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Following arm amputation the region that represented the missing hand in primary somatosensory cortex (S1) becomes deprived of its primary input, resulting in changed boundaries of the S1 body map. This remapping process has been termed 'reorganisation' and has been attributed to multiple mechanisms, including increased expression of previously masked inputs. In a maladaptive plasticity model, such reorganisation has been associated with phantom limb pain (PLP). Brain activity associated with phantom hand movements is also correlated with PLP, suggesting that preserved limb functional representation may serve as a complementary process. Here we review some of the most recent evidence for the potential drivers and consequences of brain (re)organisation following amputation, based on human neuroimaging. We emphasise other perceptual and behavioural factors consequential to arm amputation, such as non-painful phantom sensations, perceived limb ownership, intact hand compensatory behaviour or prosthesis use, which have also been related to both cortical changes and PLP. We also discuss new findings based on interventions designed to alter the brain representation of the phantom limb, including augmented/virtual reality applications and brain computer interfaces. These studies point to a close interaction of sensory changes and alterations in brain regions involved in body representation, pain processing and motor control. Finally, we review recent evidence based on methodological advances such as high field neuroimaging and multivariate techniques that provide new opportunities to interrogate somatosensory representations in the missing hand cortical territory. Collectively, this research highlights the need to consider potential contributions of additional brain mechanisms, beyond S1 remapping, and the dynamic interplay of contextual factors with brain changes for understanding and alleviating PLP., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Previous studies have indicated that amputation induces reorganization of functional brain network. However, the influence of amputation on structural brain network remains unclear. In this study, using diffusion tensor imaging (DTI), we aimed to investigate the alterations in fractional anisotropy (FA) network after unilateral upper-limb amputation. We acquired DTI from twenty-two upper-limb amputees (15 dominant-side and 7 nondominant-side amputees) as well as fifteen healthy controls. Using DTI tractography and graph theoretical approaches, we examined the topological changes in FA network of amputees. Compared with healthy controls, dominant-side amputees showed reduced global mean strength, increased characteristic path length, and decreased nodal strength in the contralateral sensorimotor system and visual areas. In particular, the nodal strength of the contralateral postcentral gyrus was negatively correlated with residual limb usage, representing a use-dependent reorganization. In addition, the nodal strength of the contralateral middle temporal gyrus was positively correlated with the magnitude of phantom limb sensation. Our results suggested a degeneration of FA network after dominant-side upper-limb amputation.

We report the case of a patient who had an important experience with painful events, allowing the investigation of brain concomitants to painful (P) memories in fMRI. The patient had to recall P events that were contrasted with non-painful (NP) memories. Painful memories of the right lower limb activated the left paracentral lobule,fronto-insular operculum and superior parietal cortex. Additionally, whilst the recall of non-painful events activated the hippocampus, the recall of painful events did not enhance the hippocampal signal to significant levels. These suggest that brain activations differ for the autobiographical recall of painful and non-painful memories.

Pain and other phantom limb (PL) sensations have been proposed to be generated in the brain and to be reflected in activation of specific neural circuits. To test this hypothesis, hypnosis was used as a cognitive tool to alternate between the sensation of PL movement and pain in 8 amputees. Brain activity was measured using positron emission tomography. PL movement and pain were represented by a propagation of neuronal activity within the corresponding sensorimotor and pain-processing networks. The sensation of movement was significantly (corrected for multiple comparisons) related to activity in the supplementary motor area and the primary sensorimotor cortex. The sensation of a painful PL posture activated the same brain areas but was weaker and less extended in the supplementary motor area. In contrast to the sensation of movement, pain was significantly related to activity in the thalamus, anterior cingulate, and lateral prefrontal cortex. Subjectively rated PL pain sensation correlated positively to activations in the anterior and posterior cingulate. These findings provide evidence that PL sensations are produced by the same central nervous processes that underlie the experience of the body when it is intact and that the corporeal awareness of PL pain is encoded in a thalamocortical network.

To explore the possible mechanisms of phantom limb discomfort after amputation, three amputees with phantom limb pain were studied. This study examined the change of regional cerebral blood flow using technetium-99m hexamethylpropyleneamine oxime-single photon emission computerized tomography, which was arranged at the time of severe phantom limb discomfort and after the discomfort subsided or was completely relieved. Nine representative transverse slices parallel to the orbitomeatal line were selected for quantification. The cortical ribbon (2-cm thickness) was equally subdivided into 12 symmetrical pairs of sector regions of interest in each slice. The irregularly shaped regions of interest were drawn manually around the right thalamus and basal ganglion and then mirrored to the left thalamus and basal ganglion. The contralateral to ipsilateral ratio of regional cerebral blood flow for each area was calculated. The intensity of phantom limb pain was evaluated on a 0 to 10 visual analog scale. In Cases 1 and 2, the contralateral to ipsilateral regional cerebral blood flow ratios of multiple areas of the frontal, temporal, or parietal lobes were increased at the time of more severe phantom limb pain, and the ratios were normalized or even decreased when the phantom limb pain subsided. In Case 3, increased contralateral to ipsilateral regional cerebral blood flow ratios were also found over the frontal, temporal, and parietal lobe. However, most of the increased regional cerebral blood flow ratios of regions of interest in the first study persisted in the follow-up study. Also, the regional cerebral blood flow ratios of greater number of regions of interest of the same gyrus and new gyrus were increased. There was no significant right-left difference of regional cerebral blood flow over bilateral thalami and basal ganglia in all three cases. The results suggested that phantom limb pain might be associated with cortical activation involving the frontal, temporal, or parietal cortex, and it may imply the possibility of the existence of an ascending polysynaptic pathway that conveys the uncomfortable phantom limb sensation to the cerebral cortex. These findings may also indicate that reorganization of the cortical blood flow occurs in amputees. However, it is still difficult to conclude that the changes in regional cerebral blood flow were attributable directly to pain. With no comparison group of amputees and because of the small number of cases, it is hard to generalize about cerebrocortical involvement in phantom pain, and it is possible that the findings represent a normal phenomenon seen after 'amputation. Another possibility is that the findings represent increased arousal caused by pain rather than an intrinsic pain pathway. Further study is worthwhile.