Innovative exploration of phantom limb pain treatment based on extended reality technology

Abstract

Phantom limb pain (PLP) is not only a physical pain experience but also poses a significant challenge to mental health and quality of life. Currently, the mechanism of PLP treatment is still unclear, and there are many methods with varying effects. This article starts with the application research of extended reality technology in PLP treatment, through describing the application of its branch technologies (virtual reality, augmented reality, and mixed reality technology), to lay the foundation for subsequent research, in the hope of finding advanced and effective treatment methods, and providing a basis for future product transformation.

Key Words: Phantom limb pain; Extended reality; Mixed reality; Virtual reality; Augmented reality

Core Tip: Phantom limb pain (PLP) is one of the most common complications of amputation. Extended reality (XR) has advantages of being a noninvasive, nonpharmacological treatment. We review the application of XR in treating PLP. We explore the potential of virtual reality, augmented reality, and mixed reality in alleviating pain and improving psychological status and quality of life of patients with PLP. We highlight the latest advances and future research directions, providing a theoretical basis for developing more effective treatment strategies.

INTRODUCTION

Phantom limb pain (PLP) is one of the most common complications of amputation. Approximately 57.7 million patients worldwide have undergone amputation as a result of trauma[1]. In China, there were approximately 2 million amputees. In the United States, there were approximately 1.7 million amputees, and the annual number of new amputations was approximately 215000[2]. The primary causes of amputation include peripheral vascular disease, severe trauma, infection, and tumors, and the incidence of PLP does not significantly differ among these various causes[3]. About 65% of amputees develop PLP within 1 month after amputation, 82% within 1 year and 87% throughout their lifetime[4]. The sensation of PLP can be likened to throbbing, stabbing, drilling, squeezing, burning, twisting, and in some patients, there may also be other bodily pain symptoms such as headaches and back pain[5]. The precise mechanism underlying PLP remains unclear, but likely involve a complex interplay of peripheral, central and psychological factors[6]. Currently, there are > 25 treatment methods for PLP in clinical practice[7]. Mirror therapy (MT) has become an important choice due to its low cost, noninvasiveness and effectiveness that is not significantly inferior to that of other methods[8-11]. However, MT is not without its limitations. Specifically, it imposes constraints on the patient's posture and restricts the range of limb movement. Additionally, the size of the mirror itself is limited. These limitations can easily cause the mirrored limb to break the illusion, thereby providing patients with a suboptimal experience. With the advancement of computer technology, new approaches have emerged that can create virtual limb mirroring, allowing patients to immerse themselves in a more engaging and realistic experience. In recent years, extended reality (XR) technology, including virtual reality (VR) and augmented reality (AR), has developed rapidly. This technological progress has made it possible to construct highly immersive limb mirroring environments, which show promise in the treatment of PLP. This article reviews the advancements in XR technologies for treating PLP, with the aim of providing a foundation and reference for future research.

BASICS OF XR TECHNOLOGY

XR technology refers to the use of computer technology and wearable devices to create a human–computer interactive environment, which is the general term for VR, AR, mixed reality (MR) and other emerging immersive technologies[12]. VR provides a fully virtual environment where users can interact with computer-generated imagery and audio, completely immersing them without the need to perceive the real world. AR overlays virtual objects onto the real environment, enabling users to simultaneously experience both reality and virtual content. MR integrates the advantages of both VR and AR, allowing users to interact with virtual objects in real time within the real world. This makes virtual content responsive to changes in the real environment and enables users to adjust visual and auditory stimuli in a multisensory setting. The main features of XR technology are compared in Table 1, and the visual difference is showed in Figure 1.

Figure 1  Visual difference of virtual reality/augmented reality/mixed reality.

Table 1 Comparison of virtual reality/augmented reality/mixed reality.

