phantom limb pain pathophysiology

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Phantom Limb Pain

Introduction.

In the United States (U.S.), 30,000 to 40,000 amputations are performed each year. Amputations can occur for many reasons including severe trauma, tumors, vascular disease, and infection. Pain after amputation of a limb is a common symptom and is separated into two types of pain including residual limb pain (RLP) and phantom limb pain (PLP). PLP is clinically defined as the perception of pain or discomfort in a limb that no longer exists. Although PLP most commonly presents as pathological sequelae in amputee patients, the underlying pathophysiology remains poorly understood. Furthermore, PLP can present along a wide clinical spectrum and varying severity of symptoms. The condition should be differentiated from other related but separate clinical conditions, including RLP. This latter condition, formerly known as "stump pain", is pain that originates from the actual site of the amputated limb. It is most common in the early post-amputation period and tends to resolve with wound healing. Unlike PLP, RLP is often a manifestation of an underlying source, such as nerve entrapment, neuroma formation, surgical trauma, ischemia, skin breakdown, or infection. [1] [2]  Of note, more than half of people with PLP also have RLP. It is important to know the difference between the two because the causes and treatments for each differ, but also be aware that both of these elements can coexist at the same time. [3]  

PLP and RLP represent an important challenge in medicine, in terms of epidemiology and therapeutic difficulties. Ninety-five percent of patients, indeed, report experiencing some amputation-related pain, with 79.9% reporting phantom pain and 67.7% reporting RLP. Again, these clinical manifestations can significantly worsen the health-related quality of life (HR-QOL) and in some cases are very difficult to manage. 

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The exact etiology of PLP is unclear. Multiple theories have been debated, and the only agreement is that multiple mechanisms are likely responsible. The predominant theory for years involved the irritation of the severed nerve endings causing phantom pain. This was enforced by evidence that almost all amputation patients will develop neuromas in the residual limb. Over the last few decades, advances in imaging and laboratory techniques have shown evidence of central nervous system (CNS) involvement. Imaging studies such as MRI and PET scans show activity in the areas of the brain associated with the amputated limb when the patient feels phantom pain. The pain is now thought to involve many peripheral and central nervous system factors. [4] [5]

Epidemiology

In 2005, there were 1.6 million people (1 in 190) living with limb loss in the U.S. This same study projected a striking increase to 3.6 million cases by 2050.  The literature reports PLP affecting 60% to 85% of amputee patients. [6]   The following underlying causes are given clinical consideration:

  • Vascular etiologies (most common)
  • Cancer/malignancy
  • Congenital conditions

Pathophysiology

Despite, the phantom limb sensation was described by French military surgeon Ambroise Pare (1510-1590) in the sixteenth century, even today we do not have a clear explanation of this complex phenomenon and, therefore, the pathophysiology is explained by a wide range of mechanisms. These mechanisms. which are the basis of theories, they are not necessarily mutually exclusive

Peripheral Nerve Changes

During the amputation, there is a significant amount of trauma that occurs in the nerves and surrounding tissues. This damage disrupts the normal afferent and efferent signals involved with the missing limb. The proximal portions of the severed nerves start to sprout neuromas, and the nerves become hyper-excitable due to an increase in sodium-channels and resulting in spontaneous discharges.

Spinal Cord Changes

In the spinal cord, a process called central sensitization occurs. Central sensitization is a process where neural activity increases, the neuronal receptive field expands, and the nerves become hypersensitive. This is due to an increase in the N-methyl-D-aspartate, or NMDA, activity in the dorsal horn of the spinal cord making them more susceptible to activation by substance P, tachykinins, and neurokinins followed by an upregulation of the receptors in that area. This restructuring of the neural components of the spinal cord can cause the descending inhibitory fibers to lose their target sites. The combination of increased activity to nociceptive signals as well as a decrease in the inhibitory activity from the supraspinal centers is thought to be one of the major contributors to phantom limb pain.  [7]

Brain Changes

Over the past few years, there has been significant research into cortical reorganization and is a commonly cited factor in phantom limb pain.  During this process, the areas of the cortex that represent the amputated area are taken over by the neighboring regions in both the primary somatosensory and the motor cortex. Cortical reorganization partially explains why nociceptive stimulation of the nerves in the residual limb and surrounding area can cause pain and sensation in the missing limb. There is also a correlation between the extent of cortical reorganization and the amount of pain that the patient feels.  [8]

Psychogenic Factors

Chronic pain has been shown to be multi-factorial with a strong psychological component. Phantom limb pain can often develop into chronic pain syndrome and for treatment to have a higher chance of success the patient's pain behaviors and pain processing should be addressed. Depression, anxiety, and increased stress are all triggers for phantom limb pain.  [9]

History and Physical

PLP is often described as tingling, throbbing, sharp, pins/needles in the limb that is no longer there. It occurs more commonly in upper extremity amputations than lower extremities and tends to be intermittent in frequency. Pain severity varies, and onset can be immediate or years afterward. It is important to try and distinguish PLP from RLP. The goal of the physical exam is to rule out the causes of RLP. First, the skin should be carefully inspected for evidence of wounds or infection. Sensation needs to be tested, along with looking for allodynia and hyperalgesia. The joint above the amputated limb should be examined for any signs of dysfunction. in terms of pain intensity, RLP usually is not severe, and features pressing, throbbing, burning, squeezing, and stabbing sensations.

The diagnosis of PLP pain is primarily a diagnosis of exclusion and heavily dependent on the patient's history.  Because of this lab tests are often not needed.  A complete blood count (CBC) can help rule out infection. An ultrasound can be ordered to look for neuromas as a possible pain generator. A psychology evaluation may be indicated if the patient is having a significant amount of extrinsic triggers that may be contributing to his or her pain.

Treatment / Management

Treatment, unfortunately, for PLP has not proven to be very effective. While treatment for RLP tends to focus on an organic cause for the pain, PLP focuses on symptomatic control.

Pharmacotherapy

  • NSAIDs/Tylenol are the most commonly used treatment for PLP. [10]
  • Opioids. Although observational and randomized controlled trials have demonstrated the effectiveness of certain opioids such as tapentadol for neuropathic pain  [11] and PLP, they should be used in conjunction with antidepressants or neural modulating agents (i.e., gabapentin, pregabalin).  [12] . Furthermore, their use in a condition of benign pain should be done with caution in order to avoid potential effects from tolerance and dependence.  [13]
  • Antidepressants are commonly used for addressing PLP. Amitryptiline, in particular, tends to be the tricyclic antidepressant (TCA) of choice as it has shown the best overall results, but other studies looking at nortriptyline and desipramine have shown them to be equally effective. However, most of these studies were not very rigorous and in a 6 week randomized trial between amitriptyline and placebo involving 39 patients, there was no significant difference between the two.  [14] Duloxetine is another medication that has been showing some positive results.  [15]   
  • Anticonvulsants (gabapentin, pregabalin) have shown mixed results.  [16]   The results overall for gabapentin have been conflicting, but a Cochrane review examining multiple studies did feel that the combined results favored Gabapentin over placebo.  [17]
  • N-methyl-d-aspartate (NMDA) receptor antagonist mechanism is not clear. These drugs have been shown to have benefit in pain syndromes, primarily with ketamine and dextromethorphan. Memantine has had mixed results. In the Cochrane review of 6 studies that were included looking at memantine versus placebo, there was no statistical improvement in pain between the groups  [17] .  Ketamine infusions have shown much better results than memantine, although the results between the two are not clear given their similar mechanisms. There is level 2 evidence to support the use of Ketamine infusions for the treatment of PLP  [18] .
  • Beta-blockers (propranolol) and calcium channel blocker (nifedipine) show unclear data.
  • Topical Analgesics like Capsaicin have been shown in some small studies to reduce hypersensitivity and PLP, but the evidence is still weak and requires more investigation.  [19] [20]
  • Botulinum toxin type B injections have been used to treat hyperhidrosis (excessive sweating) in the post-amputation patient. Hyperhidrosis can not only hinder the use of a prosthetic but can adversely affect the course of both the phantom limb and RLP. Treatment of hyperhidrosis with botulinum toxin type B injections has shown in several small studies to reduce RLP, PLP, and sweating.  [21]   Botulinum toxin type A is also being investigated, but so far has not been shown to decrease pain intensity compared to lidocaine/methylprednisolone.  [17]
  • Local anesthetics. A Cochrane review looked at two studies examining the effectiveness of local anesthetics, lidocaine infusion at 4mg/kg and bupivacaine 0.25% as a contralateral myofascial injection, in treating PLP in randomized trials. The one-time contralateral myofascial injection of 1cc bupivacaine 0.25% showed significantly improved pain relief in the 8 patients studied  [22] .  Lidocaine infusion was not found to have any significant improvement compared to placebo  [23]
  • Other pharmacological strategies such as calcitonin have no clear evidence.

