Phantom Limb Neuroplasticity and Maladaptive Sensory Perceptions: Why Phantom Limb Paresthesia Should Be Integrated into Referred Pain Discussions.

The concept of referred pain is an integral part of the anatomy didactic content taught and discussed in all medical school curricula.  However, this discussion has excluded the topic of phantom limb pain, despite the existence of parallels in neurophysiological explanations between these conditions. This brief viewpoint attempts to reason why phantom limb paresthesia or pain should be included in the fold of refereed pain discussions.

Effects of Combined and Alone Transcranial Motor Cortex Stimulation and Mirror Therapy in Phantom Limb Pain: A Randomized Factorial Trial.

Phantom limb pain (PLP) is a frequent complication in amputees, which is often refractory to treatments. We aim to assess in a factorial trial the effects of transcranial direct current stimulation (tDCS) and mirror therapy (MT) in patients with traumatic lower limb amputation; and whether the motor cortex plasticity changes drive these results. In this large randomized, blinded, 2-site, sham-controlled, 2 × 2 factorial trial, 112 participants with traumatic lower limb amputation were randomized into treatment groups. The interventions were active or covered MT for 4 weeks (20 sessions, 15 minutes each) combined with 2 weeks of either active or sham tDCS (10 sessions, 20 minutes each) applied to the contralateral primary motor cortex. The primary outcome was PLP changes on the visual analogue scale at the end of interventions (4 weeks). Motor cortex excitability and cortical mapping were assessed by transcranial magnetic stimulation (TMS). We found no interaction between tDCS and MT groups (F = 1.90, P = .13). In the adjusted models, there was a main effect of active tDCS compared to sham tDCS (beta coefficient = -0.99, P = .04) on phantom pain. The overall effect size was 1.19 (95% confidence interval: 0.90, 1.47). No changes in depression and anxiety were found. TDCS intervention was associated with increased intracortical inhibition (coefficient = 0.96, P = .02) and facilitation (coefficient = 2.03, P = .03) as well as a posterolateral shift of the center of gravity in the affected hemisphere. MT induced no motor cortex plasticity changes assessed by TMS. These findings indicate that transcranial motor cortex stimulation might be an affordable and beneficial PLP treatment modality.

Aberrant activity in an intact residual muscle is associated with phantom limb pain in above-knee amputees.

Many individuals who undergo limb amputation experience persistent phantom limb pain (PLP), but the underlying mechanisms of PLP are unknown. The traditional hypothesis was that PLP resulted from maladaptive plasticity in sensorimotor cortex that degrades the neural representation of the missing limb. However, a recent study of individuals with upper limb amputations has shown that PLP is correlated with aberrant electromyographic (EMG) activity in residual muscles, posited to reflect a retargeting of efferent projections from a preserved representation of a missing limb. Here, we assessed EMG activity in a residual thigh muscle (vastus lateralis, VL) in patients with transfemoral amputations during cyclical movements of a phantom foot. VL activity on the amputated side was compared to that recorded on patients' intact side while they moved both the phantom and intact feet synchronously. VL activity in the patient group was also compared to a sample of control participants with no amputation. We show that phantom foot movement is associated with greater VL activity in the amputated leg than that seen in the intact leg as well as that exhibited by controls. The magnitude of residual VL activity was also positively related to ratings of PLP. These results show that phantom limb movement is associated with aberrant activity in a residual muscle after lower-limb amputation and provide evidence of a positive relationship between this activity and phantom limb pain.NEW & NOTEWORTHY This study is the first to assess residual muscle activity during movement of a phantom limb in individuals with lower limb amputations. We find that phantom foot movement is associated with aberrant recruitment of a residual thigh muscle and that this aberrant activity is related to phantom limb pain.

Structural and functional motor cortex asymmetry in unilateral lower limb amputation with phantom limb pain.