	Virtual reality	Augmented reality	Mixed reality
Need a device	Yes	Yes	Yes
Virtual environment	Totally	None	Fusion
Virtual subjects	Totally	Interactive boxes	On demand
Real environment	None	Totally	Fusion
Real subjects	None	Totally	Totally
Difficulty of the development	Moderate	Difficult	Hardest

The application of XR technology within the medical field has garnered increasing attention. Its uses are expanding in surgical simulation, case presentation, rehabilitation training, medical education, and other areas. At present, there are 69 medical devices involving AR/VR approved in the United States[13]. XR technology has the potential to create immersive, interactive and realistic environments that can promote learning through feedback, reflection and practice while reducing the risks and costs associated with real-life scenarios[14]. In 2021, a VR treatment system (EaseVRx) was approved by the United States Food and Drug Administration (FDA) for the auxiliary treatment of chronic pain[15]. The VR program utilized its fully immersive characteristics to apply behavioral therapies, such as deep relaxation and attention diversion, to alleviate pain. The integrated application of XR technology fosters the development of multidisciplinary collaboration and offers a new theoretical and technical foundation for future pain management strategies.

PROGRESS IN XR TREATMENT OF PLP

When XR is applied to PLP patients, a head-mounted display must be worn. Depending on the type of XR device and the specific treatment approach, patients may need to wear handheld controllers, sensors or other interactive devices. Using the head-mounted display, patients can visualize a computer-generated representation of their amputated limb. Guided by the physician's instructions or voice prompts from the training software, they then use this virtual limb to perform a series of tasks outlined in the program, thereby completing the full treatment process. The general procedures are showed in Figure 2. Given the distinct features and developmental stages of XR technologies, VR, AR and MR methods are discussed separately. Some of the key studies are listed in Table 2[16-27].

Figure 2 General procedures of extended reality treatment of phantom limb pain. NRS: Numerical Rating Scale; PLP: Phantom limb pain; VAS: Visual Analog Scale; VR: Virtual reality.

Table 2 Summary of key studies with extended reality in phantom limb pain.