Non-Pharmacologic Options

  • Transcutaneous electrical nerve stimulation (TENS) shows moderate evidence supporting its use. Low-frequency and high-intensity are thought to be the most effective for PLP. It may also be used to help relieve RLP.
  • Mirror therapy. A small randomized trial of mirror therapy in patients with lower leg amputation showed a significant benefit of PLP. [24] Another study was minimally helpful.
  • Biofeedback shows limited evidence.
  • Acupuncture research is still ongoing.
  • Spinal cord stimulation (SCS) is obtained through an implantable device that stimulates transdural dorsal columns of the spinal cord. It is often effective therapy for PLP. 
  • Apart from TENS and SCS, other neuromodulation approaches such as peripheral nerve stimulation (PNS) can be helpful for both PLP and RLP.
  • Virtual and Augmented Reality has provided some novel opportunities to utilize technology as an advanced form of "mirror therapy."  Researchers have been able to program myoelectric movement patterns from the RLP into the virtual or augmented reality headsets and then correlate those movements to the movements of the "complete" limb in the virtual world.  This has been shown in several case studies to be effective treatments for PLP, but no large studies have been conducted.  [25]   [26]
  • A sympathetic block may also help.
  • Stump revision

Differential Diagnosis

  • Septic arthritis
  • Osteomyelitis
  • Foreign body reaction

Enhancing Healthcare Team Outcomes

PLP is very complex and difficult to treat. It is best managed by an interprofessional team The first treatment is usually conservative and should include nonpharmacological and nonsurgical methods. The prosthetic professional should assess the stump and train the patient in the use of the prosthetic device. A mental health nurse and psychotherapist should help ease anxiety and depression. If this fails, The pharmacist should work with the clinician to select an appropriate agent, as well as educate the patient on the different pharmacological agents available, their effectiveness, and their adverse effects. A pain specialist should be involved as well

There is no one treatment that works reliably or consistently in all patients. Most patients are prescribed multiple agents to control pain, but tragically, this polypharmacy also has serious adverse effects that tend to lower compliance. Patients with PLP often doctor shop and try many types of conventional and non-conventional therapies to relieve the pain.

A pain referral should be ordered and the patient's HR-QOL should be improved. 

Patient education is key and members of the team should communicate with each other so that the patient is provided with optimal treatment. The outcomes for most patients are guarded and the quality of life is poor.

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Phantom-limb pain: characteristics, causes, and treatment

Affiliation.

  • 1 Department of Clinical and Cognitive Neuroscience, University of Heidelberg, Central Institute of Mental Health, Mannheim, Germany. [email protected]
  • PMID: 12849487
  • DOI: 10.1016/s1474-4422(02)00074-1

Phantom-limb pain is a common sequela of amputation, occurring in up to 80% of people who undergo the procedure. It must be differentiated from non-painful phantom phenomena, residual-limb pain, and non-painful residual-limb phenomena. Central changes seem to be a major determinant of phantom-limb pain; however, peripheral and psychological factors may contribute to it. A comprehensive model of phantom-limb pain is presented that assigns major roles to pain occurring before the amputation and to central as well as peripheral changes related to it. So far, few mechanism-based treatments for phantom-limb pain have been proposed. Most published reports are based on anecdotal evidence. Interventions targeting central changes seem promising. The prevention of phantom-limb pain by peripheral analgesia has not yielded consistent results. Additional measures that reverse or prevent the formation of central memory processes might be more effective.

Publication types

  • Research Support, Non-U.S. Gov't
  • Neuronal Plasticity / physiology
  • Pain, Postoperative / etiology*
  • Pain, Postoperative / physiopathology
  • Pain, Postoperative / psychology
  • Pain, Postoperative / therapy*
  • Phantom Limb / etiology*
  • Phantom Limb / physiopathology
  • Phantom Limb / psychology
  • Phantom Limb / therapy*

phantom limb pain pathophysiology

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Review Free access | 10.1172/JCI94003

A review of current theories and treatments for phantom limb pain

Kassondra l. collins, 1 hannah g. russell, 2 patrick j. schumacher, 2 katherine e. robinson-freeman, 2 ellen c. o’conor, 2 kyla d. gibney, 2 olivia yambem, 2 robert w. dykes, 3 robert s. waters, 1 and jack w. tsao 2,4,5.

1 Department of Anatomy and Neurobiology and

2 Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

3 School of Physical and Occupational Therapy, McGill University, Montreal, Quebec, Canada.

4 Department of Neurology, Memphis Veterans Affairs Medical Center, Memphis, Tennessee, USA.

5 Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, Tennessee, USA.

Address correspondence to: Jack W. Tsao, Department of Neurology, University of Tennessee Health Science Center, 855 Monroe Avenue, Suite 415, Memphis, Tennessee 38163, USA. Phone: 901.448.7674; Email: [email protected] .

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Published June 1, 2018 - More info

phantom limb pain pathophysiology

Following amputation, most amputees still report feeling the missing limb and often describe these feelings as excruciatingly painful. Phantom limb sensations (PLS) are useful while controlling a prosthesis; however, phantom limb pain (PLP) is a debilitating condition that drastically hinders quality of life. Although such experiences have been reported since the early 16th century, the etiology remains unknown. Debate continues regarding the roles of the central and peripheral nervous systems. Currently, the most posited mechanistic theories rely on neuronal network reorganization; however, greater consideration should be given to the role of the dorsal root ganglion within the peripheral nervous system. This Review provides an overview of the proposed mechanistic theories as well as an overview of various treatments for PLP.

Amputations cause changes in both the PNS and CNS, including the emergence of phantom limb sensations (PLS), characterized by the feeling that the amputated limb is still present. Most amputees experience PLS and can even control phantom movements, such as wiggling toes or opening and closing the hand, immediately after surgery ( 1 , 2 ). The majority of amputees also experience intense episodes of pain throughout the missing limb that are termed phantom limb pain (PLP), characterized by throbbing, stabbing, electric shock sensations, and even cramped and painfully immobile limb sensations ( 3 ).

A French surgeon, Ambroise Paré, was likely the first to document an instance of PLP, in the 16th century ( 4 ), but the term did not arise until the American Civil War, when it was described by military battlefield surgeon (and later, neurologist) Silas Weir Mitchell ( 5 ). Clinicians did not appreciate the high incidence or pathophysiological basis of PLP until recently. They often attributed PLP to psychological problems, especially during the Civil War era ( 6 , 7 ). During World War II, nearly 15,000 US service members lost a limb during combat ( 8 ). Many amputees did not publicly share their PLP experiences for fear of being stigmatized as mentally ill ( 7 ).

Approximately 1.9 million amputees live in the US, with worldwide projections expected to double by the year 2050 ( 9 ). Amputations are commonly a consequence of diabetes mellitus, trauma, and cancer ( 9 ). Combat-related limb loss is also a frequent cause of amputation: as of January 1, 2018, 1,718 US military service members had lost at least one major limb in Iraq or Afghanistan ( 10 ). The majority of amputees, but not all, experience PLP to some extent, with varying degrees of severity, frequency, and episode duration. PLP eventually dissipates or disappears in some, while others report no change in frequency or severity ( 11 ). Estimates of PLP incidence differ considerably, depending in part on the sampled population as well as the methods of reporting and data collection. In one large, frequently cited survey of amputees, 78% reported experiencing PLP ( 12 ).

Considered a neuropathic pain or “complex pain state of the somatosensory nervous system” ( 13 ), PLP is thought to be driven by CNS abnormalities. However, research investigating the contribution of the PNS and its function also needs to be considered ( 14 ). While the mechanisms underlying PLP remain unclear, it is known that sensitized and reorganized nerve endings and cell bodies within the peripheral limb affect the CNS, causing changes in somatosensory processing pathways ( 15 ). PLP presents a considerable impairment to amputees’ quality of life, and a better understanding of its pathophysiology and etiology could lead to new modalities to alleviate the suffering it causes. This Review aims to provide up-to-date knowledge regarding the current state of PLP theories, research, and therapies.

Researchers and clinicians continually debate the mechanisms of PLP and the contributions of the CNS and/or the PNS. Currently, the most commonly posited CNS theory is the cortical remapping theory (CRT), in which the brain is believed to respond to limb loss by reorganizing somatosensory maps ( 16 ). Early theories focused solely on the contribution of neuromas (abnormal growth or thickening of nerve tissue), although there was evidence of pain immediately after surgery ( 17 ). More recent research on the peripheral causes of PLP focuses on the inability of the severed nerves to repair previous connections (with or without neuroma formation), the role of the dorsal root ganglion (DRG), and preamputation pain ( 18 , 19 ). While an amputation directly affects the PNS, the CNS is also affected due to changes in sensory and movement signaling. Debate still remains over the cause and maintaining factors of both phantom limbs and the associated pain.

