Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex for Phantom Limb Pain.

BACKGROUND: Phantom limb pain (PLP) is a prevalent and distressing occurrence in 60-80% of individuals who have undergone amputations. Recent research underscores the significance of maladaptive cortical plasticity in the genesis of PLP, emphasizing the importance of targeting cortical areas for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive tool for cortical stimulation, demonstrates effectiveness in treating various chronic pain conditions of neuropathic origin. Nevertheless, there exists a limited body of research investigating the application of rTMS as a therapeutic intervention specifically for managing PLP. Notably, the dorsolateral prefrontal cortex (DLPFC) plays a crucial role in central pain processing, suggesting its potential as a key therapeutic target in PLP treatment. There is a lack of adequate data regarding the effectiveness of DLPFC-targeting rTMS in alleviating the pain experienced by PLP patients. OBJECTIVE: In this study, our aim was to investigate the impact of 10 sessions of DLPFC-targeting rTMS on the pain status of individuals experiencing PLP. STUDY DESIGN: Randomized controlled trial. SETTING: Traumatic amputees reporting to the tertiary care center with PLP. METHODS: The study was approved by the Institute Ethics Committee (IECPG-299/27.04.2022) and registered in the Clinical Trials Registry of India (CTRI/2022/07/043938). Nineteen patients suffering from PLP were recruited and randomized into real or sham rTMS groups. In the real rTMS group, patients received 10 sessions of rTMS at the DLPFC contralateral to the amputation site. The rTMS, administered at 90% of the resting motor threshold (RMT), was delivered as 8 trains of 150 pulses per train at the rate of one Hz and an inter-train interval of 60 seconds. The total number of pulses per session was 1,200. The sham group received 10 sessions of sham rTMS through the perpendicular placement of an rTMS coil over the DLPFC. These sessions lasted for the same duration and included the same sounds as the real group but involved no active stimulation. The patients' pain status was evaluated using the Visual Analog Scale (VAS) at baseline, at the end of each session of real or sham rTMS and at the 15th, 30th, and 60th day after the the completion of real or sham therapy. RESULTS: A significant decrease in VAS scores was noted after 10 sessions of real rTMS that targeted the DLPFC, in contrast to the sham rTMS group. The real rTMS group's reduction in VAS scores also persisted during the follow-up. LIMITATIONS: A few patients had to drop out due to physical restrictions and financial constraints. Consequently, only a small number of individuals were able to complete the study protocol successfully. CONCLUSION: A regimen of 10 sessions of real rTMS of the DLPFC was associated with significant pain relief in patients with PLP, and the effects were sustained for 2 months. Therefore, the present study shows that rTMS of the DLPFC has potential as an effective therapeutic intervention for sustained pain relief in PLP patients.

Identifying discriminant factors between phantom limb pain, residual limb pain, and both in people with lower limb amputations: a cross-sectional study.

Postamputation pain is a common condition in patients with lower limb amputation (LLA), which compromises amputees' rehabilitation, use of the prosthesis, and quality of life. The aim of our study was to investigate the prevalence of phantom limb pain (PLP), residual limb pain (RLP), or both types of pain among individuals with LLA, and to identify the factors associated with the presence of one type of pain versus the other. Patients who underwent amputation for traumatic or vascular reasons and who reported on RLP or PLP were analyzed and divided into three groups: PLP, RLP, or a group of subjects that presented both pains. We searched for factors that affect the occurrence of limb pain using univariate analyses, followed by multinomial logistic regression. Among the 282 participants with transtibial and transfemoral amputations, 192 participants (150 male and 42 female) presented PLP, RLP, or both types of pain, while 90 participants declared to perceive no pain. The estimated prevalence of any type of pain after transfemoral and transtibial amputation was therefore 68% (27% PLP, 10% RLP, and 31% both). Among the studied characteristics, only amputation level was associated with the type of pain ( P  = 0.001). Multinomial logistic regression identified transfemoral amputation as the only statistically significant predictor for PLP (odds ratio = 2.8; P  = 0.002). Hence, it was estimated that individuals with transfemoral amputation have nearly three times higher odds of experiencing PLP compared with those with transtibial amputation.