Ref.	Type of study design	VR/AR/MR	Intervention	Treatment duration	No. of sessions	Pain assessment	Pretreatment	Post-treatment	Treatment efficiency
Ortiz-Catalan et al[20], 2016 (n = 14)	Single-group clinical trial	AR/VR	Machine learning-based myoelectric control of virtual limb in AR/VR environments, including gaming tasks (e.g., racing car, target matching)	2 hours/session	12	NRS, PRI	NRS: 5.2 ± 1.6, PRI: 19.2 ± 10.5	NRS: 3.5 ± 2.1, PRI: 9.6 ± 8.1	50% of patients reduced medication intake; 71% reported ≥ 50% pain reduction at 6 months follow-up
Osumi et al[17], 2017 (n = 8)	Clinical trial	VR	VR system using head-mounted display to show mirror-reversed computer graphic image of intact arm, simulating phantom limb movement	10 minutes (single session)	1	NRS, SF-MPQ	NRS: 5.2 ± 2.4, SF-MPQ: 8.3 ± 7.6	NRS: 3.0 ± 2.1, SF-MPQ: 2.5 ± 3.2	39.1% reduction in NRS; 61.5% reduction in SF-MPQ
Lendaro et al[19], 2017 (n = 1)	Case study	VR	Phantom motor execution with myoelectric pattern recognition and virtual reality for lower-limb amputee	Approximately 2 hours/session	23	NRS, PRI	NRS: 4, PRI: 32	NRS: 2, PRI: 10	50% reduction in NRS; 68% reduction in PRI
Perry et al[22], 2018 (n = 8)	Clinical trial	VR	Virtual integration environment using electromyography to control virtual avatar limb movements	30 minutes/session	Average 18	VAS, SF-MPQ	VAS: Curve in figure, SF-MPQ: Curve in figure	VAS: Curve in figure, SF-MPQ: A curve in figure	88% of participants reported pain reduction; 29% sustained relief at 6 months
Rothgangel et al[23], 2018 (n = 75)	Single-blind RCT	AR	Group A: MT (4 weeks) + AR (6 weeks); group B: MT (4 weeks) + self-delivered MT (6 weeks); group C: Sensomotor exercises of intact limb (10 weeks)	10 weeks (4 weeks initial + 6 weeks follow-up)	10 individual sessions (first 4 weeks)	NRS	NRS: Mean 5.7	Group A: 4.6 (10 weeks), 4.1 (6 months); group B: 3.6 (10 weeks), 2.7 (6 months); group C: 4.1 (10 weeks), 4.5 (6 months)	No significant between-group differences in NRS; 3 patients in group B showed complete recovery of PLP at 6 months
Rutledge et al[18], 2019 (n = 14)	Feasibility study	VR	VR MT with bicycle pedaler and motion sensor to synchronize real/virtual limb motion	Single session (feasibility testing)	1	Phantom Limb Pain Questionnaire	57.1% (8/14) participants reported PLP; 93% (13/14) reported one or more unpleasant phantom sensations	28.6% (4/14) continued to report PLP symptoms and 28.6% (4/14) reported phantom sensations	Participants rated the treatment highly (75%) on the dimensions of helpfulness, immersion, realism, and satisfaction
Kulkarni et al[24], 2020 (n = 9)	Pilot study	VR	Immersive VR with virtual limb visualization and interactive tasks	55 minutes/session/months	3 sessions (3 month)	NRS	NRS: Mean 6.11	Mean NRS: 3.56	Reduction in NRS with no significant difference
Thøgersen et al[21], 2020 (n = 7)	Case series	AR	Customized AR training with virtual limb visualization matched to individual phantom perception, controlled via myoelectric signals; 3 tasks (pick-and-place, imitation, sorting), functional magnetic resonance imaging before and after intervention	45 minutes/session, over 2 weeks	8	SF-MPQ, NRS	NRS: Mean 2.26 (for responding patients)	SF-MPQ: Mean change = -1.884, NRS: 1.31 (mean change = -0.93)	52% reduction in SF-MPQ; 41% reduction in NRS; cortical reorganization correlated with pain relief
Tong et al[25], 2020 (n = 5)	Case series	VR	Immersive VR where intact limb movements control a virtual avatar, providing mirrored visual feedback	4–6 weeks	3–10	VAS, SF-MPQ	VAS: Mean 7.6, SF-MPQ: Mean 16.4	VAS: Mean 6.15, SF-MPQ: Mean 7.06	19.04% reduction in VAS; 56.96% reduction in SF-MPQ; all participants showed pain reduction; improvements in anxiety and depression
Ambron et al[16], 2021 (n = 7)	Clinical trial	VR	Custom VR games controlling avatar legs via motion-tracking sensors on intact/residual limbs	55 minutes/session	5–7 distractor sessions + 10–12 targeted sessions	VAS	VAS: 6.1 ± 2.1	VAS: 3.1 ± 2.1	28% reduction after distractor sessions; 39.6% reduction after targeted sessions
Annaswamy et al[27], 2022 (n = 4)	Pilot study	MR	Home-based use of Mr. MAPP system (mixed reality MT with exergames: Bubble Burst, Pedal, Piano games)	1 month	Daily sessions	NRS, SF-MPQ, Patient-Specific Functional Scale	No clear baseline pain intensity reported	No clear trends in pain scores	Not statistically significant due to small sample size; 1/4 participants reported functional improvement
Lendaro et al[26], 2024 (n = 81)	RCT	XR (VR/AR)	Phantom motor execution using myoelectric pattern recognition to control XR environment vs PMI with guided mental rehearsal	Variable (28–40 weeks total)	15	PRI from SF-MPQ, NRS	Phantom motor execution: NRS: 4.48 ± 2.77, PRI: 14.5 ± 8.78, PMI: NRS: 4.04 ± 2.87, PRI: 14.71 ± 7.28	Phantom motor execution: NRS change = 1.97 ± 0.11, PRI change = 9.35 ± 0.22 PMI: NRS change = 1.25 ± 0.18, PRI change = 10.03 ± 0.45	64.5% (phantom motor execution) and 68.2% (PMI) reduction in PRI; 71% (phantom motor execution) and 68% (PMI) experienced ≥ 50% pain reduction

