Hypothesis of peripheral nerve regeneration induced by terminal effectors

Abstract

Peripheral nerve injury (PNI) is a common trauma in clinical practice. A number of techniques to deal with PNI repair have been designed in clinics. From these methods for nerve repairing shown to be effective in clinics, as well as related experiments, we formulated a hypothesis that PNI regeneration and functional repair are induced by terminal effectors. Regeneration of peripheral nerves is the process whereby the nerve fibers regenerated by the induction of terminal effectors establish connections with effector organs and induce the spinal cord and upper centers to recognize effector organs and to re-model them for effective innervations. The hypothesis has two major components: (1) after surgical repairing of the injured nerves, the functional localization of regenerated nerves is determined by the connected effector organs and (2) the upper nervous system enables structural remodeling and functional changes according to the functions of the effector organs.

Keywords::

• hypothesis
• induction
• peripheral nerve
• regeneration
• terminal effectors

It is difficult to treat peripheral nerve injuries (PNIs), and the effect of the repair of injured nerves depends on the effectiveness of the innervations of terminal effector organs by the regenerated nerves. Many experimental results and clinical phenomena indicate that the terminal effectors play the main role in peripheral nerve regeneration, being involved in the whole process of nerve regeneration and inducing regeneration and functional remodeling of peripheral nerves. Here we propose our hypothesis of peripheral nerve regeneration induced by terminal effectors, which will be elucidated in the present review.

Evidence supporting the hypothesis

Basis for successful surgical methods in clinics

1. Nerve translocation and transplantation (e.g., the repairing of contralateral brachial plexus with the C7 nerve in intact lateral) (Gu et al. 1998). After the completion of nerve regeneration and rehabilitation exercises over a certain period of time, the patient can achieve effective innervations of the injured limbs such as shoulder abduction and elbow flexion. It is apparent that during this process, the nervous system has new recognition of the terminal effectors: the preliminary innervations area for the nerve root of the donor C7 nerve is the upper limb in intact lateral; after regeneration, the orientation of the terminal effectors switches to contralateral from ipsilateral, while the effectors switch to the area innervated by C5–C8 nerve in the injured lateral, resulting in large changes in the location, number and function of effectors. Examining the activation changes of corresponding cortices to limbs with superconducting fMRI demonstrated increased activation of contralateral primary motor cortex following functional recovery after surgery (Perani et al. 2001). These results suggest that, following the induction of terminal effectors, the nerve centers at the spinal cord and upper levels that initially control the effectors of the C7 nerve undergo changes in orientation and differentiation of functional areas through corresponding functional and structural remodeling, establish connections with the synapses formed by the new lower nerves and terminal effectors, and finally achieve effective innervations of terminal effectors. This verifies the hypothesis of peripheral nerve regeneration induced by terminal effectors.

2. In repairing the ulnar nerve with translocation of partial branches of the median nerve, the terminal effectors of the donor nerve switch to musculatures such as interossei muscles, lumbricals and adductor pollicis, from musculatures such as flexor digitorum muscles and abductor pollicis. In repairing the upper brachial plexus with the partial median nerve, ulnar nerve, intercostal nerves or phrenic nerve by translocation, the effectors of the donor nerve switch to the effectors related to shoulder abduction and elbow flexion from corresponding effectors innervated by these nerves. Similarly, the terminal effectors need to induce the nervous system to form new recognition of the newly formed innervating area and to induce the nerve centers at the spinal cord and upper levels to recognize the effectors, remodel the function and structure, and finally achieve effective innervations (Korak et al. 2004, Muñetón-Gómez et al. 2004). These clinical phenomena verify the hypothesis of peripheral nerve regeneration induced by terminal effectors.

3. The surgery of functional reconstruction of the extensor tendon with translocation of the flexor tendon is common. The activities induced by the contraction of flexor tendon before surgery are completely different from those induced by the extensor tendon. However, following a certain period of time of functional exercise after reconstruction, the donor flexors will become the synergist of extensors to play the functions with the innervations of nerves. During this process, the nerves innervating flexors need to re-recognize the function of effectors from flexion to extension; the commands of flexion from the nerve center will be changed to commands of extension. This change needs to be achieved through corresponding remodeling of the functions and structures of nerve centers (Gansel et al. 1990, Freehafer 1998). Although these surgeries do not involve regeneration of peripheral nerves but only change the locations and functions of terminal effectors, the terminal effectors still show robust induction of nerves at different levels, which verifies the hypothesis from a lateral aspect.