OBJECTIVE: The role of motor cortex reorganization in the development and maintenance of phantom limb pain (PLP) is still unclear. This study aims to evaluate neurophysiological and structural motor cortex asymmetry in patients with PLP and its relationship with pain intensity. METHODS: Cross-sectional analysis of an ongoing randomized-controlled trial. We evaluated the motor cortex asymmetry through two techniques: i) changes in cortical excitability indexed by transcranial magnetic stimulation (motor evoked potential, paired-pulse paradigms and cortical mapping), and ii) voxel-wise grey matter asymmetry analysis by brain magnetic resonance imaging. RESULTS: We included 62 unilateral traumatic lower limb amputees with a mean PLP of 5.9 (SD = 1.79). We found, in the affected hemisphere, an anterior shift of the hand area center of gravity (23 mm, 95% CI 6 to 38, p = 0.005) and a disorganized and widespread representation. Regarding voxel-wise grey matter asymmetry analysis, data from 21 participants show a loss of grey matter volume in the motor area of the affected hemisphere. This asymmetry seems negatively associated with time since amputation. For TMS data, only the ICF ratio is negatively correlated with PLP intensity (r = -0.25, p = 0.04). CONCLUSION: There is an asymmetrical reorganization of the motor cortex in patients with PLP, characterized by a disorganized, widespread, and shifted hand cortical representation and a loss in grey matter volume in the affected hemisphere. This reorganization seems to reduce across time since amputation. However, it is not associated with pain intensity. SIGNIFICANCE: These findings are significant to understand the role of the motor cortex reorganization in patients with PLP, showing that the pain intensity may be related with other neurophysiological factors, not just cortical reorganization.

Cortical plasticity in phantom limb pain: A fMRI study on the neural correlates of behavioral clinical manifestations.

The neural mechanism of phantom limb pain (PLP) is related to the intense brain reorganization process implicating plasticity after deafferentation mostly in sensorimotor system. There is a limited understanding of the association between the sensorimotor system and PLP. We used a novel task-based functional magnetic resonance imaging (fMRI) approach to (1) assess neural activation within a-priori selected regions-of-interested (motor cortex [M1], somatosensory cortex [S1], and visual cortex [V1]), (2) quantify the cortical representation shift in the affected M1, and (3) correlate these changes with baseline clinical characteristics. In a sample of 18 participants, we found a significantly increased activity in M1 and S1 as well as a shift in motor cortex representation that was not related to PLP intensity. In an exploratory analyses (not corrected for multiple comparisons), they were directly correlated with time since amputation; and there was an association between increased activity in M1 with a lack of itching sensation and V1 activation was negatively correlated with PLP. Longer periods of amputation lead to compensatory changes in sensory-motor areas; and itching seems to be a protective marker for less signal changes. We confirmed that PLP intensity is not associated with signal changes in M1 and S1 but in V1.

BCI training to move a virtual hand reduces phantom limb pain: A randomized crossover trial.

OBJECTIVE: To determine whether training with a brain-computer interface (BCI) to control an image of a phantom hand, which moves based on cortical currents estimated from magnetoencephalographic signals, reduces phantom limb pain. METHODS: Twelve patients with chronic phantom limb pain of the upper limb due to amputation or brachial plexus root avulsion participated in a randomized single-blinded crossover trial. Patients were trained to move the virtual hand image controlled by the BCI with a real decoder, which was constructed to classify intact hand movements from motor cortical currents, by moving their phantom hands for 3 days ("real training"). Pain was evaluated using a visual analogue scale (VAS) before and after training, and at follow-up for an additional 16 days. As a control, patients engaged in the training with the same hand image controlled by randomly changing values ("random training"). The 2 trainings were randomly assigned to the patients. This trial is registered at UMIN-CTR (UMIN000013608). RESULTS: VAS at day 4 was significantly reduced from the baseline after real training (mean [SD], 45.3 [24.2]-30.9 [20.6], 1/100 mm; p = 0.009 < 0.025), but not after random training (p = 0.047 > 0.025). Compared to VAS at day 1, VAS at days 4 and 8 was significantly reduced by 32% and 36%, respectively, after real training and was significantly lower than VAS after random training (p < 0.01). CONCLUSION: Three-day training to move the hand images controlled by BCI significantly reduced pain for 1 week. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that BCI reduces phantom limb pain.

