In this study of PLP in upper limb amputees, the remarkably simple technique of imagining movement and sensation in the missing limb resulted in significant pain relief. All subjects found learning the body scan useful as a means of relaxation, regardless of whether their pain lessened, and they all felt that the body scan was a useful facilitator to imagining the return of the phantom limb.
Other researchers have reported the clinical benefit of imagined and virtual movement in patients with long-standing pain conditions. Moseley (2006
) demonstrated significant pain relief in patients with complex regional pain syndrome (CRPS) and PLP when they first learned to improve laterality recognition using photographs of hands in varying positions, and then learned to imagine the injured hand in non-painful postures. Mirror therapy has also been reported to have an analgesic effect in PLP (Chan et al
). So it seems that different ways of stimulating the motor and sensory cortices can be effective in relieving pain. Cortical reorganization patterns have also been shown to be a feature of CRPS, with changes in somatotopic cortical maps which normalize upon symptomatic recovery due to physiotherapy (Maihofner et al
) or treatment with memantine (Sinis et al
The primary focus of the present study was to evaluate the relationship between cortical reorganization, the various forms of pain in patients with phantom limb pain syndrome and the analgesic effect of mental imagery. We employed lip purse as a tool to demonstrate activation, measured by fMRI, in the hand area; such activation is not seen in healthy participants and is best explained by a change in the excitability of cortical neurons previously responsive to functions involving the hand or arm only. The relevance of this finding comes from the direct correlation between the hand area activation and contemporaneous pain (i.e. pain experienced during scanning), and is emphasized by the fact that, with significant pain reduction during the second scanning session, no such abnormal activation was elicited. That the association was seen in contemporaneous pain only and not with the pain scores obtained from pain diaries, suggests that in a given patient with PLP the at-present state of pain is a better indication of reorganization than is a general disposition of pain. Disappearance on the post-training scan of this abnormal activation in the patients, who for the major part experienced significant pain relief, points in the same direction. The contemporaneous pain scores on that occasion were so low that no correlation with them and the BOLD signal in the hand area could be reasonably expected; indeed none was found.
Another tool used in this study to measure cortical reorganization was that of imagined movement of the phantom. A novel finding in the present study was that cortical reorganization appears to have taken place in a more random fashion than previously thought, although such a finding supports clinical observations such as sensory experiences in the head reported by patients with a phantom arm (Ramachandran and Hirstein, 1998
). Imagined movement of the phantom hand led to activation of the lip area which was not seen in healthy volunteers, which may be a form of ‘reverse’ functional reorganization (H→F). Interestingly, however, this change did not covary with any pain type. We conclude that this abnormality is likely to represent the effect of amputation per se
and may not be critical for the development of pain. In line with this, movement of the intact hand resulted in activation of the ipsilateral lip area in the motor strip (i.e. contralateral to the phantom) and was also devoid of any covariance with pain scores.
Additionally, we were impressed by the consistent extensive activation of the M1 and S1 hand representation area contralateral to the phantom, irrespective of the task (lip purse, imagined movement of the phantom, imagined movement of the intact arm or executed movement of the intact arm). This kind of universal activation, exemplifying a lack of neural efficiency has been reported by others using motor evoked potentials (MEP; Cohen et al
); transcranial magnetic stimulation (TMS; Roricht et al
; Karl et al
) and fMRI (Lotze et al
). Interestingly, this excessive activation during intact arm movement, which was lacking in controls, covaried with constant pain, and adds to the significance of altered activity in M1/S1 region following nervous system injury (Navarro et al
It has been proposed that the perception of phantom movement relies upon the preservation of a cortical representation of the missing limb, itself dependent upon intact neuronal connections (Mercier et al
; Reilly et al
). It is of interest that our patients recognized improvement in freedom of movement of the phantom as training progressed, suggesting they achieved better mental access to the deafferented cortical areas (Mercier et al
). The decrease in activation post-training seen in this area is likely to reflect improved neural efficiency and precision, similarly to that seen after other forms of cognitive training (Kelly et al
). A further interesting finding was the extensive bilateral activation in primary sensory and motor cortices observed in patients during every task.
