patient recovery. [7] [8]

How do nerves regrow?

A cut nerve regenerating

A cut axon in the peripheral nervous system has two parts: a distal and a proximal axon stump. The space in between the two stumps is known as the gap, and it is what the nerve must grow through in order to fully regenerate and reinnervate. The distal axon is degenerated through the body's own mechanisms, mostly macrophage consumption and enzymes breaking it down. The proximal part of the cut axon is often able to regenerate. [5] [9] The regeneration and reinnervation of the cut nerve are affected by multiple factors, including how far the nerve must regrow, what kind of environment it is growing in, and the different Schwann cells and pathway options available. PMR indicates that a regenerating motor neuron will choose a motor pathway Schwann cell over a cutaneous pathway Schwann cell when regenerating. [10] [11]

The role of Schwann cells

Cultured Schwann cell Cultured schwann cell.jpg
Cultured Schwann cell

Schwann cells are the myelination cells that surround nerves. When multiple nerves are cut, they must regrow and enter back through one of the Schwann cells that makes up the distal stump of the gap. These Schwann cells support axonal regrowth through their production of trophic factors as well as surface expression of multiple cell adhesion molecules that help influence axonal growth. [4] [12]

Neurotrophic support

Neurotrophic factors are support proteins and factors that help assist in the growth and maintenance of axons throughout the body. Different cells emanate different proteins, but the ones specific to the peripheral nervous system play a major role in regeneration of cut nerves in the peripheral nervous system. [13] [14] In relation to reinnervation, neurotrophic support is key in assisting with supporting the regeneration of axons. Some discussion has led investigators to believe that neurotrophic factors only led to more axonal sprouting rather than actually influencing the regeneration. The ability of neurotrophic factors to influence the sprouting of axons has been seen with electron microscopic images and in multiple studies extensively detailed in a review of the role of neurotrophic factors in regeneration. In addition to the ability of the factors to influence sprouting, Schwann cells in particular show a significant upregulation of a number of trophic factors after undergoing axotomy. [12] [14] One major difference in motor and sensory pathways is the difference in what trophic factors are upregulated by the Schwann cells of those pathways. Denervenated motor Schwann cells upregulate BDNF and p75, whereas sensory pathway Schwann cells upregulate a number of other varied trophic factors. This difference in trophic factor support is suspected to be a major influencer of preferential motor reinnervation. [12] [14] Though it is a major factor, inherent molecular differences do not alone determine the reinnervation pathway of the motor neurons, [15] as demonstrated in a study done in a mouse femoral nerve, where the size of the pathways were manipulated, leading to incorrect motor axon pathway reinnervation. [16]

PMR influencing factors

End organ contact

End-organ contact can also have a major effect on the reinnervation accuracy of the axon. The first two weeks following the damage, it is statistically insignificant, because end-plate reinnervation is just starting. However, after that time period, end-organ contact plays a role in influencing the reinnervation ability of the axon. When the end of the pathway is a muscle contact area, there is a significant difference in the number of motor neurons reinnervating. [2] [15]

Cellular and molecular mechanisms

These are trophic factors that are discussed in detail in above sections. These factors can influence where an axon grows towards, mostly from chemotaxis effects that the different proteins have on the growing axon's directionality. The trophic factors differ between motor and sensory pathways, which is a major influential factor in preferential motor reinnervation. [12] [14] [17]

Terminal nerve branch size

The terminal nerve branch size has a lot of influence on the reinnervation pathway of the axon. When two pathways, one cutaneous and one motor, are roughly comparable in size, the motor axons follow preferential reinnervation patterns along the motor pathways. However, enlargement of sensory pathways in the same experiment led to the motor axons to reinnervate those pathways, indicating that trophic factors alone do not cause reinnervation of motor neurons. This is shown because the motoneurons wrongly reinnervate down pathways that are sensory, thus demonstrating that the size of the terminal nerve branch pathway can affect the axonal reinnervation patterns. [16]

Reinnervation accuracy

The ability of an axon to "choose" the accurate Schwann cell and eventually site of innervation is interconnected to preferential motor reinnervation. The specificity of a motor axon to preferentially choose the motor pathway is the very essence of preferential motor reinnervation. Additionally, it influences whether or not a nerve can truly experience full reinnervation and recovery of function that is likened to what it had before the injury. Thus, this accuracy influences whether or not a motor axon preferentially reinnervates. Different studies are investigating how an axon pathway specificity can be manipulated in order to see what kind of surgical advances can be made regarding neuron repair. [1] [15]

Use in medicine

The varied accuracy of damaged axons regenerating and reaching their original target end is a large reason that functional recovery of damaged nerves is such a variable in the peripheral nervous system. [10] The understanding of what Schwann cell tube axons tend to reinnervate has implications for whether a nerve will be able to become functional again after damage. If the axon is a subcutaneous axon and ends up in a motor Schwann cell tube, it will not be able to innervate the muscle it ends up connected to. Thus, understanding how axons do reinnervate, and how motor axons can be pushed towards the correct regeneration site is an area of study that is extremely beneficial in helping to advance nerve repair in the PNS system.

