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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. •Technological advancements provide new insight into the neural basis of phantom pain.•Traditional mechanistic accounts of remapping in somatosensory cortex are incomplete.•Related contextual factors such as adaptive behaviour will contribute to brain plasticity.•A broader mechanistic focus beyond primary sensorimotor cortex is needed.•Plasticity and stability of the sensorimotor body maps may vary across time scales.

Despite humanity’s long experience with amputations, postamputation pain remains a highly prevalent, incompletely understood, and clinically challenging condition. There are two main types of postamputation pain: residual limb pain (including but not limited to the “stump”) and phantom limb pain. Despite considerable overlap between the two, they also have distinct clinical features, risk factors, and pathophysiological mechanisms. Central, peripheral, and spinal mechanisms may all contribute to the protean manifestations of persistent postamputation pain; an improved understanding of these mechanisms will be essential to identify the most promising interventions for the prevention and treatment of postamputation pain. Although there are currently no standardized prevention or treatment recommendations for any type of postamputation pain, an evidence-based, multimodal strategy including pharmacological agents, nonsurgical procedures, surgery, complementary and integrative techniques, and assistive technologies may prevent the development of chronic postamputation pain after amputation and/or optimize treatment outcomes.

•Multisensory integration hubs exhibit heightened activation in PLP patients compared to healthy two-handed controls.•Among these hubs, only posterior parietal cortex activity appears to correlate with effective pain-modulating therapies.•Posterior parietal cortex activity is most plausibly understood within the framework of conflicting and contrasting sensory and motor signals. Phantom limb pain (PLP) is a debilitating neuropathic pain syndrome characterized by the perception of pain in an amputated or deafferented limb. Maladaptive cortical reorganization is proposed as its primary mechanism, yet a comprehensive analysis of functional alterations is lacking due to methodological variability across studies. We employed an activation likelihood estimation (ALE) meta-analysis of fMRI and [15O]H2O-PET studies to compare brain activity in post-amputation PLP patients with that of healthy controls. A systematic search of PubMed, Embase, Scopus, Cochrane Library, and Web of Science identified relevant studies. Following exclusion of unsuitable studies, an ALE meta-analysis was conducted with sub-analyses for movement tasks, facial stimulation, and pain-reducing interventions. A total of 972 articles was identified, of which eleven met the inclusion criteria. ALE results of the sub-analysis for facial stimulation (four studies; 43 PLP patients) showed increased activation in medial pain network regions (e.g., anterior cingulate cortex and anterior insula). The movement analysis sub-analysis (seven studies, 66 PLP patients) revealed heightened activity in the same medial pain network regions, though also in multisensory integration areas, particularly the posterior parietal cortex (PPC). Intervention-related analyses (four studies, 46 PLP patients) demonstrated reduced activation in the PPC but not in the medial pain network regions. The observed hyperactivity in multisensory integration regions supports the hypothesis that PLP arises from attempts to reconcile conflicting sensory inputs, leading to a dysregulated PPC that modulates pain intensity. Further research should elucidate the role of the PPC in PLP, guiding novel therapeutic interventions.

Phantom limb pain (PLP)-pain felt in the amputated limb-is often accompanied by significant suffering. Estimates of the burden of PLP have provided conflicting data. To obtain a robust estimate of the burden of PLP, we gathered and critically appraised the literature on the prevalence and risk factors associated with PLP in people with limb amputations. Articles published between 1980 and July 2019 were identified through a systematic search of the following electronic databases: MEDLINE/PubMed, PsycINFO, PsycArticles, Cumulative Index to Nursing and Allied Health Literature, Africa-Wide Information, Health Source: Nursing/Academic Edition, SCOPUS, Web of Science and Academic Search Premier. Grey literature was searched on databases for preprints. Two reviewers independently conducted the screening of articles, data extraction and risk of bias assessment. The meta-analyses were conducted using the random effects model. A statistically significant level for the analyses was set at p<0.05. The pooling of all studies demonstrated a prevalence estimate of 64% [95% CI: 60.01-68.05] with high heterogeneity [I2 = 95.95% (95% CI: 95.10-96.60)]. The prevalence of PLP was significantly lower in developing countries compared to developed countries [53.98% vs 66.55%; p = 0.03]. Persistent pre-operative pain, proximal site of amputation, stump pain, lower limb amputation and phantom sensations were identified as risk factors for PLP. This systematic review and meta-analysis estimates that six of every 10 people with an amputation report PLP-a high and important prevalence of PLP. Healthcare professionals ought to be aware of the high rates of PLP and implement strategies to reduce PLP by addressing known risk factors, specifically those identified by the current study.