Against this background it is of interest that during active movement of the intact limb, our patient group showed increased activation in the M1 and S1 hand areas contralateral to the phantom (ipsilateral to the intact arm) that at baseline correlated with the intensity of constant pain. Activation of ipsilateral S1 and M1 has been shown in patients with neuropathic pain in response to provocation of allodynic pain (Peyron et al
). Our finding needs to be interpreted with caution, however. First, no patient reported any pain associated with the increased use of the intact arm and secondly, functional cortical reorganization, both inter- and intra-hemispheric, is well documented in the brain imaging literature in models of health and disease (Pascual-Leone et al
). Although earlier primate studies suggest that cortical reorganization after amputation in primates is contralateral from neighbouring areas of the somatotopic map (Wu and Kaas, 1999
), a later study using an animal model of extensive hind- and forepaw surgical peripheral denervation has established bilateral cortical–cortical reorganization (Pelled et al
Bilateral cortical activation is reported in amputees without pain. Hamzei et al
) studied seven participants who had been missing an arm since childhood (six amputees and one dysmelia)—all demonstrated bilateral structural and functional cortical changes [measured using MRI, fMRI and transcranial stimulation mapping (TMS)], including contralateral and ipsilateral M1 activation in response to finger tapping. Similar bilateral activation has been shown in lower limb amputees using TMS during movement of the intact limb (Schwenkreis et al
). Kelly and Garavan (2005
) suggest that in healthy volunteers, cortical plasticity in response to the challenge of learning a new task (in our case, mental imagery of the phantom) has a 2-fold physiological mechanism. Developing greater motor skill rests on increased neural efficiency (demonstrated in our participants by the reduction in activation shown after regular practice of imagined movement and sensation in the phantom limb), while developing a new strategy (for example, learning to be one-armed following amputation) relates to plastic change which usually presents itself in enhancement of activation.
Thus it seems that cortical reorganization following amputation is 2-fold—with intrahemispheric reorganization from the adjacent area on the homunculus, and interhemispheric reorganization from the recruitment of horizontal connections of the intact limb representation to the deafferented cortex. Why cortical reorganization of the kind we report here is associated with pain cannot be answered. The cortical reorganization we witnessed in patients during various tasks, prior to the clinical intervention, reduced in relation to the reduction in pain, but we cannot offer evidence that the link is causative. Nevertheless, reduction of cortical reorganization (i.e. reduction of activation in contralateral M1 and S1 hand area, induced by lip purse, to sub-threshold levels in group analysis) after training in our patients covaried with reduction of their constant pain scores. Reductions in activations in ipsilateral hand MI and SI covaried with intensity of contemporaneous and constant pain intensity, and unpleasantness of exacerbation scores. These findings are supportive of the concept of a relationship between cortical reorganization and PLP as previously suggested (Lotze et al
; Flor et al
). It is reinforced by the fact that we intentionally chose an intervention that was minimalist and aimed at repeatedly activating the primary motor and sensory cortices. It is intriguing that the relationship appears to be selective: it was condensed to F → H type reorganization, and primarily associated with ongoing and constant pain, and not exacerbations. For the latter, alternative mechanisms should be explored.
While the focus of this study was on the association of pain relief and reorganization of the sensory and motor cortices, we did observe a general reduction in all brain areas during the second scan after training. These more general activations could be explored in future studies using a control group of either healthy volunteers subjected to an intervention mimicking treatment, or patients with similar amputations not subjected to treatment, to establish whether they are a pathophysiological correlate of amputation or pain or mainly reflect natural fluctuation, familiarization with imagined movement or a similar non-specific effect. A further limitation of this study lies in the fact that we have reported group results with the danger of missing individual data due to normalization. However, inspection of individual activation maps showed little variability or deviation from the mean coordinates and boundaries described in the methodology. A future study where analysis of the individual relationship between BOLD response and pain measurements may be desirable, using a technique such as flatmapping to measure the definitive spatial extent of activation maps.
In conclusion, we have shown that, significant associations exist between different types of phantom limb pain and cortical reorganization, and that regularly practiced mental imagery results in pain relief, which is associated with a reduction in cortical reorganization. These results in part corroborate previous findings and add new important information, especially in the domain of neuroplasticity, suggesting that plastic changes may be surprisingly responsive to internally generated manipulation. Challenges that remain for future research include how to establish which aspect of reorganization is related to pain, whether reorganization drives the pain or vice versa, the role of any morphological changes and investigation of measures that might prevent the maladaptive effect of amputation on the cortex. Perhaps the most pivotal question relates to the exact mechanisms, whereby cortical reorganization is linked to PLP, which no study to date has unravelled. The therapeutic efficacy of the intervention in the present study was so impressive that a controlled trial seems warranted, encompassing a design that can bring together the various therapies (imagery, laterality recognition, mirror box), to determine which virtual therapy best suits which patient.