Neuromatrix representation. Many of the theories explaining the causation of PLP rely on the concept of a representation of the self within the brain that is modified by life experiences, termed the neuromatrix ( 19 ). After limb amputation, an individual’s cortical and peripheral body representations remain intact, but no longer correspond, and this mismatch is enhanced by a lack of visual feedback from the missing limb, thus generating excessive pain, in spite of the lack of a sensory stimulus ( 20 ). A study investigating the relationship between body representation within a dream and the experience of PLP found a positive correlation between increased PLP after lower limb amputation and the ability to recall intact body representations ( 21 ). These findings suggest that aversive somatosensory experiences mediate the skewed interactions between mental and physical body representations, which then facilitate PLP ( 21 ).

Research investigating the malleability of the neuromatrix has attempted to determine the ability of the brain to adjust to sensory stimuli. An example is the rubber hand phenomenon, which occurs when an able-bodied person perceives a rubber hand as his or her own. To achieve this effect, the person’s own hand is hidden from view, typically under a table, while a rubber hand is put in front of his or her body ( 22 ). Both the rubber and the actual hands are synchronously stroked with a brush, causing the person to perceive the rubber hand as his or her own ( 22 ). To test rubber hand incorporation into the neuromatrix, the researchers strike the rubber hand with a hammer ( 23 ). Participants flinch in fear of pain, even though the actual body part is unharmed ( 23 ), demonstrating that the neuromatrix is rapidly malleable/adaptable and is greatly affected by visual representations and somatosensory stimuli.

Although the rubber hand demonstration does not show that conflicts within the neuromatrix cause pain, discomfort similar to that experienced by amputees can be induced in able-bodied volunteers by causing conflict between motor and sensory processes ( 24 ). In another study, volunteers moved their upper and lower extremities in a congruent or incongruent fashion while viewing such movements in a mirror or with their view blocked by a whiteboard. The majority of reported symptoms occurred while participants completed incongruent movements while viewing the reflection of the limb in the mirror, causing the most conflict between motor and sensory processes. The symptoms reported included numbness, pins and needles, aching, and uncomfortable pain ( 24 ), demonstrating that conflicts among visualization, somatosensory input, and cortical representation may play a role in PLP.

The CRT posits that cortical reorganization accounts for the neurophysiological origin of PLP (ref. 17 and Figure 1A ). According to the CRT, neurons that received input from an arm before its amputation subsequently respond to new inputs from the face that invade the nearby arm-associated somatosensory region; consequently, with facial stimulation, an amputee may experience PLS, including pain ( 11 , 25 ). Expansion and invasion within the somatosensory cortex have been attributed to a lack of sensory information reaching the cortical area that once controlled the missing limb ( 26 ). The mammalian brain is remarkably plastic, and investigations of both simian and human brains have shown somatosensory cortical rearrangement in response to amputation.

Cortical contributions to PLS and PLP. ( A ) Body part sensory and motor representation are laid out in a pattern that forms the cortical homunculus and receives sensory information (e.g., tactile, olfactory, or pain) from different areas of the body ( 24 ). Following amputation, a cortical region that received sensory or motor projections from the amputated limb may begin to receive sensory or motor input, respectively, from neighboring cortical regions, which expand to take over the region that previously controlled the amputated limb ( 27 , 28 ). ( B ) Proprioceptive memory, which stores information about the position of the limb in space relative to the body, may influence cortical reorganization in the CNS. These memories may store information about the final position of the missing limb or, in combination with cortical reorganization, may affect PLS or PLP. This image illustrates rapid changes in cortical activation patterns that can occur simply with repositioning of the phantom limb, manifested as changes in the location of hand sensations mapped onto the face.

Early research on animals using microelectrode-mapping techniques provided evidence for the reorganization of cortical maps in the somatosensory cortex following amputation ( 27 ). In their seminal study, Merzenich and colleagues found that after long-term deafferentation from removal of a digit, the neurons in the cortical map of an amputated middle finger started to respond to stimuli applied to the adjacent digits. Similarly, facial sensations in a corresponding area of the phantom hand were detectable 24 hours after amputation in a person, which is suggestive of cortical reorganization ( 28 ). In a human functional MRI study, investigators reported that the lip area of the somatosensory cortex contralateral to the side of amputation was located more medial and superior than the lip area contralateral to the intact limb ( 29 ). Researchers also observed reduced cortical reorganization after the administration of brachial plexus anesthesia, with the lip area shifting away laterally from the amputation zone ( 29 ). Furthermore, under spinal anesthesia, PLS and pain arise in patients who have never experienced PLS or PLP previously ( 30 ). Recently, we reported that a man who suffered a brachial plexus avulsion (BPA) (an injury to the nerves of the cervical spinal cord) noted rapid onset of PLS and developed hand-to-face remapping, which reversed following nerve grafting ( 31 ). These observations suggest that cortical remapping might be explained by an unmasking of normally dormant synaptic connections or a rapid shift of cortical network connections in addition to the formation of new connections that occurs later with axonal sprouting ( 31 , 32 ). This unmasking could result from a decrease in the number of neurons releasing GABA, the main inhibitory neurotransmitter in the brain, after deafferentation ( 33 ). A study of cortical maps found that GABA-mediated inhibition in the motor cortex led to sporadic, involuntary limb movements, suggesting that maintenance of normal GABA levels can suppress cortical reorganization that might lead to PLP ( 33 ). Furthermore, GABA levels are also known to fluctuate in the PNS.

Other research, however, argues that the integrity of the excised limbs’ cortical map during PLS is maintained due to PLP experiences. A recent series of experiments found no robust relationship between cortical rearrangement and PLP, arguing that many different factors may play roles in maintaining structural, and even functional, capabilities necessary to control phantom limbs ( 34 ). Makin’s group proposes that both bottom-up (peripheral to central) and top-down (central to peripheral) pain pathways maintain the cortical representation of the limb and facilitate PLP ( 34 ). In this research, phantom movements and motor imagery were used to elicit responses instead of sensory stimulation. Such factors may explain the different findings.

The role of the somatosensory cortex in PLP is greatly debated. Penfield extensively studied the brain with electrical stimulation, finding no areas that produced pain, not even the somatosensory cortex ( 35 ). However, transcranial magnetic stimulation (TMS) to the sensory cortex has been shown to reduce PLP, demonstrating that the area does play some role in such pain ( 36 ). A recent case study reported that upper-extremity PLP relief was achieved in a person after 28 sessions of repetitive TMS ( 36 ). More research is needed to determine the mechanisms and causation of PLP and whether changes in the cortex after amputation play a role in pain and/or sensation.

Somatosensory and motor cortices may not be the only areas affected by amputation. Subcortical structures, including the thalamus, may also be reorganized ( 15 , 19 , 37 ). Changes at the subcortical level may originate in the cortex and cause reorganization through strong efferent connections to the thalamus and lower structures ( 37 ). It is also possible that reorganizational processes begin at the thalamic level and changes are relayed up to the cortex ( 19 ). In an effort to map the thalamus in amputees, researchers using microstimulation and microelectrode recordings found that the representation of the residual limb in the thalamus was enlarged compared with that of corresponding areas of individuals with intact limbs and that thalamic stimulation could evoke PLS and even PLP in amputees ( 38 ).

The thalamus has also been investigated as the sole pain-generating structure. Studies have shown that, following spinal cord injury, hyperexcitability of thalamic neurons is independent of synaptic drive from spinal neurons, suggesting that the thalamus can be transformed into an autonomous pain-signal generator ( 39 ). Patients with spinal cord injury often experience PLP and PLS ( 39 ). In a rodent model, forelimb amputation resulted in reorganization in both deafferented primary somatosensory cortex and the ventral posterior nucleus of the thalamus, the latter of which relayed the new input to the deafferented cortex ( 40 ). This finding lends further credence to a thalamic contribution to cortical reorganization.

Another possible mechanism underlying PLP is proprioceptive memory. Proprioception is the brain’s awareness of the position of the body’s limbs in 3D space. Amputees continue to have proprioception of missing limbs, including both voluntary and involuntary movements. A voluntary movement sensation includes an amputee’s attempt to move the phantom limb, while an involuntary movement sensation is the feeling of the limb being frozen or sporadically moving on its own ( 32 ). One theory posits that the proprioception needed to perform specific tasks may be incorporated into a “proprioceptive memory” that aids us in accomplishing the tasks more quickly and efficiently in the future ( 41 ). When an amputation occurs, memory engrams of the limb are retained even though visual feedback confirms limb absence ( Figure 1B ). Supporting this theory is a study of limb repositioning after regional anesthesia, with patients reporting that their limbs remained in the last position they remembered before anesthesia ( 42 ). It is also possible that proprioceptive memories provide a protective feature, serving as a reminder of painful situations and how to remedy them, such as moving a joint out of hyperextension without having to confirm with visual feedback ( 41 ). Thus, certain positional movements with the phantom limb may trigger these painful proprioceptive memories. Amputees have reported feeling their phantom limbs stuck in the last positions they remembered prior to amputation, supporting a stored proprioceptive memory as the final feedback from the limb ( 43 ).