Acute versus non-acute targeted muscle reinnervation for pain control following major limb amputation: A comparative study.

BACKGROUND: Targeted muscle reinnervation (TMR) has been shown to reduce phantom limb pain (PLP) and residual limb pain (RLP) after major limb amputation. However, the effect of the timing of surgery on pain control and quality of life outcomes is controversial. We conducted a retrospective study to compare the outcomes of acute TMR for pain prevention with non-acute TMR for the treatment of established pain. METHODS: All patients treated with TMR in our institution between January 2018 and December 2021 were evaluated at 6, 12, 18 and 24 months post-operatively. Pain intensity and quality of life outcomes were assessed using the Brief Pain Inventory (Pain Severity and Pain Interference scales) and Pain Catastrophizing Scale. Outcomes were compared between acute and non-acute TMR using the Wilcoxon ranked-sum test or Fisher's exact test as appropriate. Multilevel mixed-effects linear regression was used to account for repeat measures and potential pain confounders. RESULTS: Thirty-two patients with 38 major limb amputations were included. Acute TMR patients reported significantly lower RLP and PLP scores, pain interference and pain catastrophisation at all time points (p < 0.05). Acute TMR was significantly associated with lower pain severity and pain interference in a linear mixed-effects model accounting for patient age, gender, amputation indication, amputation site, time post-TMR and repeated surveys (p < 0.05). There was no significant difference in the complication rate (p = 0.51). CONCLUSION: Acute TMR was associated with clinically and statistically significant pain outcomes that were better than that in non-acute TMR. This suggests that TMR should be performed with preventative intent, when possible, as part of a multidisciplinary approach to pain management, rather than deferred until the development of chronic pain.

Analysis of Natural Antibodies during the Development of Phantom Pain Syndrome.

We determined natural antibodies (n-Abs) to the regulators of the main systems of biochemical homeostasis: ß-endorphin, serotonin, dopamine, histamine, orphanin, angiotensin, GABA, glutamate, bradykinin, vasopressin, thrombin, and α-2-macroglobulin in individuals with phantom pain syndrome (PPS), resulting from amputation after injury. It was established that each patient has an individual immunoprofile, but for all of them there was a significant increase in the level of antibodies to serotonin, histamine, and angiotensin, which reflect the chronicity of the pain syndrome and do not depend on the self-assessment of the severity of PPS. Determination of the role of regulators of biochemical homeostasis in the development of phantom pain showed that, at high, moderate, and weak severity of PPS, the biogenic amine and angiotensinergic systems are activated. A decrease in PPS intensity normalizes deviations in all immunological parameters. The levels of n-Abs for the pain (ß-endorphin) and analgesic (orphanin) systems are significant only at low PPS. Monitoring the individual profile of n-Abs to endogenous regulators allows us to obtain an objective picture of the pain status of the patient's body.

[Medical-surgical complications and their impact on patients' return to work whilst follow-up major lower-limb amputations in Hospital del Trabajador in Santiago (HTS)]. / Complicaciones médico-quirúrgicas y su impacto en el retorno laboral durante el seguimiento de pacientes con amputación mayor de extremidades inferiores en el Hospital del Trabajador de Santiago (HTS).

INTRODUCTION: The presence of different complications whilst follow-up amputee patients reaches 10-80%. The main objective of this research is to assess the impact of these in the return-to-work of lower-limb traumatic amputation cases. MATERIALS AND METHODS: A retrospective cohort research was carried out. Clinic-demographic variables information was recollected in order to assess its linkage to different medical-surgical complications and functional outcomes. Survival curves were created to evaluate the return-to-work of patients with and without complications. RESULTS: A total of 46 patients, on average aged 45.7 years old (91.3% men, 71.7% without comorbidities), were included on this research. The most frequent level of amputation was transtibial (65.2%). Residual limb pain, phantom pain, dermatological-infectious complications and painful neuroma were registered in 80.4%, 58.7%, 50% y 30.4% of the cases respectively. Half of the patients had returned to their workplace after 2years of post-surgical follow-up. The return-to-work rates were significantly lower in patients suffering from residual limb pain (p=0.0083) and from painful neuroma (p=0.0051). CONCLUSION: Complications are frequent during traumatic-amputee patients' follow-up and, some of them, may impact on the return-to-work rate.

