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Tanner et al. Plast Aesthet Res 2023;10:11 https://dx.doi.org/10.20517/2347-9264.2022.95 Page 7 of 12

Phantom limb pain is a complex interplay between neuromas and the central nervous system. PLP is a type
of neuropathic pain that can include burning, throbbing, crushing, cramping, or sharp pain in the missing
[36]
limb . Cortical reorganization is a key component of PLP, and it is even more difficult than neuroma pain
[4]
to prevent or reverse . Therefore, treating neuromas may prevent cortical reorganization and further
centralization of PLP [4,34] . In a prospective, multicenter, randomized clinical trial, Dumanian et al. found
evidence that TMR significantly decreases phantom pain in major limb amputees compared to standard
treatment at 1 year . Therefore, TMR may prevent PLS and PLP by addressing the contribution of
[4]
peripheral nerve injury to these experiences.

SIZE MISMATCH AND AXONAL PRUNING
TMR often involves a size mismatch between the donor and recipient nerves at the nerve coaptation site
[37]
[Figure 4]. The ideal nerve coaptation is a 1:1 diameter ratio and the recommended size ratio is less than
[20]
2:1 . However, the current practice is to accept large size mismatches in TMR . Depending on the
[37]
available anatomy, the physiological and clinical implications of the size mismatch are unknown, but Kim
et al. and Dumanian et al. found that patients having TMR did not develop symptomatic neuromas at nerve
coaptation sites despite large size mismatches [4,10] . No prior works have addressed why TMR is successful
despite large size mismatches between the donor and recipient nerves. Kim et al. posited that there is likely a
critical mass effect where TMR is successful after enough targets are provided for the regenerating nerve
sprouts . However, this does not explain what comes of the growing nerve sprouts that fail to reach their
[10]
targets.

A possible theory to explain why TMR works despite a large size discrepancy between transferred nerves is
the process of axonal pruning. Axonal pruning is selective axon degeneration that removes unnecessary,
misguided, or excessive axon sprouts while maintaining the integrity of the cell body [26,38,39] [Figure 5]. Singh
et al. showed that during axon competition, active (i.e., winning) axons can eliminate less active, competing
[40]
axons by axonal pruning . Axonal pruning is well established in the development of the CNS and
PNS [26,40] . Selective degradation of axons that unsuccessfully innervate their targets or are no longer
necessary allows for optimal wiring of neural connections in the developing nervous system .
[26]

Axonal pruning has previously been described in the context of nerve injury. Following an injury to a mixed
peripheral nerve, regenerating motor axons will preferentially enter both sensory and motor Schwann cell
tubes over regenerating sensory axons . The preferential motor reinnervation of distal targets - known as
[42]
preferential motor reinnervation (PMR) - is made possible by the pruning of sensory axon sprouts while
maintaining motor axons [27,42] [Figure 6]. We believe axonal pruning may explain the elimination of
misguided axonal sprouting in TMR, allowing for successful reinnervation despite large size mismatches
between the donor and recipient nerves.

Axonal pruning is distinct from Wallerian degeneration and neuronal apoptosis, although all three
[26]
processes result in axon degeneration . A key feature of axonal pruning is the selective, controlled
degradation of axon fibers without inflammation or damage to the cell body . As previously described,
[26]
Wallerian degeneration is an inflammatory reaction that occurs in response to nerve injury , while
[17]
[26]
apoptosis is the programmed death of the entire neuron, including the axon and cell body . The apoptosis
pathway is highly restricted after development as neurons cannot regenerate . Axonal pruning, however, is
[44]
critical to adult neural plasticity, as it permits the selective loss of specific axon sprouts while maintaining
nearby axon segments and the integrity of the cell body . Therefore, axonal pruning is the most likely
[26]
mechanism to explain the behavior of axon sprouts at nerve coaptation sites in TMR.