• Giovanni DI Pino, Valeria Piombino, Massimiliano Carassiti, and Max Ortiz-Catalan.
• Research Unit of Neurophysiology and Neuroengineering of Human-Technology Interaction (NeXTlab), Campus Bio-Medico University, Rome, Italy - g.dipino@unicampus.it.
• Minerva Anestesiol. 2021 Apr 1; 87 (4): 481-487.

AbstractPhantom Limb Pain (PLP) is a dysesthesic painful sensations perceived in the lost limb, resulting from complex interactions between structural and functional nervous systems changes. We analyze its main pathogenetic models and speculate on candidate therapeutic targets. The neuroma model considers PLP to arise from spontaneous activity of residual limb injured axons. Other peripheral-origin models attribute PLP to damage of somatosensory receptors or vascular changes. According to the cortical remapping model, the loss of bidirectional nervous flow and the need to enhance alternative functions trigger reorganization and arm and face skin afferents "invade" the hand territory. On the contrary, the persistent representation model suggests that continued inputs preserve the lost limb representation and that, instead to a shrinkage, PLP is associated with larger representation and stronger cortical activity. In the neuromatrix model, the mismatch between body representation, which remains intact despite limb amputation, and real body appearance generates pain. Another hypothesis is that proprioceptive memories associate specific limb positions with pre-amputation pain and may be recalled by those positions. Finally, the stochastic entanglement model offers a direct relationship between sensorimotor neural reorganization and pain. Amputation disrupts motor and somatosensory circuits, allowing for maladaptive wiring with pain circuits and causing pain without nociception. Relief of PLP depends solely on motor and somatosensory circuitry engagement, making anthropomorphic visual feedback dispensable. Existing and apparently contradicting theories might not be mutually exclusive. All of them involve several intertwined potential mechanisms by which replacing the amputated limb by an artificial one could counteract PLP.

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