The Test-Retest Reliability of Pain Outcome Measures in People With Phantom Limb Pain.

OBJECTIVES: To quantify the test-retest reliability of 3 patient-reported outcome measures of pain for people living with phantom limb pain (PLP) and assess the impact of test-retest errors on future research and clinical decisions. METHODS: Thirty-nine participants (30 males), mean (SD) age: 55 (16), mean (SD) years postamputation: 6.8 (8.3), reported their PLP levels on a visual analogue scale (VAS) for pain intensity, the revised short-form McGill Pain Questionnaire (SF-MPQ-2), and a pain diary, on 2 occasions 7 to 14 days apart. Mean systematic change, within-subjects SD, limits of agreement (LOA), coefficient of variation, and the intraclass correlation coefficient (ICC) were quantified alongside their respective 95% confidence intervals (95% CIs). RESULTS: Systematic learning effects (mean changes) were not clinically relevant across the VAS, SF-MPQ-2, and pain diary. Within-subject SDs (95% CI) were 11.8 (9.6-15.3), 0.9 (0.7-1.2), and 8.6 (6.9-11.5), respectively. LOA (95% CI) were 32.6 (26.5-42.4), 2.5 (2-3.3), and 23.9 (19.2-31.8), respectively. ICCs (95% CI) were 0.8 (0.6-0.9), 0.8 (0.7-0.9), and 0.9 (0.8-0.9), respectively, but may have been inflated by sample heterogeneity. The test-retest errors allowed detection of clinically relevant effect sizes with feasible sample sizes in future studies, but individual errors were large. DISCUSSION: For people with PLP, a pain intensity VAS, the SF-MPQ-2, and a pain diary show an acceptable level of intersession reliability for use in future clinical trials with feasible sample sizes. Nevertheless, the random error observed for all 3 of the pain outcome measures suggests they should be interpreted with caution in case studies and when monitoring individuals' clinical status and progress.

The effectiveness of targeted muscle reinnervation in reducing pain and improving quality of life for patients following lower limb amputation.

BACKGROUND: Globally, over 1 million lower limb amputations are performed annually, with approximately 75% of patients experiencing significant pain, profoundly impacting their quality of life and functional capabilities. Targeted muscle reinnervation (TMR) has emerged as a surgical solution involving the rerouting of amputated nerves to specific muscle targets. Originally introduced to enhance signal amplification for myoelectric prosthesis control, TMR has expanded its applications to include neuroma management and pain relief. However, the literature assessing patient outcomes is lacking, specifically for lower limb amputees. This systematic review aims to assess the effectiveness of TMR in reducing pain and enhancing functional outcomes for patients who have undergone lower limb amputation. METHODS: A systematic review was performed by examining relevant studies between 2010 and 2023, focusing on pain reduction, functional outcomes and patient-reported quality of life measures. RESULTS: In total, 20 studies were eligible encompassing a total of 778 extremities, of which 75.06% (n = 584) were lower limb amputees. Average age was 46.66 years and patients were predominantly male (n = 70.67%). Seven studies (35%) reported functional outcomes. Patients who underwent primary TMR exhibited lower average patient-reported outcome measurement information system (PROMIS) scores for phantom limb pain (PLP) and residual limb pain (RLP). Secondary TMR led to improvements in PLP, RLP and general limb pain as indicated by average numeric rating scale and PROMIS scores. CONCLUSION: The systematic review underscores TMR's potential benefits in alleviating pain, fostering post-amputation rehabilitation and enhancing overall well-being for lower limb amputees.

[Bionic Surgery Meets Bionic Reconstruction - First In-human use of Robotic Microsurgery in Targeted Muscle Reinnervation]. / Bionische Chirurgie trifft Bionische Rekonstruktion ­ erstes in-human Projekt von robotischer Mikrochirurgie zur Targeted Muscle Reinnervation.