Limb movement typically relies on both visual and proprioceptive systems working together. For instance, vision primarily guides hand movements toward a target. While the hand is moving, the brain receives proprioceptive feedback regarding the location of the limb relative to the body. The brain coordinates each piece of information to complete the directed movement. With an amputation, visual feedback of the now-removed limb is no longer available. However, proprioception regarding the location of the once-intact limb still remains, either through proprioceptive memories or activation from the residual limb nerve endings. Perhaps the inability to visualize the amputated limb is insufficient to override the proprioceptive information from the residual limb. An alternative possibility is that the brain’s interpretation of conflicting signals from the two systems resurrects a phantom limb. The fact that visualization therapies have been relatively successful at reducing PLP implies that the accuracy provided by both visualization and proprioception may be critical in reducing PLP ( 44 ).

Unlike the well-protected CNS, the PNS is highly susceptible to injury. Early research focused on the PNS as the sole cause and maintenance factor of PLP. However, peripheral factors alone cannot mediate the emergence of PLP ( 19 ); rather, the PNS may work in conjunction with the CNS to cause and maintain the persistence of PLP. There is much debate over whether “top-down” or “bottom-up” maintenance is the cause of PLP. Bottom-up pain mechanisms imply that peripheral nerve injury causes excessive aberrant inputs that, in turn, influence changes (or lack thereof) in the cortex ( 12 , 34 ). Top-down pain modulation refers to painful sensations that are maintained by the CNS and are greatly affected by emotional state, memories, and attention ( 45 ). Some regions of the brain experience reorganizational changes after an amputation. Therefore, further research investigating the changes that occur within the residual limb after an amputation, the effects of peripheral changes on the CNS, and how each effect is maintained are crucial to expanding the knowledge regarding PLP.

The cell bodies for the somatic-component PNS axons are located in the DRG. Neurons in the DRG are PNS afferents, relaying sensory information, such as fine touch, proprioception, and vibration, to the CNS (ref. 46 and Figure 2 ). The proximal ends of DRG axons terminate in the spinal cord, the target of the somatic component being the superficial layers of the dorsal horn (DH) and the dorsal column nuclei of the brain stem. Following limb amputation, DRG axons are disconnected from their distal targets and inflammation and sprouting occur in the resulting residual limb, where a neuroma can form. Far from becoming silent and idle, the injured axons within the residual limb and remaining segment of the peripheral nerves generate spontaneous activity from ectopic, hyperexcitable loci that are propagated along the remaining pathway to the spinal cord. The electrical activity has been described as ectopic, since it is not coming from the normal end points of the axons. Thresholds are abnormal and action potentials seem to be generated spontaneously or in response to stimuli that normally would not provoke an action potential, such as mechanical stimuli (e.g., Tinel’s sign) or circulating substances, such as adrenaline ( 33 ). In the past, activity in a neuroma has been considered a possible source for PLP. Anesthetizing the residual limb or neuroma by injection was reported to attenuate or abolish PLP in some, but not all, instances ( 2 , 18 , 38 , 47 – 50 ), subsequently leading to diminished enthusiasm for a peripheral origin hypothesis of pain ( 15 , 29 , 51 ). Currently, supraspinal central mechanisms receive more attention.

Proposed peripheral contributions to PLS and PLP. The dorsal root fibers of the DRG split into lateral and medial divisions ( 38 ). The lateral division sections contain most of the unmyelinated and small myelinated axons and specifically carry pain and temperature information. The medial division sections of the dorsal root fibers (not shown) contain mostly myelinated axons that convey sensory information from the skin, muscles, and joints, such as touch, pressure, proprioception, and vibration ( 38 ). When an injury occurs to the nerves, neurons in the DRG increase their nociceptive signaling through increases in neuronal excitability and the creation of ectopic discharges ( 25 ). The resulting aberrant signaling through the spinothalamic tract may produce PLP.

Although the trauma at the site of the injury may elicit local inflammation, the responses of injured axons depend upon the cell body receiving messages from the periphery to alter somatic metabolic machinery and start the repair process. The messages that signal the nature of an injury to the cell body could be a loss of tonic electrical or chemical messages that the amputation removed. These might include lost molecular signals, sometimes known as trophic factors, from end organs or supporting elements that are no longer being sent to the nucleus by axonal transport. Alternatively, the signals could represent the loss of electrical activity that arises from the innervated tissues. Additionally, nerve transection may trigger the central propagation of molecular signals arising from the local inflammatory processes at the site of transection or from action potentials arising from the same site, perhaps secondarily to molecular changes in the environment of the severed axons ( 52 ).

The nature and time course of morphological changes in the DRG cell body following axotomy have been documented by a number of investigators (reviewed in ref. 52 ). Histological and biochemical evidence show that the cellular metabolic machinery is modified dramatically, which is described as a “phenotypic change” in the neuron ( 53 ). Although some changes are related to the growth response at the end of the residual limb, other changes occur at the axonal extensions into the spinal cord dorsal root. Modifications of the central terminals of transected axons could induce further “phenotypic changes” in the postsynaptic neurons, and the surrounding supporting elements and hundreds or even thousands of gene and protein changes occur in the transected neurons ( 52 ). Changes in the DH begin within minutes after the pattern of sensory input changes; central sensitization also begins within minutes ( 54 ), and the amplitude of the spinal reflex changes ( 55 ). It is likely that similar alterations in neuronal responsiveness occur centrally within minutes of nerve transection.

DRG soma express receptors for acetylcholine ( 56 ), glutamate ( 57 , 58 ), and GABA ( 59 ) in quantities sufficient to have strong neuromodulatory effects on sensory signaling. The receptors’ presence raises two issues. What could be the source of the substances that activate these receptors in the DRG, and what is the impact of their activation? Activation of the somatic GABA receptors may gate nociceptive transmission, but even more complex neuromodulatory effects are possible ( 59 ).

Amputation or nerve transection changes the distribution of the receptors on DRG cell bodies. Those alterations may play an important role in various forms of chronic pain, including PLP, and lend credence to the hypothesis ( 53 ) that DRG neuronal cell bodies are the source of electrical activity that drives neuropathic pain and PLP ( 60 ). Potential determinants of DRG neuronal hyperactivity include, but are not limited to, upregulation of voltage-gated sodium channels ( 61 – 63 ), downregulation of potassium channels ( 64 , 65 ), increased expression of neurotropic factors ( 66 ), and sprouting of sympathetic noradrenergic axons into the DRG ( 67 ). Over the course of the neuronal response to nerve transection, thousands of genes are either upregulated or downregulated, suggesting a potentially large list of gene products that might alter neuronal behavior after nerve transection ( 68 ).

If the PNS is the sole contributor to PLP, then it should be possible to induce anesthesia into the limb and eliminate the experience of PLP. Local anesthesia directly injected into the residual limb of amputees experiencing PLP does not lead to reduced PLP in all instances ( 29 ). However, changes within the PNS may affect the amount of cortical reorganization experienced. Even if a neuroma does not form, the nerve fibers within the residual limb can undergo spontaneous sprouting and seek new connections. Such random connections may lead to abnormal CNS feedback, resulting in modulation of cortical reorganization and the experience of PLP ( 19 ).

There is solid evidence to support the notion that the formerly unappreciated PNS, and DRGs in particular, may be important drivers of PLP and PLS. While we still do not understand the mechanisms underlying PLP, the PNS must now be considered a viable component of any theory of PLP. Currently, there are hundreds of theories in the literature, and few or none are capable of being tested rigorously. The new approaches demonstrated by Devor and colleagues ( 60 ) may help the development of testable theories able to eliminate alternative explanations.

Studies have shown that persons who experienced pain prior to amputation have higher rates of PLP ( 18 , 69 , 70 ). These studies, however, find no evidence that preamputation pain plays a role in persistent PLP, only PLP experienced immediately after surgery. For instance, one prospective study of 58 patients undergoing an amputation showed that 72% of those with preamputation pain experienced PLP eight days after amputation, which decreased to 65% at six months and 59% after two years ( 18 ). However, the location and characterization of the pain was only similar to that experienced before amputation in 10% of patients ( 18 ).