4. In the surgical reconstruction of micturition function utilizing the somatic reflex transposed to the sacral nerve root, the proximal end of the ventral root above the paraplegia level and the distal end of the dorsal root innervating the bladder are anastomosed within the spinal dura mater. After a certain period of time of rehabilitation training, the patient can induce contraction of detrusor of bladder to urinate by scratching the abdominal skin, and partial patients can even achieve automatic micturition. During this process, the terminal effector, bladder smooth muscle, first induces the axons of somatic motor nerves to grow into the parasympathetic ganglion cells, the corresponding segments of spinal cord re-recognize the connection between somatic skin and bladder and achieve effective connection, which smoothly transmits the somatic reflex pulses to bladder smooth muscle allowing micturition by finally establishing the artificial reflex arc of skin-spinal cord center-bladder (Xiao et al. 1999, Xiao 2006). This process also verifies the hypothesis of peripheral nerve regeneration induced by terminal effectors.

A substantial amount of experimental data also implies the establishment of the hypothesis of peripheral nerve regeneration induced by terminal effectors

1. In the experiment where the ulnar nerve trunk is repaired with the pronator teres branch of Rhesus monkey, the number of effectors of the regenerating nerve increases, including interossei muscles and lumbricals, from the single pronator teres (Zhang et al. 2011). In addition, the recovery of the ulnar nerve function is good. In accordance with the experimental results, we predict that the terminal effector first induces the regenerated nerve fibers from the pronator teres branch to grow toward the respective effectors, then to re-recognize the newly formed synapses, and finally the nerve centers at the spinal cord and upper levels corresponding to the pronator teres branch re-integrate, during which new inter-neuronal connections may be formed. Because of the increase in the terminal effector numbers and the complicated functions, the cortical activation area of the initial pronator teres branch may be extended and differentiated into several areas with interconnection. Following a certain period of time of re-modeling, the nervous system can reach coordinated control of the terminal effectors of pronator teres. The whole process involves the establishment of the connection between the effectors and the regenerated nerve fibers induced by the terminal effectors, as well as the induction of the re-recognition of effectors by nerve centers at the spinal cord and upper levels, and the remodeling of the functions and structures in order to achieve effective innervations, that is, the hypothesis of peripheral nerve regeneration induced by terminal effectors.

2. In the experiment where the distal large nerve is connected to the small donor nerve, the number of regenerated nerve fibers can be much larger than the fiber number of the proximal donor nerve, with the maximal regeneration rate of 3.3 (Jiang et al. 2007). The more terminal effectors there are, the more nerve fibers are induced by the distal large nerve; the multiple regeneration rate is correlated with the diameter of the distal nerve and the requirement of the dynamic nerves by the terminal effectors, that is, the fiber number of the regenerated nerve shows magnified innervations according to the requirement of terminal effectors. This result proves the hypothesis of peripheral nerve regeneration induced by terminal effectors.

3. In the experiment with a multiple nerve injury repaired using a single nerve (Yin et al. 2011, Yin et al. 2011, Kou et al. 2011), the common peroneal nerve and tibial nerve of a rat are repaired, the anterior and posterior musculatures belonging to antagonistic muscles, respectively, functional recovery is achieved at a different extent following a period of time after nerve repairing, suggesting that within the central region corresponding to the common peroneal nerve structure and function re-modeling takes place and coordinated control of the corresponding effectors of the tibial nerve is achieved. This result is also consistent with the hypothesis of peripheral nerve regeneration induced by terminal effectors.

Conclusions

As stated previously, we formulated a hypothesis that PNI regeneration and functional repair are induced by terminal effectors. Regeneration of peripheral nerves is the process whereby the nerve fibers regenerated by the induction of terminal effectors establish connections with effector organs and induce the spinal cord and upper centers to recognize effector organs and to re-model for effective innervations. If correct, the hypothesis will help explain many phenomena occurring during peripheral nerve regeneration; in addition, it will provide the theoretical basis for nerve repair involving sewing injured large nerves with small nerves, repairing multiple injured nerves with a single nerve, and cross-innervation repairing in different locations.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported by a grant from Chinese National Natural Science Youth Fund (31100860), Chinese National Natural Science Fund (30971526, 31171150, 31271284), Chinese National Natural Science Fund (81171146), and Chinese Educational Ministry New Century Excellent Talents Support Project (BMU20110270).