AR: Augmented reality; MR: Mixed reality; MT: Mirror therapy; NRS: Numerical Rating Scale; PLP: Phantom limb pain; PMI: Phantom motor imagery; PRI: Pain Rating Index; RCT: Randomized controlled trial; SF-MPQ: Short-Form McGill Pain Questionnaire; VAS: Visual Analog Scale; VR: Virtual reality; XR: Extended reality.

VR treatment of PLP

VR technology has shown promise by providing a sense of realism during training, thereby promoting skill acquisition and retention, and inducing functional recovery in area of neurorehabilitation[28]. The reduction and cure of PLP is achieved through activated the cortical representation of the phantom[29]. This indicates that PLP is also a task for neurorehabilitation, so VR technology should be equally effective in alleviating PLP. In terms of technical application, constructing a virtual environment provides participants with immersive visual VR experiences. By engaging multiple senses, it diverts attention from PLP and guides the reshaping of brain neurons, thereby achieving pain relief[16].

First of all, VR can completely substitute MT. There are several methods to achieve the reproduction of residual limbs. The first method is to display the image of the healthy side in reverse, which is a direct copy of MT. Osumi et al[17,30] had the patient wear a display that presented an inverted image of their entire arm (virtual phantom limb), inducing the patient to perceive the autonomous execution of the phantom limb during residual limb movement. They utilized the Short-form McGill Pain Questionnaire to assess the characteristics of PLP in 19 patients, achieving a pain relief rate (or PLP alleviation rate) of 52.1% ± 38.2% from a single session of VR mirror visual feedback therapy. Compared to MT, this method increases the range of motion; however, if the patient has bilateral amputations, the mirror effect is absent. The second method involves a fully virtual limb, similar to those in a VR game, where the patient controls the movement of the virtual limb using a joystick[31]. Rutledge et al[18] developed a VR environment for cycling and designed a specialized device for patients with prosthetic limbs. This device allows the movement of the prosthetic limb to be reflected in the VR environment and displayed in the imaging system of the helmet, enabling patients to see the feedback of their phantom limb movements within the virtual setting. A meta-analysis[32] showed that both MT and VR were equally effective in alleviating PLP, with neither demonstrating superior efficacy. Nonetheless, larger randomized controlled trials are still needed.

VR technology achieves its intervention effect by cheating the brain, but patients often harbor higher expectations for such technology. The interaction between patients and their limbs in the virtual world is achieved through simple movements, yet it lacks the patients' own perception. Ichinose et al[33] had participants to use VR devices for neurorehabilitation exercises. During this process, participants operated the virtual limbs to touch their cheeks, while real tactile stimuli were provided through motors. The results showed that the median pain reduction rate in the cheek intervention group (33.3% ± 24.4%) was significantly higher than that in the intact hand control group (16.7% ± 12.3%) and the no-stimulation control group (12.5% ± 13.5%, P < 0.05). This indicates that applying sensory feedback to the patient's cheeks can significantly enhance the analgesic effect of visual feedback during phantom limb movement. This suggests that a treatment approach combining VR with tactile and visual multisensory feedback is of great significance for pain relief in patients.