The correlation among cortical reorganization, the experience of PLP, and daily prosthesis usage has also been studied, with daily prosthesis usage found to be hindered by both the amount of cortical reorganization and the cumulative amount of PLP experienced ( 71 ). A study of a small number of amputees found those who experienced PLP demonstrated more excitable motor cortex areas and greater reorganization within the areas of the somatosensory cortex that represent the tongue and amputated limb ( 71 ). These findings suggest that somatosensory reorganization is correlated with PLP and that such reorganization may cause a secondary reorganization in the motor cortex ( 71 ). Motor reorganization and PLP severity were found to be negatively correlated with prosthesis usage, implying that the more an amputee uses the prosthesis, the less reorganization and PLP occur ( 71 ). Questions do arise, however, such as the following. Does wearing a prosthesis reduce cortical reorganization, which in turn reduces PLP? Or are those amputees who experience less cortical reorganization the ones who are more likely to use a prosthesis? Further, does the act of using the residual limb to control the prosthesis affect PLP?

A recent study examined PLP in nine BPA patients and one hand amputee using prostheses controlled by a brain-machine interface (BMI) ( 72 ). This study found that altering the plasticity of the cortical representation of the phantom hand drastically altered the associated PLP. However, in direct opposition to the ideas postulated by the CRT, increasing the phantom representation increased PLP, whereas increasing the representation of the intact hand reduced PLP, suggesting that BMI training aimed at dissociating the phantom hand from the prosthesis could be a clinically advantageous treatment for PLP ( 72 ). Many of the questions mentioned above also apply to the relationship between treating PLP using either mirror therapy (MT) or virtual reality (VR) and prosthesis usage. Preißler and colleagues recently investigated plasticity in the ventral visual streams in relationship to prosthesis usage, postulating that the observed plasticity is related to functional prosthesis use that provides increased visual feedback to the user, which is necessary for controlling the device ( 73 ). The study initially did not find a simple correlation between PLP experiences and prosthesis usage. However, a subanalysis revealed that the group experiencing high PLP rates (severity indicated on a visual analog scale) spent less time using prostheses. Amputees experiencing high amounts of PLP and with high prosthesis usage had smaller posterior parietal cortices than patients who did not use prostheses ( 73 ). Variability in the posterior parietal cortex volumes indicates that prosthesis use may drive adaptations that lead to changes within the visual stream ( 73 ). Without a somatosensory component associated with prosthesis usage, visualization is crucial and may enable changes in PLP experiences similar to MT.

A 2007 study examining the roles of vision and kinesthetic information in proprioception found that vision is more influential in regard to spatial location of a limb ( 74 ). During this study, participants experienced tendon vibration to cause the feeling of flexion movements of a limb that was immobilized. When the participants’ eyes were closed, they reported feelings of slow movement due to the vibrations. In contrast, if the participants viewed their static vibrating limbs, the perception of movement was drastically hindered, with functional imaging revealing activity in the posterior parietal cortex correlated to the attenuation of movement ( 74 ). These findings imply that the posterior parietal cortex plays a role in overcoming kinesthetic proprioceptive information when visual information is provided. Thus, from the experimental evidence, it seems reasonable to conclude that MT, VR, and prosthesis usage all may play a role in diminishing PLP by enabling the amputee to visualize a limb moving in a natural manner. However, each of these methods involves the activation of the residual limb muscles, the role of which in the reduction of PLP remains to be determined.

The most commonly administered pharmacological treatments for PLP are gabapentin and pregabalin, antiseizure medications that reduce the frequency and intensity of neuropathic pain ( 75 ). Opioids and opiates have long been used to treat neuropathic pain as well, and some research suggests that they are effective at ameliorating the symptoms of PLP ( 76 , 77 ). Opioids may relieve PLP by reducing cortical reorganization in the somatosensory cortex ( 78 ). Despite their effectiveness, opiates are frequently associated with adverse side effects, such as sedation, dizziness, nausea, vomiting, and constipation, coupled with high rates of addiction and dependence ( 79 ). Memantine is an NMDA glutamate receptor agonist that has been implicated in the development of neuropathic pain, including the development of PLP ( 80 ). Compared with a placebo, memantine reduced acute and subacute PLP after traumatic amputation in a randomized, double-blind, controlled trial and several case studies ( 81 , 82 ). This medication, however, has not been shown to effectively treat chronic PLP ( 83 , 84 ).

Therapeutic efforts to target the DRG have shown promise in temporarily eliminating PLP by reducing hyperexcitability of neurons, thereby prohibiting pain signals from firing ( 85 , 86 ). Injection of lidocaine, a sodium channel blocker, into the DRG transiently relieved PLP and PLS ( 60 ). When delivered continuously via an indwelling catheter, relief of PLP and PLS could be extended for the duration of the lidocaine administration, up to 12 days in the above study, demonstrating the importance of long-term repeated blocking in the PNS as a valuable clinical tool for alleviating PLP. Although these studies were small and require further investigation, they show promise in discovering therapies that can aid in PLP relief.

MT ( Figure 3A ) is noninvasive and perhaps one of the least expensive and most effective modalities used for the treatment of PLP. Chan and colleagues conducted the first randomized sham-controlled MT study showing that MT was effective in reducing PLP in 93% of participants ( 87 ). Additional findings showed that amputees who practiced MT reported a larger reduction in PLP than those amputees who only mentally visualized and attempted to move their absent limbs ( 87 ), and the time to pain relief was dependent upon the starting pain level ( 88 ). A study on bilateral lower-limb amputees found reduced PLP in both phantom legs when participants viewed another person’s limbs moving in the same way as their phantom legs ( 44 ). Such findings further support the role of visual feedback in modulating pain responses. A study by Foell and colleagues suggests that MT causes the somatosensory cortex of amputees to return to the baseline configuration existing before amputation ( 89 ). Further, MT has been shown to reduce PLP after BPA (where the limb is deafferented but intact), supporting the hypothesis that both the PNS and CNS interact to facilitate the reduction of PLP ( 31 ). Thus, MT may aid in the reestablishment of somatosensory cortex organization that existed before the amputation (or disconnection, in the case of BPA) ( 31 ). More work is needed, however, to elucidate the clinical efficacy of MT and the mechanisms by which this therapy alleviates PLP and lead to an understanding of why some people do not benefit from MT.

PLP-targeting interventions. ( A ) MT is a potential treatment option for PLP. In this approach, devised by Ramachandran, an amputee attempts to alleviate PLP by moving his/her intact right limb in front of a mirror to create a visual representation of the missing limb while simultaneously moving the phantom limb ( 94 ). Although MT has been shown to be effective at reducing PLP in many, but not all, amputees, the mechanisms of pain reduction are not well understood. MT uses visual feedback of movements by the intact limb to reduce pain, which is crucial to efficacy, as pain reduction was not seen when the mirror was covered with a sheet ( 75 ). ( B ) Similarly to MT, VR therapy relies on visual feedback by simulating both intact and missing limbs. Participants wear VR goggles to visualize a representation of the missing limb.

VR ( Figure 3B ) holds the potential to create a more “sophisticated” immersive form of MT ( 90 ). The use of advanced technology to create virtual images of amputees’ missing limb(s) has demonstrated encouraging results for alleviating PLP. One study used a VR therapy with eight participants viewing a virtual image of a limb enacting various movements and replicating the movements with their phantom limbs, which resulted in an average 38% decrease in PLP ( 91 ). Seven of eight participants saw pain reduction during the intervention, with five of eight reporting more than a 30% decrease. In an effort to utilize intrinsic brain neuroplasticity, a more recent study reported pain relief in upper-limb amputees participating in biweekly augmented reality and VR ( 92 ). These results indicate that VR therapy should be further examined and compared with traditional MT.

Although PLP has plagued amputees for millennia, the condition still perplexes researchers today, with no universally efficacious treatment available. Further research investigating the etiology of both PLS and PLP, especially targeting PNS roles, and developing novel treatments are absolutely necessary. Investigation of the role of vision in PLP experiences is an important avenue to follow. Vision seems to play a critical role in reducing PLP in MT and VR therapies and in prosthesis usage that lacks somatosensory input. To date, there have been no studies conducted on visually impaired amputees to determine the presence or lack of PLP. In conjunction with vision, the other component that seems to be necessary in the most effective treatments is muscle activation of the residual limb. Activating the remaining muscles to complete natural movements may assist in diminishing cortical reorganization and/or connecting vision to proprioceptive sensations of movement. The efficacies of therapies that target both vision and muscle activity seem to underscore the general characterization of PLP as a complex neuropathic syndrome with PNS and CNS components.

This work was supported by start-up funds from the University of Tennessee Health Science Center to JWT.

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information: J Clin Invest. 2018;128(6):2168–2176.https://doi.org/10.1172/JCI94003.