[Perioperative measures for prevention of phantom pain: an evidence-based approach to risk reduction]. / Perioperative Maßnahmen zur Prävention von Phantomschmerz: ein evidenzbasierter Ansatz zur Risikoreduktion.

Prevention of phantom limb pain is one of the biggest and still largely unsolved challenges in perioperative medicine. Despite many study efforts and optimization of postoperative pain treatment over the last 30 years, a significant reduction in the incidence of phantom limb pain has not been achieved. Current studies have also shown that at least 50% of patients develop phantom pain after 6 months. A possible approach could be to combine multiple synergistic interventions and implement them as a perioperative phantom pain management strategy bundle. In addition to regional anesthesia, NMDA antagonists, gabapentinoids, antidepressants and systemic lidocaine could play a relevant role. The aim of this pharmacological intervention was the modification of the pathophysiological changes in peripheral nerves and in the central nervous system after amputation.

Assessment of cortical reorganization and preserved function in phantom limb pain: a methodological perspective.

Phantom limb pain (PLP) has been associated with reorganization in primary somatosensory cortex (S1) and preserved S1 function. Here we examined if methodological differences in the assessment of cortical representations might explain these findings. We used functional magnetic resonance imaging during a virtual reality movement task, analogous to the classical mirror box task, in twenty amputees with and without PLP and twenty matched healthy controls. We assessed the relationship between task-related activation maxima and PLP intensity in S1 and motor cortex (M1) in individually-defined or group-conjoint regions of interest (ROI) (overlap of task-related activation between the groups). We also measured cortical distances between both locations and correlated them with PLP intensity. Amputees compared to controls showed significantly increased activation in M1, S1 and S1M1 unrelated to PLP. Neural activity in M1 was positively related to PLP intensity in amputees with PLP when a group-conjoint ROI was chosen. The location of activation maxima differed between groups in S1 and M1. Cortical distance measures were unrelated to PLP. These findings suggest that sensory and motor maps differentially relate to PLP and that methodological differences might explain discrepant findings in the literature.

Brain (re)organisation following amputation: Implications for phantom limb pain.

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.

Targeted Muscle Reinnervation Improves Residual Limb Pain, Phantom Limb Pain, and Limb Function: A Prospective Study of 33 Major Limb Amputees.

BACKGROUND: Targeted muscle reinnervation is an emerging surgical technique to treat neuroma pain whereby sensory and mixed motor nerves are transferred to nearby redundant motor nerve branches. In a recent randomized controlled trial, targeted muscle reinnervation was recently shown to reduce postamputation pain relative to conventional neuroma excision and muscle burying. QUESTIONS/PURPOSES: (1) Does targeted muscle reinnervation improve residual limb pain and phantom limb pain in the period before surgery to 1 year after surgery? (2) Does targeted muscle reinnervation improve Patient-reported Outcome Measurement System (PROMIS) pain intensity and pain interference scores at 1 year after surgery? (3) After 1 year, does targeted muscle reinnervation improve functional outcome scores (Orthotics Prosthetics User Survey [OPUS] with Rasch conversion and Neuro-Quality of Life [Neuro-QOL])? METHODS: Data on patients who were ineligible for randomization or declined to be randomized and underwent targeted muscle reinnervation for pain were gathered for the present analysis. Data were collected prospectively from 2013 to 2017. Forty-three patients were enrolled in the study, 10 of whom lacked 1-year follow-up, leaving 33 patients for analysis. The primary outcomes measured were the difference in residual limb and phantom limb pain before and 1 year after surgery, assessed by an 11-point numerical rating scale (NRS). Secondary outcomes were change in PROMIS pain measures and change in limb function, assessed by the OPUS Rasch for upper limbs and Neuro-QOL for lower limbs before and 1 year after surgery. RESULTS: By 1 year after targeted muscle reinnervation, NRS scores for residual limb pain from 6.4 ± 2.6 to 3.6 ± 2.2 (mean difference -2.7 [95% CI -4.2 to -1.3]; p < 0.001) and phantom limb pain decreased from 6.0 ± 3.1 to 3.6 ± 2.9 (mean difference -2.4 [95% CI -3.8 to -0.9]; p < 0.001). PROMIS pain intensity and pain interference scores improved with respect to residual limb and phantom limb pain (residual limb pain intensity: 53.4 ± 9.7 to 44.4 ± 7.9, mean difference -9.0 [95% CI -14.0 to -4.0]; residual limb pain interference: 60.4 ± 9.3 to 51.7 ± 8.2, mean difference -8.7 [95% CI -13.1 to -4.4]; phantom limb pain intensity: 49.3 ± 10.4 to 43.2 ± 9.3, mean difference -6.1 [95% CI -11.3 to -0.9]; phantom limb pain interference: 57.7 ± 10.4 to 50.8 ± 9.8, mean difference -6.9 [95% CI -12.1 to -1.7]; p ≤ 0.012 for all comparisons). On functional assessment, OPUS Rasch scores improved from 53.7 ± 3.4 to 56.4 ± 3.7 (mean difference +2.7 [95% CI 2.3 to 3.2]; p < 0.001) and Neuro-QOL scores improved from 32.9 ± 1.5 to 35.2 ± 1.6 (mean difference +2.3 [95% CI 1.8 to 2.9]; p < 0.001). CONCLUSIONS: Targeted muscle reinnervation demonstrates improvement in residual limb and phantom limb pain parameters in major limb amputees. It should be considered as a first-line surgical treatment option for chronic amputation-related pain in patients with major limb amputations. Additional investigation into the effect on function and quality of life should be performed. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Management of Post-Amputation Pain.