Robotic microsurgery is an emerging field in reconstructive surgery, which provides benefits such as improved precision, optimal ergonomics, and reduced tremors. However, only a few robotic platforms are available for performing microsurgical procedures, and successful nerve coaptation is still a challenge. Targeted muscle reinnervation (TMR) is an innovative reconstructive procedure that rewires multiple nerves to remnant stump muscles, thereby reducing neuroma and phantom limb pain and improving the control of bionic prostheses. The precision of surgical techniques is critical in reducing axonal sprouting around the coaptation site to minimise the potential for neuroma formation. This study reports the first use of a microsurgical robotic platform for multiple nerve transfers in a patient undergoing TMR for bionic extremity reconstruction. The Symani robotic platform, combined with external microscope magnification, was successfully used, and precise handling of nerve tissue and coaptation was easily feasible even in anatomically challenging environments. While the precision and stability offered by robotic assistance may be especially useful for nerve surgery, the high economic costs of robotic microsurgery remain a major challenge for current healthcare systems. In conclusion, this study demonstrated the feasibility of using a robotic microsurgical platform for nerve surgery and transfers, where precise handling of tissue is crucial and limited space is available. Future studies will explore the full potential of robotic microsurgery in the future.

Using Home-based, Remotely Supervised, Transcranial Direct Current Stimulation for Phantom Limb Pain.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low-amplitude direct currents to alter cortical excitability. Previous trials have established the safety and tolerability of tDCS, and its potential to mitigate symptoms. However, the effects are cumulative, making it more difficult to have adherence to the treatment since frequent visits to the clinic or outpatient center are required. Moreover, the time needed for transportation to the center and the related expenses limit the accessibility of the treatment for many participants. Following guidelines for remotely supervised transcranial direct current stimulation (RS-tDCS) implementation, we propose a protocol designed for remotely supervised and home-based participation that uses specific devices and materials modified for patient use, with real-time monitoring by researchers through an encrypted video conferencing platform. We have developed detailed instructional materials and structured training procedures to allow for self- or proxy-administration while supervised remotely in real time. This protocol has a specific design to have a series of checkpoints during training and execution of the visit. This protocol is currently in use in a large pragmatic study of RS-tDCS for phantom limb pain (PLP). In this article, we will discuss the operational challenges of conducting a home-based RS-tDCS session and show methods to enhance its efficacy with supervised sessions.

Targeted Muscle Reinnervation: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain.

Over the past decade, the field of prosthetics has witnessed significant progress, particularly in the development of surgical techniques to enhance the functionality of prosthetic limbs. Notably, novel surgical interventions have had an additional positive outcome, as individuals with amputations have reported neuropathic pain relief after undergoing such procedures. Subsequently, surgical techniques have gained increased prominence in the treatment of postamputation pain, including one such surgical advancement - targeted muscle reinnervation (TMR). TMR involves a surgical approach that reroutes severed nerves as a type of nerve transfer to "target" motor nerves and their accompanying motor end plates within nearby muscles. This technique originally aimed to create new myoelectric sites for amplified electromyography (EMG) signals to enhance prosthetic intuitive control. Subsequent work showed that TMR also could prevent the formation of painful neuromas as well as reduce postamputation neuropathic pain (e.g., Residual and Phantom Limb Pain). Indeed, multiple studies have demonstrated TMR's effectiveness in mitigating postamputation pain as well as improving prosthetic functional outcomes. However, technical variations in the procedure have been identified as it is adopted by clinics worldwide. The purpose of this article is to provide a detailed step-by-step description of the TMR procedure, serving as the foundation for an international, randomized controlled trial (ClinicalTrials.gov, NCT05009394), including nine clinics in seven countries. In this trial, TMR and two other surgical techniques for managing postamputation pain will be evaluated.

Mesenchymal Stem Cell Engagement Modulates Neuroma Microenviroment in Rats and Humans and Prevents Postamputation Pain.