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  • Introduction
  • Mechanistic theories of PLP: CNS versus PNS
  • Mechanistic theories of PLP involving the CNS
  • Subcortical theories: thalamic contributions
  • Proprioceptive memory
  • Dissociation of vision and proprioception
  • Theories involving the PNS
  • Neuromas and the DRG
  • Preamputation pain
  • Role of prostheses
  • Treatments for PLP
  • Acknowledgments
  • Version history

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L. Nikolajsen, T. S. Jensen, Phantom limb pain, BJA: British Journal of Anaesthesia , Volume 87, Issue 1, 1 June 2001, Pages 107–116, https://doi.org/10.1093/bja/87.1.107

Br J Anaesth 2001; 87 : 107–116

The first medical description of post‐amputation sensation was given by Ambroise Paré (1510–1590), a French military surgeon, who noticed that patients may complain of severe pain in the missing limb following amputation. In his ‘Haquebusses and other guns’, Paré characterized the post‐amputation syndrome and proposed different models to explain the pain. 45 Subsequent studies by Charles Bell (1830), Magendie (1833), Rhone (1842), Guéniot (1861) and others provided detailed descriptions of the phenomenon and, in 1871, Mitchell coined the term ‘phantom limb’. 26 57 98

In modern times, traumatic amputations originating from World War I and II, Vietnam and Israeli wars and from landmine explosions all over the world are a tragic cause of phantom pain in otherwise healthy people. Other major reasons for amputation and phantom pain are peripheral vascular disease and neoplasms. Today, it is common knowledge that virtually all amputees experience phantom sensations, painful or not, after limb amputation. Non‐painful phantom sensations rarely pose a clinical problem. However, in some amputees, the phantom becomes the site of severe pain, which may be exceedingly difficult to treat. A large number of different treatments have been suggested but the vast majority of studies concerning the treatment of phantom pain are based on small groups with no controls. A clear and rational treatment regimen is difficult to establish as long as the underlying patophysiology is not fully known. The development of animal models mimicking neuropathic pain, together with research in other neuropathic pain conditions, have contributed significantly to our understanding of phantom pain. It is now clear that nerve injury is followed by a series of changes in the peripheral and the central nervous system and that these changes may play a role in the induction and maintenance of chronic phantom pain. Although phantom pains may occur following amputation of body parts other than limbs, 27 49 66 the present review will focus on clinical characteristics, mechanisms, treatment, and possible preventive measures of phantom pain after limb amputation. The phantom complex includes three different elements.

Phantom limb pain: Painful sensations referred to the absent limb.

Phantom limb sensation: Any sensation in the absent limb, except pain.

Stump pain: Pain localized in the stump.

These elements often coexist in each patient and may be difficult to separate.

Early literature suggested that the incidence of phantom pain was as low as 2%. However, more recent studies report incidences of 60–80% (Table 1 ). The discrepancy in reported frequencies mainly occurred because early studies based prevalence rates on patients’ request for pain treatment. This will substantially underestimate the problem of phantom pain as many amputees, at least in the past, were reluctant to report pain to health care providers. Sherman and Sherman (1983) reported that, although 61% of amputees with phantom pain had discussed the problem with their doctor, only 17% were offered treatment and a large proportion of the rest were told that they were mentally disturbed. 80

The occurrence of phantom pain seems to be independent of age in adults, gender and level, or side of amputa tion. 37 46 54 59 80 Phantom pain is less frequent in young children and congenital amputees. In a recent study of 60 child and adolescent amputees who were missing a limb because of congenital limb deficiency ( n =27) or surgery/trauma ( n =33), the incidence of phantom pain was 3.7% in the congenital group and 48.5% in the surgical group. 99 Some authors have suggested a relationship between phantom limb pain and the aetiology of the amputa tion. 30 67 96 In a study of 92 lower limb amputees, Weiss and Lindell found that patients with a history of gangrene and/or infection had higher pain levels. 96 However, most studies have found no relationship between the amputees health status and incidence of phantom pain. It is also generally agreed that the incidence of pain is similar following civilian or military accidents. 32 37 59 81

Onset and duration

Onset of pain is early. Several studies have show that 75% of patients develop pain within the first few days after amputation. 9 37 48 59 67 However, phantom pain may be delayed for months or years. Rajbhandari and colleagues described a 58‐yr‐old man, who had undergone left below knee amputation at the age of 13. Eight months before a diagnosis of diabetes, he began to complain of typical diabetic neuropathy pain in the phantom leg, which was followed by a similar pain complaint in the intact limb. 72

At least three prospective studies have examined the duration of phantom pain. Parkes found that 85% of 46 amputees experienced phantom pain immediately post‐amputation. One year later, 61% still had some pain. 67 Jensen and colleagues (1985) studied 58 amputees and found that the incidence of phantom pain was 72, 65 and 59% after 1 week, 6 months and 2 yr, respectively. 38 In a recent study by Nikolajsen and coworkers (1997) 56 patients who underwent amputation of the lower limb (mainly because of peripheral vascular disease) were questioned about phantom pain 1 week, and 3 and 6 months after the operation. Although the incidence and intensity of pain remained constant during follow‐up, both frequency and duration of pain attacks decreased significantly. 59 Similar results have been found in retrospective studies based on questionnaires. Houghton and collaborators asked 176 amputees to specify on a scale of 0 to 10 the degree of phantom pain at 6 months, 1, 2 and 5 yr after amputation. The median phantom pain score decreased from 4 (moderate) immediately after amputation to 1 (slight), 5 yr post‐operatively. 32 In a survey of 526 veterans with longstanding amputations, phantom pain had disappeared in 16%, decreased markedly in 37%, remained similar in 44% and increased in 3% of respondents reporting phantom pain. 93

Character and localization

Phantom pain is usually intermittent; only a few patients are in constant pain. 46 59 93 Kooijman and colleagues studied 99 upper limb amputees of which 37 experienced phantom pain. Nine amputees were in constant pain, nine had attacks of pain a few times per day and the rest only experienced phantom pain weekly or less. 46 Phantom pain is described as shooting, stabbing, boring, squeezing, throbbing, and burning. A few patients more vivid and colourful descriptions. 9 37 38 42 54 59 93

Phantom pain is primarily localized in distal parts of the missing limb (fingers and palms in upper limb amputees and toes, instep, top of the foot and ankle in lower limb amputees). 38 59

Pre‐amputation pain and phantom pain

Several retrospective studies—but not all 29 46 92 —have pointed to pre‐amputation pain as a risk factor for post‐operative phantom pain. 3 32 42 75 In paediatric amputees, Krane and Heller found that most children with phantom pain also experienced pre‐operative pain. 48 In the study by Houghton and colleagues there was a significant relationship, in vascular amputees, between pre‐amputation pain and phantom pain in the first 2 yr after amputation. In traumatic amputees phantom pain was only related to pre‐amputation pain immediately after the amputation. 32 Similar findings have been described in prospective studies. 38 59 In the recent study of mostly vascular amputees by Nikolajsen and colleagues, a relationship was found between pre‐operative pain and incidence of phantom pain 1 week and 3 months after amputation, but not after 6 months. However, as can be seen from Figure 1 , the relation is not simple. Some patients with severe pre‐amputation pain never developed phantom pain while others with only modest pre‐operative pain developed intense phantom pain. 59

Another issue concerns the possible persistence or revival of pain experienced before amputation. Striking case reports show that phantom pain may mimick pre‐amputation pain both in quality and in location. 5 29 31 42 56 59 A recent study describes a woman who had her left leg amputated because of recurrent wound infection over a period of 2 yr. The most distressing pre‐operative pain was invoked by the treatment carried out on the open drainage site on the calf, which required cleaning and re‐packing twice daily. Immediately after amputation the patient experienced phantom pain localized to the open drainage site, which was no longer there. The patient continued to suffer from episodes of phantom pain similar to the pain experienced pre‐operatively for several years after the amputation. 31

In a retrospective study by Katz and Melzack, 68 amputees were questioned about pre‐amputation and phantom pain from 20 days to 46 yr after amputation. Fifty‐seven of those who had experienced pre‐amputation pain claimed that their phantom pain resembled the pain they had before amputation. 42 Jensen and colleagues prospectively examined the incidence of pre‐amputation pain persisting as phantom pain. A similarity between pre‐amputation pain and phantom pain, with respect to both character and location, was found in one‐third of patients after 8 days, but only in 10% of patients after 6 months and 2 yr. 38 In another, more detailed prospective study by Nikolajsen and colleagues, patients were requested to describe pain and its localization before amputation. This was done using different word descriptors, the McGill Pain Questionnaire and their own words. After amputation, 42% of those who experienced phantom pain felt that the pain was similar to the pain they had experienced before amputation. However, when comparing preoperative and postoperative pain descriptions, the incidence of actual similarity was not higher in patients who claimed similarity than in those who found their phantom pain did not resemble pain experienced preoperatively. This indicates that patients memory of their pain does not always reflect the truth. 59 So, while a few case reports suggest that pre‐amputation may persist as post‐amputation pain, this is not the case in the vast majority of amputees.