Background Postamputation neuroma pain can prevent comfortable prosthesis wear in patients with limb amputations, and currently available treatments are not consistently effective. Targeted muscle reinnervation (TMR) is a decade-old technique that employs a series of novel nerve transfers to permit intuitive control of upper-limb prostheses. Clinical experience suggests that it may also serve as an effective therapy for postamputation neuroma pain; however, this has not been explicitly studied. Questions/purposes We evaluated the effect of TMR on residual limb neuroma pain in upper-extremity amputees. Methods We conducted a retrospective medical record review of all 28 patients treated with TMR from 2002 to 2012 at Northwestern Memorial Hospital/Rehabilitation Institute of Chicago (Chicago, IL, USA) and San Antonio Military Medical Center (San Antonio, TX, USA). Twenty-six of 28 patients had sufficient (> 6 months) followup for study inclusion. The amputation levels were shoulder disarticulation (10 patients) and transhumeral (16 patients). All patients underwent TMR for the primary purpose of improved myoelectric control. Of the 26 patients included in the study, 15 patients had evidence of postamputation neuroma pain before undergoing TMR. Results Of the 15 patients presenting with neuroma pain before TMR, 14 experienced complete resolution of pain in the transferred nerves, and the remaining patient’s pain improved (though did not resolve). None of the patients who presented without evidence of postamputation neuroma pain developed neuroma pain after the TMR procedure. All 26 patients were fitted with a prosthesis, and 23 of the 26 patients were able to operate a TMR-controlled prosthesis. Conclusions None of the 26 patients who underwent TMR demonstrated evidence of new neuroma pain after the procedure, and all but one of the 15 patients who presented with preoperative neuroma pain experienced complete relief of pain in the distribution of the transferred nerves. TMR offers a novel and potentially more effective therapy for the management of neuroma pain after limb amputation. Level of Evidence Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Background Painful conditions such as residual limb pain (RLP) and phantom limb pain (PLP) can manifest after amputation. The mechanisms underlying such postamputation pains are diverse and should be addressed accordingly. Different surgical treatment methods have shown potential for alleviating RLP due to neuroma formation — commonly known as neuroma pain — and to a lesser degree PLP. Two reconstructive surgical interventions, namely targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI), are gaining popularity in postamputation pain treatment with promising results. However, these two methods have not been directly compared in a randomised controlled trial (RCT). Here, we present a study protocol for an international, double-blind, RCT to assess the effectiveness of TMR, RPNI, and a non-reconstructive procedure called neuroma transposition (active control) in alleviating RLP, neuroma pain, and PLP. Methods One hundred ten upper and lower limb amputees suffering from RLP will be recruited and assigned randomly to one of the surgical interventions (TMR, RPNI, or neuroma transposition) in an equal allocation ratio. Complete evaluations will be performed during a baseline period prior to the surgical intervention, and follow-ups will be conducted in short term (1, 3, 6, and 12 months post-surgery) and in long term (2 and 4 years post-surgery). After the 12-month follow-up, the study will be unblinded for the evaluator and the participants. If the participant is unsatisfied with the outcome of the treatment at that time, further treatment including one of the other procedures will be discussed in consultation with the clinical investigator at that site. Discussion A double-blind RCT is necessary for the establishment of evidence-based procedures, hence the motivation for this work. In addition, studies on pain are challenging due to the subjectivity of the experience and the lack of objective evaluation methods. Here, we mitigate this problem by including different pain evaluation methods known to have clinical relevance. We plan to analyse the primary variable, mean change in NRS (0–10) between baseline and the 12-month follow-up, using the intention-to-treat (ITT) approach to minimise bias and keep the advantage of randomisation. The secondary outcomes will be analysed on both ITT and per-protocol (PP). An adherence protocol (PP population) analysis will be used for estimating a more realistic effect of treatment. Trial registration ClinicalTrials.gov NCT05009394.

Among the leading etiologies of limb amputations are diabetes mellitus, alongside trauma and peripheral vascular disease conditions, whose complications are major indications for surgery, which can subsequently elicit chronic refractory postamputation pain. ‘Phantom limb pain’ (PLP) denotes pain that is perceived as occurring in an absent part of the limb following amputation. Even though it is a relatively common complication among amputees—with an estimated prevalence as high as ~80 percent—the underlying mechanisms of this puzzling condition remain poorly understood. Current theories predominantly emphasize the role of the nervous system and neuropsychopathology in the development of PLP. However, these neurocentric explanations are disputed and have not yet been translated into effective treatments or a definitive cure for the condition, nor have several notable anomalies been settled, which has prompted researchers to call for the exploration of alternative theories. The aim of this paper is to offer an alternative mechanical mechanism for explaining PLP and spontaneous phantom sensations. This work introduces a theoretical model for the mechanism of PLP, drawing on a recent study that proposed this model to explain fibromyalgia-type psychosomatic syndromes as disorders driven by overactive soft tissue myofibroblasts. The manuscript proposes a shift from purely neurocentric models of PLP to a framework where the extracellular matrix and connective tissue, specifically myofascial tissue and inflammatory myofibroblasts—which are often overlooked in research—take part in its pathogenesis. In this suggested model, surgical interventions disrupt the biomechanical stability of the fascio-musculoskeletal biotensegrity-like system, thus acting as a contributing factor in the chronic pain manifestation. The term ‘biotensegrity’ refers to the dynamic biomechanical behavior of a living system that is stabilized by compressive and tensile force elements, a characteristic quality of myofascial tissue. In this framework, abnormal extracellular matrix remodeling, driven by overactive peripheral myofibroblasts, and the concomitant mechanical effects exerted on sensory nerves embedded within the fascia and reaching the neuroma microenvironment contribute to the generation and perception of spontaneous PLP and phantom sensations. The interplay between abnormal extracellular matrix, the neuroma’s intrinsic excitability, as well as peripheral and central neurophysiological mechanisms, collectively provide a biophysical neuropathophysiological basis to help explain PLP. This offers a different unexplored perspective on a condition with poorly understood mechanisms.