Postamputation pain is currently managed unsatisfactorily with neuron-targeted pharmacological and interventional therapies. Non-neuronal pain mechanisms have emerged as crucial factors in the development and persistence of postamputation pain. Consequently, these mechanisms offer exciting prospects as innovative therapeutic targets. We examined the hypothesis that engaging mesenchymal stem cells (MSCs) would foster local neuroimmune interactions, leading to a potential reduction in postamputation pain. We utilized an ex vivo neuroma model from a phantom limb pain patient to uncover that the oligodeoxynucleotide IMT504 engaged human primary MSCs to promote an anti-inflammatory microenvironment. Reverse translation experiments recapitulated these effects. Thus, in an in vivo rat model, IMT504 exhibited strong efficacy in preventing autotomy (self-mutilation) behaviors. This effect was linked to a substantial accumulation of MSCs in the neuroma and associated dorsal root ganglia and the establishment of an anti-inflammatory phenotype in these compartments. Centrally, this intervention reduced glial reactivity in the dorsal horn spinal cord, demonstrating diminished nociceptive activity. Accordingly, the exogenous systemic administration of MSCs phenocopied the behavioral effects of IMT504. Our findings underscore the mechanistic relevance of MSCs and the translational therapeutic potential of IMT504 to engage non-neuronal cells for the prevention of postamputation pain. PERSPECTIVE: The present study suggests that IMT504-dependent recruitment of endogenous MSCs within severely injured nerves may prevent post-amputation pain by modifying the inflammatory scenario at relevant sites in the pain pathway. Reinforcing data in rat and human tissues supports the potential therapeutic value of IMT504 in patients suffering postamputation pain.

Is it really on your hand? Spontaneous sensations are not peripheral sensations - Evidence from able-bodied individuals and a phantom limb syndrome patient.

Among other bodily signals, the perception of sensations arising spontaneously on the skin with no external triggers contributes to body awareness. The topic of spontaneous sensations (SPS) being quite recent in the literature, there is still a debate whether this phenomenon is elicited by peripheral cutaneous units' activity underlying tactile perception or originates directly from central mechanisms. In a first experiment, we figured that, if SPS depended on peripheral afferents, their perception on the glabrous hand should relate to the hand tactile sensitivity. On the contrary, we found no relationship at all, which led us to envisage the scenario of SPS in the absence of cutaneous units. In a second experiment, we present the case of Julie, a right-hand amputee that could perceive and report SPS arising on her phantom limb syndrome. We found that SPS distribution on the phantom limb followed the same gradient as that observed in control participants, unlike SPS perceived on the intact left hand. Those findings are crucial to the understanding of neural factors determining body awareness through SPS perception and provide insights into the existence of a precise neural gradient underlying somesthesis.

The prevalence and risk factors for phantom limb pain: a cross-sectional survey.

BACKGROUND: We previously performed a systematic review and meta-analysis which revealed a Phantom Limb Pain (PLP) prevalence estimate of 64% [95% CI: 60.01-68.1]. The prevalence estimates varied significantly between developed and developing countries. Remarkably, there is limited evidence on the prevalence of PLP and associated risk factors in African populations. METHODS: Adults who had undergone limb amputations between January 2018 and October 2022 were recruited from healthcare facilities in the Western and Eastern Cape Provinces. We excluded individuals with auditory or speech impairments that hindered clear communication via telephone. Data on the prevalence and risk factors for PLP were collected telephonically from consenting and eligible participants. The prevalence of PLP was expressed as a percentage with a 95% confidence interval. The associations between PLP and risk factors for PLP were tested using univariate and multivariable logistic regression analyses. The strength of association was calculated using the Odds Ratio where association was confirmed. RESULTS: The overall PLP prevalence was 71.73% [95% CI: 65.45-77.46]. Persistent pre-operative pain, residual limb pain, and non-painful phantom limb sensations were identified as risk factors for PLP. CONCLUSION: This study revealed a high prevalence of PLP. The use of effective treatments targeting pre-amputation pain may yield more effective and targeted pre-amputation care, leading to improved quality of life after amputation.

A sensory-motor hand prosthesis with integrated thermal feedback.