Not surprisingly, stump pain is common in the early post‐amputation period but, in most patients, it subsides with healing. However, in 5–10%, stump pain persists and may even get worse with time. Stump and phantom pain are interrelated phenomena and several authors have reported a higher prevalence of phantom pain among amputees with coexistent stump pain compared with amputees without stump pain. 9 37 38 46 59 80 Examination of the stump frequently reveals factors that may be related to pain. These include obvious pathology such as infection, bone spurs, neuromas and adherent and wrinkled scars. Further examination may reveal reduction in pain threshold (hyperalgesia), evocation of pain by non‐noxious stimuli (allodynia) and pain elicited by repeated pricking stimuli (‘wind‐up’ like pain). 9 37 38 62 71 Persistent stump pain may be very difficult to treat and it often interferes with prosthetic use and rehabilitation.

Phantom sensation

Phantom sensation is experienced by almost everyone who undergoes limb amputation, but it is rarely a clinical problem. Immediately after amputation, the phantom limb often resembles the pre‐amputation limb in shape, length, and volume. The sensation can be very vivid and often includes feelings of posture and movement. Over time, the phantom sensation may fade. In some patients, a phenomenon called ‘telescoping’ occurs when the distal part of the phantom is gradually felt to approach the residual limb and, in the end, it may even be experienced within the stump. 37 38 46 54 93 An example of telescoping is shown in Figure 2 . Phantom sensation and phantom pain are interrelated. In a recent study by Kooijman and colleagues, phantom pain was present in 36 of 37 patients experiencing phantom sensation but only in one of 17 who did not experience phantom sensations. Stump pain is also more frequent in patients with coexistent phantom sensation. 46

Other factors

Evidence is growing that the individual’s genetic predisposition to develop neuropathic pain may be important. 53 However, an inherited component is not always a feature of phantom pain. Schott described an interesting case in which five members of a family sustained traumatic amputations of their limbs. The development of phantom pain was unpredictable. 77

It has been claimed that severe phantom pain may recur in lower‐limb amputees undergoing spinal anaesthesia. Tessler and Kleiman prospectively investigated 23 spinal anaesthetics in 17 patients. Only one patient developed phantom pain, which resolved in 10 min. 88

Phantom phenomena may be modulated be several other internal and external factors, such as stress, attention, urination, stump massage, and weather change. In a group of upper extremity amputees, Weiss and colleagues found that phantom pain was decreased by the use of a prosthesis, which allowed extensive use of the affected limb. A cosmetic prosthesis had no effect. 97 Successful rehabilitation may reduce the amount of pain. 69 A list of modulating factors is shown in Table 2 .

Mechanisms of phantom pain

The mechanisms underlying phantom pain have not been clarified completely. However, experimental and, to some extent, also clinical studies have contributed to our understanding of phantom pain after amputation. There is now evidence for peripheral and central contributions to phantom pain, as briefly outlined below. An understanding of the mechanisms underlying phantom pain is likely to lead to new and rational types of treatments.

Peripheral factors

1. Phantom pain is significantly more frequent in those amputees with long‐term stump pain than in those without persistent pain. 9 37 38 46 59 67 80 It has been noted that phantom pain decreases with the resolution of stump‐end pathology. 9

2. Following a nerve cut, formation of neuromas are seen universally. Such neuromas show spontaneous and abnormal evoked activity following mechanical or chemical stimulation. 2 91 (for review 17 ) The ectopic and increased spontaneous and evoked activity from the periphery is assumed to be the result of a novel expression or upregulation of sodium channels. 15 63

3. Percussion of the stump or of identified stump neuromas induces stump and phantom pain. In a classical microneurographic study in two amputees, Nyström and Hagbarth showed that tapping of neuromas was associated with increased activity in afferent C fibres and increased pain sensation. 64 Consistent with these findings, a recent study shows that there is an inverse correlation between phantom pain intensity and pressure pain threshold of the stump early after amputation. 62

4. Chabal and colleagues 10 showed that perineuromal injection of gallamine, which increases sodium conductance, produces phantom pain in amputees. However, lidocaine (an unspecific sodium channel blocker), when injected into the neuroma or surrounding tissue, blocks phantom pain. 10

5. Also, in the dorsal root ganglion (DRG) cells, changes occur following a complete nerve cut. Cell bodies in DRG cells show similar abnormal spontaneous activity and increased sensitivity to mechanical and neurochemical stimulation. 39 DRG cells exhibit major changes with respect to the expression of sodium channels with a switch of one channel type to another. 95

6. The sympathetic nervous system may also play an important role in generating and, in particular, in maintaining phantom pain. From animal studies, it is well known that application of norepinephrine or activation of the post‐ganglionic sympathetic fibres excites and sensitizes damaged but not normal nerve fibres. 16 Sympatholytic blocks can abolish neuropathic pain and, in patients with pain relieved after a sympatholytic block, pain can be rekindled by injection of norepinephrine into the skin. 89 Long after limb amputation, injection of norepinephrine around a stump neuroma is reported to be intensely painful. 11 Catecholamine sensitivity may also manifest itself by the occurrence of a cooler extremity on the amputated side and it has been suggested that phantom pain intensity is inversely related to skin temperature of the stump. 44 82 83

Spinal plasticity

Sensitization of spinal pain transmission neurons is a normal physiological response of the undamaged nervous system. After nerve injury, there is an increase in this general excitability of spinal cord neurons, and C‐fibres and Aδ‐afferents gain access to secondary pain signalling neurons. Sensitization of dorsal horn neurons is mediated by release of glutamate and neurokinins. This sensitization may manifest itself as mechanical hyperalgesia and an expansion of peripheral receptive fields [for review 19 ].

While some amputees may show an abnormal superficial sensitivity to touching the stump, this is rarely sufficient to evoke phantom pain. On the other hand, pressure can often provoke phantom pain. The pharmacology of spinal sensitization involves increased activity in N‐methyl d ‐aspartate (NMDA) receptor operated systems and many aspects of the central sensitization can be reduced by NMDA receptor antagonists. 19 In human amputees, for example, the stump or phantom pain evoked by repetitive stimulation of the stump (‘wind‐up’ like pain) can be reduced by the NMDA antagonist ketamine. 58

Another type of anatomical reorganization, which also may produce dynamic mechanical allodynia, has been described recently. Neurons in lamina II normally receive A delta‐ and C‐fibre input and respond best to noxious stimulation. Peripheral nerve damage may result in a substantial degeneration of C‐fibre primary afferent terminals in laminae II. As a consequence of this loss of synaptic contacts normally made by C‐fibre afferents onto pain signalling neurons in lamina II, central terminals of Aβ‐mechanoreceptive afferents, which normally terminate in deeper laminae (III and IV), sprout into laminae I and II. 100 To what extent this spinal reorganization contributes to phantom pain is not known. But the fact that some patients do not show marked changes in stump sensitivity despite considerable phantom pain may be consistent with such spinal reorganization.

Cerebral reorganization

The phantom limb percept, with its complex perceptual qualities and its modification by a variety of internal stimuli (e.g. attention, distraction or stress), shows that the phantom image may be a product of the brain.

Electrophysiological studies have documented the existence of nociceptive specific neurons and wide dynamic range neurons in the cerebral cortex. Following limb amputation and deafferentation of adult monkeys, there is a reorganization of the primary somtosensory cortex, subcortex and thalamus. 24 After dorsal rhizotomy, a lowered threshold required to evoke activity in thalamus and cortex can be demonstrated. Also, adult monkeys display cortical reorganization in which the mouth and chin invade cortices corresponding to the representation of the arm and digits which have lost their normal afferent input. 18

In humans, similar reorganization has been observed using magnetoencephalographic techniques. Interest ingly, this cerebral reorganization was seen mostly in patients with phantom pain and there was a linear relationship between pain and degree of reorganization. 25 Changes have also been observed at more subcortical levels. Using neuronal recording and stimulation techniques, Davis and colleagues found an unusually large thalamic stump representation. 13

Summary of mechanisms

The above findings indicate that a series of mechanisms are involved in generating phantom pains and that these include elements in the periphery, spinal cord and brain. It is likely that the first events occur in the periphery, which subsequently generates a cascade of events that sweep more centrally and also recruit cortical brain structures. The latter may be reponsible for the complex and vivid sensation that characterizes certain phantom pain sensations. The unraveling of neuroplastic changes in periphery, spinal cord, and brain are also reflected in many of the features seen in phantom pain phenomena.