INTRODUCTION: The prevalence of amputation and post-amputation pain (PAP) is rising. There are two main types of PAP: residual limb pain (RLP) and phantom limb pain (PLP), with an estimated 95% of people with amputations experiencing one or both. Medical Management: The majority of chronic PAP is due to phantom limb pain, which is neurogenic in nature. Common medications used include tricyclic antidepressants, gabapentin, and opioids. Newer studies are evaluating alternative drugs such as ketamine and local anesthetics. Rehabilitation Management: Mirror visual feedback and cognitive behavioral therapy are often effective adjunct therapies and have minimal adverse effects. Surgical Management: Neuromodulatory treatment and surgery for neuromas have been found to help select patients with PAP. CONCLUSION: PAP is a complex condition with mechanisms that can be located at the residual limb, spinal cord, and brain - or a combination. This complex pain can be difficult to treat. The mainstays of treatment are largely medical, but several surgical options are also being studied.

Selective nerve root injection of ozone for the treatment of phantom limb pain: Three case reports.

RATIONALE: Phantom limb pain (PLP) refers to a common complication following amputation, which is characterized by intractable pain in the absent limb, phantom limb sensation, and stump pain. The definitive pathogenesis of PLP has not been fully understood, and the treatment of PLP is still a great challenge. Till now, ozone injection has never been reported for the treatment of PLP. PATIENT CONCERNS: We report 3 cases: a 68-year-old man, a 48-year-old woman, and a 46-year-old man. All of them had an amputation history and presented with stump pain, phantom limb sensation, and sharp pain in the phantom limb. Oral analgesics and local blocking in stump provided no benefits. DIAGNOSIS: They were diagnosed with PLP. INTERVENTIONS: We performed selective nerve root ozone injection combined with ozone injection in the stump tenderness points. OUTCOMES: There were no adverse effects. Postoperative, PLP, and stump pain were significantly improved. During the follow-up period, the pain was well controlled. LESSONS: Selective nerve root injection of ozone is safe and the outcomes were favorable. Ozone injection may be a new promising approach for treating PLP.

And Yet It Moves: What We Currently Know about Phantom Arm Movements.

What is left over if I subtract the fact that my arm goes up from the fact that I raise my arm? Neurological evidence invites the provocative hypothesis that what is left over is a phantom arm movement-a movement of an arm that has been amputated. After arm/hand amputation, many amputees report that they can generate voluntary movements of the phantom limb; that is, they can move the arm that was amputated. But what is it like to move an arm/hand that is not there? Here, we review what is currently known about phantom limb movements at three descriptive levels: the kinematic level, the muscle level, and the cortical level. We conclude that phantom arm movements are best conceptualized as the real movements of a dematerialized hand.