BACKGROUND: Recently, we reported the presence of phantom thermal sensations in amputees: thermal stimulation of specific spots on the residual arm elicited thermal sensations in their missing hands. Here, we exploit phantom thermal sensations via a standalone system integrated into a robotic prosthetic hand to provide real-time and natural temperature feedback. METHODS: The subject (a male adult with unilateral transradial amputation) used the sensorized prosthesis to manipulate objects and distinguish their thermal properties. We tested his ability to discriminate between (1) hot, cold, and ambient temperature objects, (2) different materials (copper, glass, and plastic), and (3) artificial versus human hands. We also introduced the thermal box and block test (thermal BBT), a test to evaluate real-time temperature discrimination during standardized pick-and-place tasks. FINDINGS: The subject performed all three discrimination tasks above chance level with similar accuracies as with his intact hand. Additionally, in all 15 sessions of the thermal BBT, he correctly placed more than half of the samples. Finally, the phantom thermal sensation was stable during the 13 recording sessions spread over 400 days. CONCLUSION: Our study paves the way for more natural hand prostheses that restore the full palette of sensations. FUNDING: This work was funded by the Bertarelli Foundation (including the Catalyst program); the Swiss National Science Foundation through the National Centre of Competence in Research (NCCR) Robotics; the European Union's Horizon 2020 research and innovation program; the Horizon Europe Research & Innovation Program; the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP); and the Tuscany Health Ecosystem.

Distinct patterns of metabolic motor cortex activity for phantom and residual limb pain in people with amputations: A functional near-infrared spectroscopy study.

BACKGROUND: Phantom pain limb (PLP) has gained more attention due to the large number of people with amputations around the world and growing knowledge of the pain process, although its mechanisms are not completely understood. OBJECTIVES: The aim of this study was to understand, in patients with amputations, the association between PLP and residual limb pain (RLP), and the brain metabolic response in cortical motor circuits, using functional near-infrared spectroscopy (fNIRS). METHODS: Sixty participants were recruited from the rehabilitation program in São Paulo, Brazil. Included patients were aged over 18 years, with traumatic unilateral lower-limb amputation, with PLP for at least 3 months after full recovery from amputation surgery. PLP and RLP levels were measured using visual analogue scales. fNIRS was performed during motor execution and motor mirror tasks for 20 s. In order to highlight possible variables related to variation in pain measures, univariate linear regression analyses were performed for both experimental conditions, resulting in four fNIRS variables (two hemispheres x two experimental conditions). Later, in order to test the topographic specificity of the models, eight multivariate regression analyses were performed (two pain scales x two experimental conditions x two hemispheres), including the primary motor cortex (PMC) related channel as an independent variable as well as five other channels related to the premotor area, supplementary area, and somatosensory cortex. All models were controlled for age, sex, ethnicity, and education. RESULTS: We found that: i) there is an asymmetric metabolic activation during motor execution and mirror task between hemispheres (with a predominance that is ipsilateral to the amputated limb), ii) increased metabolic response in the PMC ipsilateral to the amputation is associated with increased PLP (during both experimental tasks), while increased metabolic response in the contralateral PMC is associated with increased RLP (during the mirror motor task only); ii) increased metabolic activity of the ipsilateral premotor region is associated with increased PLP during the motor mirror task; iii) RLP was only associated with higher metabolic activity in the contralateral PMC and lower metabolic activity in the ipsilateral inferior frontal region during motor mirror task, but PLP was associated with higher metabolic activity during both tasks. CONCLUSION: These results suggest there is both task and region specificity for the association between the brain metabolic response and the two different types of post-amputation pain. The metabolic predominance that is ipsilateral to the amputated limb during both tasks was associated with higher levels of PLP, suggesting a cortical motor network activity imbalance due to potential interhemispheric compensatory mechanisms. The present work contributes to the understanding of the underlying topographical patterns in the motor-related circuits associated with pain after amputations.

Cortical Reorganization after Limb Loss: Bridging the Gap between Basic Science and Clinical Recovery.

