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Page 6 of 12 Tanner et al. Plast Aesthet Res 2023;10:11 https://dx.doi.org/10.20517/2347-9264.2022.95

Successful nerve regeneration is established when neurotransmission through the injured neuron is
restored [17,21] . Axon sprouts that successfully enter the distal target will become re-myelinated and grow
[13]
stronger with use . Once regeneration is complete, chromatolysis is reversed and cell function returns to
[17]
normal .

NEUROMA FORMATION/FAILURE OF REGENERATION
[17]
Nerve regeneration can fail at any step in this process . If the cell body is injured, retrograde chromatolysis
may result in the production of apoptotic proteins and cell death [17,26] . If regenerative axon sprouts fail to
cross the injury site due to large gaps, a physical barrier formed by scarring, or other factors, the axon
sprouts will form a neuroma . Aberrant sprouting may occur in limb amputation when nerves are not
[17]
[10]
given a new target . Neuromas are a common cause of postamputation pain and may negatively impact
the function and quality of life of amputees .
[3,4]
Collateral axonal branching is frequently misdirected and can cause improper innervation of distal
targets [27,28] . For instance, nearby sensory nerves can branch to reinnervate the distribution of an injured or
cut motor neuron [27,28] . This can produce painful hyperalgesia that is often misinterpreted as neuroma
pain . The hyperalgesia due to the collateral branching of sensory axons produces a burning sensation and
[28]
hypersensitivity to touch . However, collateral branching does not contribute to neuroma formation and is
[28]
[28]
not amenable to surgery. It can be treated with desensitization therapy .
PHANTOM LIMB SENSATIONS AND PAIN
PLS are any non-painful sensations that occur in the missing body part after amputation [29,30] . Over 90% of
amputees experience PLS in the first 6 months . Phantom sensations may include feelings of movement,
[30]
touch, tingling, itching, or paresthesia in the missing limb .
[31]
The causes of phantom sensations are not well understood and are thought to involve both peripheral and
central mechanisms. After amputation surgery, neuroma formation and abnormal spontaneous neuronal
activity at the proximal end of the cut peripheral nerves may contribute to phantom sensations [32,33] .
Neuromata have been shown to correlate with increased duration and intensity of phantom sensations and
phantom limb pain . Also, injured peripheral nerves have upregulated sodium channels, causing increased
[33]
sensitivity to mechanical stimulation and abnormal firing [32,33] . The increased sensitivity of the injured nerves
decreases the pressure pain threshold, which may explain why some amputees experience increased PLS
and PLP with prosthetic use [32,33] .

PLS are also thought to be modulated via central mechanisms. The somatosensory homunculus in the
cortex of the brain receives sensory, positional, and movement information from peripheral nerves . The
[34]
cortical representation of an amputated limb likely persists for some time after limb amputation resulting in
a phantom limb . Reorganization of the somatosensory cortex may also underlie phantom sensations .
[35]
[34]
Neurons in the somatosensory cortex that previously responded to signals from the missing limb can begin
[35]
to respond to signals from other nearby neurons . As a result, stimulation of nerves in other parts of the
body can be aberrantly received by the neurons of the amputated limb in the somatosensory cortex, causing
sensations to be improperly perceived . Phantom limbs usually change and fade over time, and most PLS
[35]
disappear after 2 to 3 years . However, PLS may become painful and develop into phantom limb pain in
[4]
about 45% of patients [34,36] .