Chapter 27 Neural Plasticity After Nerve Injury and Regeneration
Introduction
Injuries to the peripheral nerves result in a partial or total loss of motor, sensory, and autonomic functions mediated by the lesioned nerves to the denervated segments of the body due to the interruption of axons, degeneration of nerve fibers distal to the lesion, and eventual death of axotomized neurons. Injuries to the peripheral nervous system can result in substantial functional loss and decreased quality of life because of permanently impaired sensory and motor functions and secondary problems, such as neuropathic pain.
Functional deficits caused by nerve injuries can be compensated by three neural mechanisms: the reinnervation of denervated targets by regeneration of injured axons, the reinnervation by collateral sprouting of undamaged axons in the vicinity, and the remodeling of nervous system circuits. However, clinical and experimental evidences demonstrate that such mechanisms do not usually allow for a satisfactory functional recovery after severe nerve injuries (Kline and Hudson, 1995, Lundborg, 2004, Sunderland, 1991). The capability of transected nerves to regenerate and recover functional connections is dependent on the age of the subject, the site and type of lesion, the type and delay of surgical repair, and the distance over which axons must regrow to span the injury. Despite that fact that peripheral nerve fibers are able to regenerate across the injury site and along the distal nerve, reinnervation of target organs does not always lead to adequate recovery of motor and sensory functions. The selectivity of axon‐target reconnection plays an important role in the impairment of function after nerve injury and regeneration. Misdirection of regenerated axons leads to inappropriate reinnervation of end organs (Bodine‐Fowler et al., 1997, Molander and Aldskogius, 1992, Valero‐Cabré et al., 2004), although preferential motor reinnervation has been observed as the result of progressive withdrawal or pruning of misdirected axons (Brushart, 1993). On the other hand, collateral reinnervation has temporal and spatial constraints, especially for large sensory and motor axons (Brown et al., 1980, Jackson and Diamond, 1984), although it is helpful to recover cutaneous pain sensibility and motor strength in partially denervated muscles.
Factors contributing to poor functional recovery after peripheral nerve injuries include the following: (1) damage to the neuronal cell body due to axotomy and retrograde degeneration, excluding the possibility of regeneration; (2) inability for axonal growth due to the nerve lesion or underlying diseases; (3) poor specificity of reinnervation by regenerating axons, when target organs become reinnervated by nerve fibers of different function; (4) changes in the central circuits in which the injured neurons participate due to plasticity of neural connections. Nowadays, there are no repair techniques that ensure the recovery of normal sensorimotor functions following severe nerve trauma, and it is generally agreed that a plateau has been reached for the refinement of surgical repair techniques (Lundborg, 2000a). New therapeutic strategies are needed to potentiate axonal regeneration, promote selective target reinnervation, and modulate central reorganization.
The peripheral and central nervous systems are functionally integrated regarding the consequences of a nerve injury: a peripheral nerve lesion always results in profound and long‐lasting central modifications and reorganization (Kaas, 1991, Navarro et al., 2007, Wall et al., 2002). The mechanisms of plasticity and reorganization of spinal and brain circuits linked with the axotomized neurons are complex; they may result in either beneficial adaptative functional changes or maladaptive changes resulting in positive symptoms, such as pain, disesthesia, hyperreflexia, and dystonia. Plastic changes occur at the molecular, cellular, and circuit levels and affect injured neurons as well as neurons that interconnect with them and glial cells (Fig. 1).
Section snippets
Neuronal Survival and Reaction to Axotomy
After nerve injuries, axons distal to the lesion site are disconnected from the neuronal body and degenerate. The axotomized neurons undergo a series of phenotypic changes, known as neuronal reaction and chromatolysis, which represent the changes necessary for survival and axonal regeneration (Fu and Gordon, 1997, Verdú and Navarro, 1998). The success of nerve regeneration depends at a first instance on the capacity of axotomized neurons to survive and shift toward a regenerative phenotype. The
Plastic Changes and Remodeling at the Spinal Cord
Nerve injury may sensitize and induce remodeling of central neural structures. Experimental evidence of these changes is illustrated by the development of wind‐up, classic central sensitization, long‐term potentiation (LTP), distortion of receptive fields of CNS neurons, as well as the enhancement of spinal reflexes and the persistence of pain or hyperalgesia (Melzack et al., 2001, Woolf and Salter, 2000).
Plastic Changes and Reorganization at Cortical and Subcortical Levels
Functional reorganization of sensory and motor systems following peripheral nerve damage affects neural networks including spinal cord, brainstem, thalamus, and cortical regions directly or indirectly involved in the processing of the impacted functions (for review see Chen et al., 2002, Kaas, 1999, Kaas, 1991, Lundborg, 2000b, Navarro et al., 2007, Wall et al., 2002). Injuries in a nerve or root induce a cascade of functional changes progressing to reorganization of the entire pathway, from
Remodeling CNS Plasticity
Peripheral nerve injury induces dramatic processes of reorganization in structures across the neuraxis. These changes consist of decrease of excitability, metabolism, and surface extension of the disconnected central substrates with compensatory enhancement of neighboring representations. Plastic reorganization changes are reversible provided that adequate patterns of activity conveyed by regenerated peripheral axons are reinstated. However, when nerve regeneration is hampered or when profound
Acknowledgments
The author's research was supported by grants from the the Ministerio de Sanidad y Consumo (PI060201) of Spain, the European Commission (NEUROBOTICS project, IST‐001917; TIME project, ICT‐ 224012), and FEDER funds.
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