Despite the increasing incidence and prevalence of amputation across the globe, individuals with acquired limb loss continue to struggle with functional recovery and chronic pain. A more complete understanding of the motor and sensory remodeling of the peripheral and central nervous system that occurs postamputation may help advance clinical interventions to improve the quality of life for individuals with acquired limb loss. The purpose of this article is to first provide background clinical context on individuals with acquired limb loss and then to provide a comprehensive review of the known motor and sensory neural adaptations from both animal models and human clinical trials. Finally, the article bridges the gap between basic science researchers and clinicians that treat individuals with limb loss by explaining how current clinical treatments may restore function and modulate phantom limb pain using the underlying neural adaptations described above. This review should encourage the further development of novel treatments with known neurological targets to improve the recovery of individuals postamputation.Significance Statement In the United States, 1.6 million people live with limb loss; this number is expected to more than double by 2050. Improved surgical procedures enhance recovery, and new prosthetics and neural interfaces can replace missing limbs with those that communicate bidirectionally with the brain. These advances have been fairly successful, but still most patients experience persistent problems like phantom limb pain, and others discontinue prostheses instead of learning to use them daily. These problematic patient outcomes may be due in part to the lack of consensus among basic and clinical researchers regarding the plasticity mechanisms that occur in the brain after amputation injuries. Here we review results from clinical and animal model studies to bridge this clinical-basic science gap.

Is Phantom Limb Awareness Necessary for the Treatment of Phantom Limb Pain?

Phantom limb pain is attributed to abnormal sensorimotor cortical representations. Various feedback treatments have been applied to induce the reorganization of the sensorimotor cortical representations to reduce pain. We developed a training protocol using a brain-computer interface (BCI) to induce plastic changes in the sensorimotor cortical representation of phantom hand movements and demonstrated that BCI training effectively reduces phantom limb pain. By comparing the induced cortical representation and pain, the mechanisms worsening the pain have been attributed to the residual phantom hand representation. Based on our data obtained using neurofeedback training without explicit phantom hand movements and hand-like visual feedback, we suggest a direct relationship between cortical representation and pain. In this review, we summarize the results of our BCI training protocol and discuss the relationship between cortical representation and phantom limb pain. We propose a treatment for phantom limb pain based on real-time neuroimaging to induce appropriate cortical reorganization by monitoring cortical activities.

Modulations in high-density EEG during the suppression of phantom-limb pain with neurostimulation in upper limb amputees.

Phantom limb pain (PLP) is a distressing and persistent sensation that occurs after the amputation of a limb. While medication-based treatments have limitations and adverse effects, neurostimulation is a promising alternative approach whose mechanism of action needs research, including electroencephalographic (EEG) recordings for the assessment of cortical manifestation of PLP relieving effects. Here we collected and analyzed high-density EEG data in 3 patients (P01, P02, and P03). Peripheral nerve stimulation suppressed PLP in P01 but was ineffective in P02. In contrast, transcutaneous electrical nerve stimulation was effective in P02. In P03, spinal cord stimulation was used to suppress PLP. Changes in EEG oscillatory components were analyzed using spectral analysis and Petrosian fractal dimension. With these methods, changes in EEG spatio-spectral components were found in the theta, alpha, and beta bands in all patients, with these effects being specific to each individual. The changes in the EEG patterns were found for both the periods when PLP level was stationary and the periods when PLP was gradually changing after neurostimulation was turned on or off. Overall, our findings align with the proposed roles of brain rhythms in thalamocortical dysrhythmia or disruption of cortical excitation and inhibition which has been linked to neuropathic pain. The individual differences in the observed effects could be related to the specifics of each patient's treatment and the unique spectral characteristics in each of them. These findings pave the way to the closed-loop systems for PLP management where neurostimulation parameters are adjusted based on EEG-derived markers.

Transcranial magnetic stimulation in the treatment of phantom limb pain: a systematic review.