In addition to using VR alone, combining it with electromyographic control techniques offers new perspectives for treating PLP. Using VR technology, an immersive environment can be created that diverts patients' attention from pain, while electromyographic control captures and analyzes muscle activity in real time and regulates limb movements with external devices. This not only enhances the interactive effects of treatment but also helps patients reshape their perception of their limbs. Chau et al[34] utilized immersive VR MT, and equipped patients with armband electromyographic controllers to enable control over the virtual hand. After five treatments, scores from three scales indicated a significant reduction in pain ratings by 55%, 60% and 90%. The execution of phantom limb movement through electromyographic pattern recognition and VR-assisted percutaneous muscle electrical (PME) stimulation has been identified as a viable treatment for PLP. By positioning electrodes at the distal end of the residual limb and conducting treatments, stronger muscle signals were generated during several training sessions, significantly reducing the severity of PLP[19].

In addition to relieving PLP, VR technology has also been shown to improve depression and mental health in amputees[35]. VR has shown unique advantages in the treatment of PLP, which deserves further application and research.

AR treatment of PLP

AR technology integrates the virtual subjects generated by computers with the user's real-world surroundings. This is achieved through photoelectric display technology, interactive technology, multiple sensor technology, and computer graphics and multimedia technology. It enhances the interaction between users, digital content and the real world, allowing for the display of virtual images while maintaining transparency[36]. Compared to VR, AR has a greater degree of integration with the real environment, enabling patients to receive virtual auxiliary content related to treatment within the familiar real-world setting, thereby reducing the sense of isolation that pure virtual scenes can bring.

By overlaying a virtual hand model onto the residual limb using AR glasses and controlling it with electromyography (EMG) signals from the residual limb, patients are encouraged to practice using the virtual hand through games[37]. Ortiz-Catalan et al[20] combined machine learning, AR, VR and serious games for PLP intervention, and the treatment process selectively repeated each step according to its difficulty level. To the end, this approach reduced pain distribution by 47%, decreased Numerical Rating Scale (NRS) scores by 32%, and lowered Visual Analog Scale scores by 51%. This treatment method also reduced the impact of pain on daily life and sleep quality, and significantly decreased the use of analgesics. Studies are now required to examine the magnitude of effects compared with alternative treatments, or placebo, to determine whether this treatment warrants the investment in resources and training that would be required to deliver this therapy in practice[38]. A virtual arm visualization, aligned with the individual's phantom limb perception, was integrated into an AR intervention. Seven participants with PLP and telescoped phantom limbs underwent eight supervised, home-based AR training sessions (each lasting 45 minutes) over a period of 2 weeks. The virtual arm was superimposed onto the participants' residual limbs using EMG for control. The AR training sessions comprised three tasks designed to re-engage neural circuits associated with the lost limb. Measures of agency (using the Rubber Hand Illusion questionnaire) and telescoping (through proprioceptive drift and felt telescoping assessments) were monitored following each training session. Functional magnetic resonance imaging during lip pursing was conducted before and after the intervention. The pain rating index scores decreased by 52%, while the NRS scores for PLP severity (ranging from 0 to 6) in patients benefiting from the intervention were reduced by 41%[21].

Keesom et al[39] utilized AR devices for PME treatment. Most participants who had undergone limb amputation and experienced chronic PLP described the PME treatment as a valuable addition to their strategies for alleviating PLP. The PME treatment transformed passive pain management into an active strategy, with positive effects on quality of life, sleep and energy levels. Learning to control the phantom limb and normalizing its perceived size were found to contribute to successful treatment outcomes.

MR treatment of PLP

MR technology is a combination of VR and AR in three-dimensional (3D) applications. A core feature of MR technology is to introduce and integrate 3D hologram into the real world seen by users, and establishes interactive feedback loop between the virtual world and the real world to enhance the sense of reality and space of user experience. Compared to AR and VR, MR not only anchors virtual objects into the physical world, enabling the user to interact with both virtual and real objects, but also allows the user to experience depth and perspective, which significantly improves 3D visualization of surgical anatomy[40].