Neuromas and postamputation pain.

Postamputation stump and phantom pain are highly prevalent but remain a difficult condition to treat. The underlying mechanisms are not fully clarified, but growing evidence suggests that changes in afferent nerves, including the formation of neuromas, play an important role. The main objective of this cross-sectional study was to investigate whether ultrasound-verified neuroma swellings are more frequent in amputees with postamputation pain than in amputees without pain (primary outcome). Sixty-seven amputees were included. Baseline characteristics including the frequency and intensity of spontaneous stump and phantom pain were obtained, and sensory characteristics and evoked responses were assessed. A high-frequency ultrasound examination of the amputated extremity was performed to obtain information on the presence, size, and elasticity of swollen neuromas and pressure pain thresholds. Swollen neuromas were present in 53 (79.1%) of the 67 amputees included in the study, in 47 (82.5%) of 57 amputees with pain and in 6 (60.0%) of 10 amputees without pain (P = 0.2). No difference was found in stump pain intensity (P = 0.42) during the last week or in phantom pain intensity in the last month (P = 0.74) between amputees with and without swollen neuromas. Our findings suggest that it is not the presence of swollen neuromas itself that drives postamputation pain. However, changes in the transected nerve endings may still be crucial for driving postamputation pain because a positive Tinel sign was significantly more frequent in amputees with pain, irrespectively of the degree of neuroma swelling.

Direct evidence of EEG coherence in alleviating phantom limb pain by virtual referred sensation: Case report.

Virtual reality (VR) systems have been integrated into rehabilitation techniques for phantom limb pain (PLP). In this case report, we used electroencephalography (EEG) to analyze corticocortical coherence between the bilateral sensorimotor cortices during vibrotactile stimulation in conjunction with VR rehabilitation in two PLP patients. As a result, we observed PLP alleviation and increased alpha wave coherence during VR rehabilitation when stimulation was delivered to the cheek and shoulder (referred sensation areas) of the affected side. Vibrotactile stimulation with VR rehabilitation may enhance the awareness and movement of the phantom hand.

Sensory feedback restoration in leg amputees improves walking speed, metabolic cost and phantom pain.

Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to above-knee amputees, thereby reducing confidence and walking speed in the users that is associated with high mental and physical fatigue1-4. The lack of physiological feedback from the remaining extremity to the brain also contributes to the generation of phantom limb pain from the missing leg5,6. To determine whether neural sensory feedback restoration addresses these issues, we conducted a study with two transfemoral amputees, implanted with four intraneural stimulation electrodes7 in the remaining tibial nerve (ClinicalTrials.gov identifier NCT03350061). Participants were evaluated while using a neuroprosthetic device consisting of a prosthetic leg equipped with foot and knee sensors. These sensors drive neural stimulation, which elicits sensations of knee motion and the sole of the foot touching the ground. We found that walking speed and self-reported confidence increased while mental and physical fatigue decreased for both participants during neural sensory feedback compared to the no stimulation trials. Furthermore, participants exhibited reduced phantom limb pain with neural sensory feedback. The results from these proof-of-concept cases provide the rationale for larger population studies investigating the clinical utility of neuroprostheses that restore sensory feedback.

Mirror self recognition as a product of forward models; implications for delusions of body image and visual neglect.

Forward models allow individuals to learn to predict the sensory consequences of their own behavior. Social forward models have been proposed as an extension of forward models, allowing individuals to learn to predict the response of another to the individual's own behavior. This article proposes similarly that an individual who treats their reflection as another may learn to predict the behavior of their reflection, offering a new perspective on mirror self-recognition and a potential framework through which to investigate visual delusions. Specifically this article investigates this framework by considering four body image delusions; mirrored-self misidentification, body integrity disorder (BID), phantom limbs, and gender dysphoria, and two delusions associated with visual neglect; somatoparaphrenia and mirror agnosia.

Alterations in Brain Structural Connectivity After Unilateral Upper-Limb Amputation.

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.