BACKGROUND: Phantom limb pain (PLP) occurs after amputations and can persist in a chronic and debilitating way. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation method capable of influencing brain function and modulating cortical excitability. Its effectiveness in treating chronic pain is promising. OBJECTIVE: To evaluate the evidence on the efficacy and safety of using rTMS in the treatment of PLP, observing the stimulation parameters used, side effects, and benefits of the therapy. METHODS: This is a systematic review of scientific articles published in national and international literature using electronic platforms. RESULTS: Two hundred and fifty two articles were identified. Two hundred and forty six publications were removed because they were duplicated or met the exclusion criteria. After selection, six studies were reviewed, those being two randomized clinical trials and four case reports. All evaluated studies indicated some degree of benefit of rTMS to relieve painful symptoms, even temporarily. Pain perception was lower at the end of treatment when compared to the period prior to the sessions and remained during patient follow-up. There was no standardization of the stimulation parameters used. There were no reports of serious adverse events. The effects of long-term therapy have not been evaluated. CONCLUSION: There are some benefits, even if temporary, in the use of rTMS to relieve painful symptoms in PLP. High-frequency stimulation at M1 demonstrated a significant analgesic effect. Given the potential that has been demonstrated, but limited by the paucity of high-quality studies, further controlled studies are needed to establish and standardize the clinical use of the method.

ANTECEDENTES: A dor do membro fantasma (DMF) ocorre após amputações e pode persistir de forma crônica e debilitante. A estimulação magnética transcraniana repetitiva (EMTr) é um método de neuromodulação não invasivo capaz de influenciar a função cerebral e modular a excitabilidade cortical. Sua eficácia no tratamento da dor crônica é promissora. OBJETIVO: Avaliar as evidências sobre a eficácia e segurança do uso da EMTr no tratamento da DMF, observando os parâmetros de estimulação utilizados, efeitos colaterais e benefícios da terapia. MéTODOS: Trata-se de uma revisão sistemática de artigos científicos publicados na literatura nacional e internacional utilizando plataformas eletrônicas. RESULTADOS: Foram identificados 252 artigos. Duzentas e quarenta e seis publicações foram removidas por estarem duplicadas ou atenderem aos critérios de exclusão. Após a seleção, foram revisados seis estudos, sendo dois ensaios clínicos randomizados e quatro relatos de caso. Todos os estudos avaliados indicaram algum grau de benefício da EMTr no alívio dos sintomas dolorosos, mesmo que temporariamente. A percepção da dor foi menor ao final do tratamento quando comparada ao período anterior às sessões e permaneceu durante o acompanhamento do paciente. Não houve padronização dos parâmetros de estimulação utilizados. Não houve relatos de eventos adversos graves. Os efeitos da terapia a longo prazo não foram avaliados. CONCLUSãO: Existem alguns benefícios, mesmo que temporários, no uso da EMTr para alívio dos sintomas dolorosos na DMF. A estimulação de alta frequência em M1 demonstrou um efeito analgésico significativo. Dado o potencial demonstrado, mas limitado pela escassez de estudos de alta qualidade, são necessários mais estudos controlados para estabelecer e padronizar o uso clínico do método.

Use of virtual reality for the management of phantom limb pain: a systematic review.

PURPOSE: To summarize the research on the effectiveness of virtual reality (VR) therapy for the management of phantom limb pain (PLP). METHODS: Three databases (SCOPUS, Ovid Embase, and Ovid MEDLINE) were searched for studies investigating the use of VR therapy for the treatment of PLP. Original research articles fulfilling the following criteria were included: (i) patients 18 years and older; (ii) all etiologies of amputation; (iii) any level of amputation; (iv) use of immersive VR as a treatment modality for PLP; (v) self-reported objective measures of PLP before and after at least one VR session; (vi) written in English. RESULTS: A total of 15 studies were included for analysis. Fourteen studies reported decreases in objective pain scores following a single VR session or a VR intervention consisting of multiple sessions. Moreover, combining VR with tactile stimulation had a larger beneficial effect on PLP compared with VR alone. CONCLUSIONS: Based on the current literature, VR therapy has the potential to be an effective treatment modality for the management of PLP. However, the low quality of studies, heterogeneity in subject population and intervention type, and lack of data on long-term relief make it difficult to draw definitive conclusions.IMPLICATION FOR REHABILITATIONVirtual reality (VR) therapy has emerged as a new potential treatment option for phantom limb pain (PLP) that circumvents some limitations of mirror therapy.VR therapy was shown to decrease PLP following a single VR session as well as after an intervention consisting of multiple sessions.The addition of vibrotactile stimuli to VR therapy may lead to larger decreases in PLP scores compared with VR therapy alone.