Objective To explore the relationship between sociodemographic, clinical, and neurophysiological variables and health-related quality of life (HR-QOL) of patients with phantom limb pain (PLP). Methods This is a cross-sectional analysis of a previous clinical trial. Univariate and multivariate linear and logistic regression analyses were used to model the predictors of HR-QOL. We utilized a sequential modeling approach with increasing adjustment levels, controlling for age and sex, and other relevant clinical variables (time since amputation, level of amputation, and pain). HR-QOL was assessed by the SF-36 Health Survey and its 8 subdomains. Results We analyzed baseline data from 92 patients with lower-limb amputations. They were mostly male (63%), 45.2 ± 15.6 years, with a mean time since amputation of 82.7 ± 122.4 months, and an overall SF-36 score of 55.9 ± 21.5. We found an association between intracortical facilitation (ICF) in the affected hemisphere, gabapentin usage, and HR-QOL. ICF is a predictor of better HRQOL, whereas gabapentin usage was associated with a poorer HR-QOL, with the main model explaining 13.4% of the variance in the outcome. For the SF-36 subdomains, ICF was also a positive predictor for social functioning, bodily pain, and vitality, while medication usage was associated with lower scores in mental health, general health perception, bodily pain, and vitality. Conclusion We found firsthand 2 new independent predictors of HR-QOL in individuals with PLP, namely, the neurophysiological metric ICF and gabapentin usage. These results highlight the role of the motor cortex excitability in the HR-QOL and stress the need for treatments that favor the neuroplastic adaptation after amputation, for which ICF may be used as a possible marker.

Background and Objectives: The experience of unpleasant sensory phenomena after lower limb amputations (LLAs), including phantom limb pain (PLP), phantom limb sensation (PLS), and residual limb pain (RLP), impacts global healthcare and adversely affects outcomes post-amputation. This study aimed to describe the distribution of PLP, PLS, and RLP among patients with LLAs registered in the Heidelberg Amputation Registry. The primary objective was to determine the prevalence of sensory abnormalities across different amputation levels and causes. Materials and Methods: In this single-center, cross-sectional study, data from 459 patients registered in the Heidelberg Amputation Registry were analyzed for the occurrence of PLP, PLS and RLP. Subsequently, logistic regression models were used to identify the independent risk factors associated with sensory disturbances following LLAs. The mean age of the LLA patients (31% female, 69% male) was 58 years (SD ± 18). Results: The patients were, on average, 44 years old (SD ± 22) at the time of amputation, with a mean duration since amputation of 15 years (SD ± 17). Transtibial amputations were the most common (43%), followed by transfemoral (39%) and partial foot amputations (10%). Hip and knee disarticulations were observed in 3.7% and 3.5% of the cohort, respectively, with hemipelvectomies accounting for 1%. Traumatic injuries (32%) and neoplastic disorders (22%) were the leading causes of LLAs, while peripheral artery disease and diabetes were responsible for 12% and 6% of cases, respectively. Importantly, a significant proportion of participants (85%) reported experiencing abnormal sensations. The prevalence rates for phantom limb pain (PLP), phantom limb sensation (PLS), and residual limb pain (RLP) were 58%, 66%, and 46%, respectively. The occurrence of sensory disturbances, with the exception of RLP, was significantly affected by the level of amputation. Notably, the age at amputation emerged as an independent risk factor for developing abnormal sensations, including PLS. Conclusions: In conclusion, this study provides a comprehensive overview of sensory abnormalities in a diverse cohort of LLA patients, highlighting the age at amputation as an important factor. The findings emphasize the role of comprehensive registries in enhancing care for individuals with amputations and guiding targeted pain management strategies.

Pre-emptive targeted muscle reinnervation (TMR) at the time of amputation results in less phantom limb pain (PLP) compared with untreated amputee controls. There is limited literature describing the technique in patients undergoing hindquarter amputation despite up to 90% of these patients reporting PLP and 50% presenting with painful neuroma. The purpose of the current study was to describe the motor nerves accessible through a primary hind-quarter amputation to be used for TMR and review pain outcomes in clinical case correlates of patients with TMR. Six limbs were obtained from three fresh adult cadavers and proximal sensory and motor nerves were dissected. A review of patients undergoing hindquarter amputation with TMR was conducted. Transfers for the sciatic, femoral, and obturator nerves were identified in cadavers. In reviews of patients, they were taking narcotic and neuro-leptic pain medication for a mean of 23 days and 168 days. At most recent follow-up, no patient reported debilitating phantom pain nor pain associated with neuromas. Given the positive preliminary results in our study group as well as the accessible neuroanatomy, pre-emptive TMR should be considered at the time of surgery to limit PLP and dependence on pain medications.