In 2004, a study looked at how Lewis rats' sensory vs motor nerve grafts affected the regeneration of a cut mixed nerve system (both motor and sensory nerves). It was noted that after 3 weeks, a mixed nerve defect had undergone substantial regeneration when paired with a motor nerve graft or a mixed nerve graft. In comparison, a sensory nerve graft was statistically less affective in regeneration, looking specifically at nerve fiber count, percent nerve, and nerve densities as the main three comparisons between the different grafts. This means that the best surgical practices in regenerating nerves regarding PMR is using a nerve graft that is either a motor or a combination nerve graft. [18]

In a study published in 2009, the terminal nerve branch size was investigated to see how it affected nerve regeneration. It was discovered that the branches of similar size initially regenerated about equally between cutaneous and muscular pathways, but after a while favored muscle branch paths. The study end results predicted that axonal collateral formation at the injured site being increased could increase regeneration accuracy. Understanding PMR affects would help overall in gaining a better understanding of the forces that influence the neuron repair, which was the overall conclusion of what was needed to help nerves functionally repair. This increasing understanding will overall impact surgical and repair processes with peripheral nerve repair. Though manipulation of axonal collateral formation may help, the further understanding of PMR will allow for the surgical practices and medical advances in nerve repair to continue developing. [15] [16]

Related Research Articles

<span class="mw-page-title-main">Axon</span> Long projection on a neuron that conducts signals to other neurons

An axon or nerve fiber is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

Myelin is a lipid-rich material that surrounds nerve cell axons to insulate them and increase the rate at which electrical impulses pass along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon segmentally: in general, each axon is encased in multiple long sheaths with short gaps between, called nodes of Ranvier. At the nodes of Ranvier, which are approximately one thousandth of a mm in length, the axon's membrane is bare of myelin.

<span class="mw-page-title-main">Nerve</span> Enclosed, cable-like bundle of axons in the peripheral nervous system

A nerve is an enclosed, cable-like bundle of nerve fibers in the peripheral nervous system.

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Motor nerve</span> Nerve located in the central nervous system

A motor nerve, or efferent nerve, is a nerve that contains exclusively efferent nerve fibers and transmits motor signals from the central nervous system (CNS) to the muscles of the body. This is different from the motor neuron, which includes a cell body and branching of dendrites, while the nerve is made up of a bundle of axons. Motor nerves act as efferent nerves which carry information out from the CNS to muscles, as opposed to afferent nerves, which transfer signals from sensory receptors in the periphery to the CNS. Efferent nerves can also connect to glands or other organs/issues instead of muscles. The vast majority of nerves contain both sensory and motor fibers and are therefore called mixed nerves.

<span class="mw-page-title-main">Somatic nervous system</span> Part of the peripheral nervous system

The somatic nervous system (SNS) is made up of nerves that link the brain and spinal cord to voluntary or skeletal muscles that are under conscious control as well as to skin sensory receptors. Specialized nerve fiber ends called sensory receptors are responsible for detecting information within and outside of the body.

<span class="mw-page-title-main">Wallerian degeneration</span> Biological process of axonal degeneration

Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury degenerates. A related process of dying back or retrograde degeneration known as 'Wallerian-like degeneration' occurs in many neurodegenerative diseases, especially those where axonal transport is impaired such as ALS and Alzheimer's disease. Primary culture studies suggest that a failure to deliver sufficient quantities of the essential axonal protein NMNAT2 is a key initiating event.

Axonotmesis is an injury to the peripheral nerve of one of the extremities of the body. The axons and their myelin sheath are damaged in this kind of injury, but the endoneurium, perineurium and epineurium remain intact. Motor and sensory functions distal to the point of injury are completely lost over time leading to Wallerian degeneration due to ischemia, or loss of blood supply. Axonotmesis is usually the result of a more severe crush or contusion than neurapraxia.

Neural engineering is a discipline within biomedical engineering that uses engineering techniques to understand, repair, replace, or enhance neural systems. Neural engineers are uniquely qualified to solve design problems at the interface of living neural tissue and non-living constructs.

<span class="mw-page-title-main">Alpha motor neuron</span> Large lower motor neurons of the brainstem and spinal cord

Alpha (α) motor neurons (also called alpha motoneurons), are large, multipolar lower motor neurons of the brainstem and spinal cord. They innervate extrafusal muscle fibers of skeletal muscle and are directly responsible for initiating their contraction. Alpha motor neurons are distinct from gamma motor neurons, which innervate intrafusal muscle fibers of muscle spindles.

<span class="mw-page-title-main">Nerve injury</span> Damage to nervous tissue

Nerve injury is an injury to a nerve. There is no single classification system that can describe all the many variations of nerve injuries. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, nerve injuries are classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved.

Neuroregeneration involves the regrowth or repair of nervous tissues, cells or cell products. Neuroregenerative mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

Neural tissue engineering is a specific sub-field of tissue engineering. Neural tissue engineering is primarily a search for strategies to eliminate inflammation and fibrosis upon implantation of foreign substances. Often foreign substances in the form of grafts and scaffolds are implanted to promote nerve regeneration and to repair damage caused to nerves of both the central nervous system (CNS) and peripheral nervous system (PNS) by an injury.