MR technology is often used for surgical navigation and medical education rather than entertainment[14,41,42]. MR technology seamlessly integrates virtual limbs and scenes with the real environment, allowing patients to perceive both the real world and virtual therapeutic elements simultaneously. This approach enables treatment to occur in familiar, real-world settings. The research on MR for PLP has been conducted by the same team since 2017. Over 7 years, the team has progressed from initially using the system to verify its therapeutic effects to more recent studies that apply it to various scenarios, such as the home environment, thus achieving deeper and broader applications. In 2017, Bahirat et al[43] introduced a new MR system called Mr. MAPP, aiming to improve the treatment outcomes for patients with PLP. The system utilized an RGB-D camera to capture real-time 3D models of the patient and generates skeletal structures of the missing limb using computer vision and graphics technology, enabling natural interaction with virtual objects. Research findings indicated that Mr. MAPP had significant value in alleviating PLP and received positive feedback from users, marking a crucial breakthrough in MR technology in this field. In 2022, researchers conducted clinical feasibility studies, confirming the practicality of Mr. MAPP and demonstrating its potential to improve pain and function in patients with PLP[27]. By 2023, researchers released their latest findings, exploring the application of the Mr. MAPP system in home environments to evaluate its effectiveness for patients with PLP. The study required PLP patients to use the system at home and record their daily pain intensity to analyze its impact on pain perception and daily function. The results demonstrated that this method was indeed effective. Researchers noted that using MR technology can avoid issues such as skin color and clothing misalignment that often occur with VR due to over-reliance on virtual limb models, but its immersion is slightly less than that of VR[44].

Although research on MR for PLP is still in an early stage, it has made considerable progress by merging with the real world through virtual representations of real objects and human–computer interaction. This method overcomes the limitations of VR being isolated from the real environment and AR lacking human–computer synchronization. Treatment outcomes and patient satisfaction could be enhanced by applying MR to personalized treatment, where real-time monitoring of patient responses can assist in adjusting intervention strategies.

PERSPECTIVES

In recent years, the rapid development of XR technology has gradually drawn attention to its potential applications in the medical field, profoundly transforming human production and lifestyle. XR technology has expanded beyond gaming and commercial sectors into emerging areas such as healthcare, education and manufacturing, with industry penetration rates continuously on the rise. Many digital therapies based on XR technology have been approved by the United States FDA[13]. In addition, XR technology has been used to treat a variety of diseases, such as insomnia[45], post-traumatic stress disorder[46], stroke[47] and anxiety disorder[48], and the scope is expanding. It is believed that, in the near future, XR technology will help more diseases (Figure 3)[49].

Figure 3 Future development of extended reality. BCI: Brain–computer interface; EMG: Electromyography; PLP: Phantom limb pain; RCT: Randomized controlled trial; XR: Extended reality.

XR technology offers a new approach by providing an immersive therapeutic environment and a multisensory experience for PLP patients. However, relying solely on XR technology may not fully address PLP. Therefore, it is advisable to combine XR with other treatments, such as physical therapy and electromyographic control. During physical therapy (including massage and physiotherapy), XR technology can be utilized to control virtual limbs for simulated movements. This involves overlaying virtual motion guidance information onto the patient's residual limb, allowing for a more intuitive understanding of whether their movements meet the necessary requirements. Additionally, EMG signals can offer real-time feedback on muscle activity, enabling patients to adjust their muscle states in real-time based on this feedback, thereby enhancing the rehabilitation outcomes for patients with PLP. In the future, brain–computer interface technology could be integrated to collect and decode the EEG signals generated when patients control virtual limbs, providing a more intuitive reflection of the sensory status of the affected limb and transmitting it back to XR devices to adjust treatment plans in real time, achieving personalized and dynamic therapeutic feedback.

CONCLUSION

The number of studies using VR/AR/MR technology to treat PLP is gradually increasing. However, due to common issues such as small sample sizes and less rigorous experimental design, although many positive results suggest that XR technology may become a potential nonpharmacological treatment for PLP, more long-term research and large-scale clinical trials are still required to verify the long-term effectiveness and safety of XR technologies.