A nerve guidance conduit is an artificial means of guiding axonal regrowth to facilitate nerve regeneration and is one of several clinical treatments for nerve injuries. When direct suturing of the two stumps of a severed nerve cannot be accomplished without tension, the standard clinical treatment for peripheral nerve injuries is autologous nerve grafting. Due to the limited availability of donor tissue and functional recovery in autologous nerve grafting, neural tissue engineering research has focused on the development of bioartificial nerve guidance conduits as an alternative treatment, especially for large defects. Similar techniques are also being explored for nerve repair in the spinal cord but nerve regeneration in the central nervous system poses a greater challenge because its axons do not regenerate appreciably in their native environment.

<span class="mw-page-title-main">Group C nerve fiber</span> One of three classes of nerve fiber in the central nervous system and peripheral nervous system

Group C nerve fibers are one of three classes of nerve fiber in the central nervous system (CNS) and peripheral nervous system (PNS). The C group fibers are unmyelinated and have a small diameter and low conduction velocity, whereas Groups A and B are myelinated. Group C fibers include postganglionic fibers in the autonomic nervous system (ANS), and nerve fibers at the dorsal roots. These fibers carry sensory information.

<span class="mw-page-title-main">Olfactory ensheathing cell</span> Type of macroglia that ensheath unmyelinated olfactory neurons

Olfactory ensheathing cells (OECs), also known as olfactory ensheathing glia or olfactory ensheathing glial cells, are a type of macroglia found in the nervous system. They are also known as olfactory Schwann cells, because they ensheath the non-myelinated axons of olfactory neurons in a similar way to which Schwann cells ensheath non-myelinated peripheral neurons. They also share the property of assisting axonal regeneration.

Erythropoietin in neuroprotection is the use of the glycoprotein erythropoietin (Epo) for neuroprotection. Epo controls erythropoiesis, or red blood cell production.

<span class="mw-page-title-main">Epineurial repair</span>

Epineurial repair is a common surgical procedure to repair a nerve laceration via the epineurium, the connective tissue surrounding nerve fibers originating from the spinal cord. It is intended to allow the restoration of sensory function. When a nerve is lacerated or cut, repair is done by sewing the cut ends together through the epineurium to increase the potential of the proximal part growing correctly along the route the degrading distal part leaves behind. Usual sensation and mobility will not be an immediate result because nerves grow at a rate of approximately 1 millimeter per day, so it will take a few months to notice the final outcome. Research in use of nerve grafts and nerve growth factors is being done to speed recovery time.

Nerve allotransplantation is the transplantation of a nerve to a receiver from a donor of the same species. For example, nerve tissue is transplanted from one person to another. Allotransplantation is a commonly used type of transplantation of which nerve repair is one specific aspect.

Perisynaptic schwann cells are neuroglia found at the Neuromuscular junction (NMJ) with known functions in synaptic transmission, synaptogenesis, and nerve regeneration. These cells share a common ancestor with both Myelinating and Non-Myelinating Schwann Cells called Neural Crest cells. Perisynaptic Schwann Cells (PSCs) contribute to the tripartite synapse organization in combination with the pre-synaptic nerve and the post-synaptic muscle fiber. PSCs are considered to be the glial component of the Neuromuscular Junction (NMJ) and have a similar functionality to that of Astrocytes in the Central Nervous System. The characteristics of PSCs are based on both external synaptic properties and internal glial properties, where the internal characteristics of PSCs develop based on the associated synapse, for example: the PSCs of a fast-twitch muscle fiber differ from the PSCs of a slow-twitch muscle fiber even when removed from their natural synaptic environment. PSCs of fast-twitch muscle fibers have higher Calcium levels in response to synapse innervation when compared to slow-twitch PSCs. This balance between external and internal influences creates a range of PSCs that are present in the many Neuromuscular Junctions of the Peripheral Nervous System.

References

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  11. ↑ Abdullah, M.; O'Daly, A; Vyas, A; Rohde, C.; Brushart, T. M. (2013). "Adult motor axons preferentially reinnervate predegenerated muscle nerve". Experimental Neurology. 249C: 1–7. doi:10.1016/j.expneurol.2013.07.019. PMC   3818708 . PMID   23933577.
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  13. ↑ Deister, C.; Schmidt, C. E. (2006). "Optimizing neurotrophic factor combinations for neurite outgrowth". Journal of Neural Engineering. 3 (2): 172–9. Bibcode:2006JNEng...3..172D. doi:10.1088/1741-2560/3/2/011. PMID   16705273.
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  18. ↑ Nichols, C. M.; Brenner, M. J.; Fox, I. K.; Tung, T. H.; Hunter; Rickman, S. R.; Mackinnon, S. E. (2004). "Affects of motor versus sensory nerve grafts on peripheral nerve regeneration". Experimental Neurology. 190 (2): 347–55. doi:10.1016/j.expneurol.2004.08.003. PMID   15530874. S2CID   36508970.
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