Treatment of phantom pain after amputation is difficult. Various treatment regimens have been, or are currently, in use. A survey of the literature in 1980 identified 68 different methods, of which 50 were still in use. 79 Clear evidence‐based guidelines for the treatment of phantom pain can not be given, as most studies suffer from major methodological errors, such as small sample size, no or insufficient blinding and randomization, and short follow‐up periods. 6 Until more reliable data become available, guidelines are probably the best approach. The situation is similar for other neuropathic pain states, for example, post‐herpetic neuralgia and diabetic neuropathy. Treatment of phantom pain can be classified as medical, non‐medical and surgical. Medical treatment is the most effective. In general, treatment should be based on non‐invasive techniques as surgical procedures carry a risk of further deafferentiation resulting in even more pain. Table 3 lists treatments used for phantom pain.

Medical treatment

Numerous medical interventions have been proposed over the years but tricyclic antidepressants (TCA) and sodium channel blockers are currently considered to be the drug treatments of choice for neuropathic pain. 86

A large number of randomized, controlled clinical trials have shown a beneficial effect of TCA in different neuropathic pain conditions and, recently, amitriptyline was shown to relieve nerve injury pain. 40 No controlled trials have been performed in phantom limb pain but TCAs are generally considered to be effective. Selective serotonin reuptake inhibitors (SSRI) are probably less effective in neuropathic pain. The TCA drug doxepin was reported to be effective in the treatment of phantom pain. 33 Others have reported a beneficial effect of the benzodiazepine clonazepam. 7 However, there is a general clinical impression that benzodiazepines do not produce substantial pain relief.

Carbamazepine, an anticonvulsant drug which is effective in neuropathic pain, 86 is a non‐specific sodium channel blocker. Case reports have suggested that it is effective in phantom pain. 21 68 Novel anticonvulsants such as lamotrigine and gabapentin may also prove to effective in phantom pain.

Lidocaine and its oral congener mexiletine are used in different neuropathic pain conditions. 52 I.v. lidocaine was reported to be effective in neuropathic pain. 8 In an open‐label study, mexiletine produced pain relief in 18 of 31 patients with phantom pain. 12

Calcitonin may be effective in phantom pain. In a double‐blind, crossover study, Jaeger and Maier demonstrated that i.v. calcitonin was effective in phantom pain when used in the early post‐operative period. 35

The effect of NMDA receptor antagonists have been examined in different neuropathic pain conditions, including phantom pain. 58 61 87 In a double‐blind, placebo‐controlled study, i.v. ketamine reduced pain, hyperalgesia and ‘wind‐up’ like pain in 11 amputees with stump and phantom pain. 58 Memantine is another NMDA receptor antagonist available for oral use. In a recent double‐blind, crossover trial, patients with pain following amputation ( n =15) or nerve injury ( n =4) were randomized to receive memantine or placebo in a 5‐week treatment period. A washout period of 4 weeks was followed by another 5‐week treatment period. Memantine, at a daily dose up to 20 mg, failed to have an effect on spontaneous pain, allodynia and hyperalgesia. 61

Opioids were previously thought to be ineffective in neuropathic pain. Controlled studies are still lacking. However, presently, many feel that some patients can benefit from opioids with a limited risk of drug dependence. 6 14 The analgesic effect of oral and intrathecal opioids in phantom pain has been described by several authors. 34 65 90 Tramadol is an analgesic with both monoaminergic and opioid activity and it may prove to be an alternative to strong opioids as tolerance and dependence during long‐term treatment with tramadol appears to be uncommon. NSAIDs and paracetamol are considered to be ineffective in phantom pain by most practitioners.

A large number of other treatments, for example, beta‐blockers, 1 topical application of capsaicin, 74 various anaesthetic blocks 50 94 have been claimed to be effective in phantom pain but none of them have proven to be effective in well‐controlled trials.

Non‐medical treatment

Medical treatment can be combined with various non‐invasive techniques such as transcutaneous electrical nerve stimulation (TENS), vibration therapy, acupuncture, hypnosis, biofeedback, and electroconvulsive therapy. 43 51 73 84 Despite the widespread use of some of these techniques clear evidence of effect is limited 22 (for review 28 ). In a placebo‐controlled, crossover design, Katz and Melzack found that TENS, applied to the outer ear, reduced phantom pain. 43 Lundeberg and colleagues found a similar effect of vibration therapy. 51

Electrical stimulation of the spinal cord, deep brain structures, and motor cortex may relieve chronic neuropathic pain, including phantom pain. However, the effect of treatment often decreases with time. 47 55 (for review 85 )

Surgical treatment

Surgical treatment for phantom pain has been attempted for decades but the results have generally been unfavourable. Stump revision or neurectomy may be effective if there is local specific pathology at the stump but, in properly healed stumps, there is almost never an indication for proximal extension of the amputation because of pain. Dorsal root entry zone (DREZ) lesions were primarily introduced for the treatment of painful brachial plexus avulsions but the treatment has also been used in phantom pain. 76 It is believed to have a limited effect. Other neurosurgical techniques, for example, cordotomy, thalamotomy, sympathectomy may provide short‐term pain relief but pain often reappears. These treatments have been most abandoned today.

The idea of a pre‐emptive analgesic effect in phantom pain was initiated by observations that phantom pain in some cases seemed to be similar to pain experienced before the amputation 5 29 56 and that the presence of severe pain before amputation was associated with a higher risk of post‐amputation phantom pain. 3 38 75 It was hypothesized that pre‐amputation pain created an imprint in the memorizing structures of the central nervous system and that such an imprint could be responsible for persistent pain after amputation. Therefore, Bach and colleagues carried out a controlled study to examine if pre‐operative epidurals could reduce the risk of phantom pain. They randomized 25 patients undergoing amputation of the lower limb by means of their year of birth to receive either epidural morphine, epidural bupivacaine or both in combination for 3 days before amputation ( n =11) or conventional analgesia ( n =14). All patients received epidural or spinal analgesia for amputation and ‘post‐operatively’ their pain was treated with conventional analgesics. Patients were questionned about phantom pain after 1 week, and 6 and 12 months. Pain was categorized as either present or not present and, apparently, interviewers were not blinded to the treatment. Six patients died during the follow‐up period. The incidence of phantom pain was reduced 6 months after amputation but not after 1 week or after 12 months in the epidural treatment group as compared with the control group. 4 Subsequent clinical trials have confirmed these results.

Jahangiri and colleagues prospectively followed 24 patients undergoing limb amputation. In a non‐randomized design, patients received either an epidural infusion of bupivacaine, diamorphine and clonidine from 24 to 48 h pre‐operatively and for at least 3 days after surgery ( n =13) or on demand opioids ( n =11). Amputation was carried out under general anaesthesia. The presence of phantom pain was graded on a scale of 1–10 and pain was considered significant when the score was ≥3. During follow‐up, two patients died. The incidence of phantom pain was significantly lower in the epidural group after 1 week, and 6 and 12 months. 36

In a letter, Schug and colleagues presented data from a non‐randomized trial. Methods of blinding and pain assessment were not described. Twenty‐three patients were divided into three groups. One group received an epidural infusion of bupivacaine and fentanyl for 24 h before amputation and continued for at least 48 h after surgery ( n =8). Another group ( n =7) had epidural anaesthesia for the amputation and ‘post‐operatively’ pain was treated with epidural infusion of bupivacaine and fentanyl. The third group ( n =8) received surgery under general anaesthesia and systemic analgesia for pain. After 1 yr, the incidence of phantom pain was significantly lower in the patients who had received pre‐, intra‐ and post‐operative epidural analgesia. 78

Katsuly‐Liapis and colleagues reported in abstract form 45 patients who were randomized into three groups to receive: (1) epidural analgesia with bupivacaine and morphine for 3 days before amputation and continued for 3 days after surgery ( n =15), (2) epidural analgesia post‐operatively ( n =12) or (3) systemic analgesia with opioids and NSAID ( n =18). After 6 months, the incidence of phantom pain was significantly lower in the patients who had epidural analgesia before, during, and after amputation compared with the other two groups. No details with respect to randomization, blinding, or pain assessment were presented. 41

In a blinded and placebo‐controlled trial, Nikolajsen and colleagues randomly assigned 60 patients into two groups. All patients had an epidural catheter on the day before the amputation. The epidural treatment group ( n =29) received a pre‐operative infusion of epidural bupivacaine and morphine for a median time of 18 h and the infusion was continued during the amputation. The control group ( n =31) received equivalent amounts of epidural saline and systemic opioids. Both groups had general anaesthesia for the amputation and all received epidural bupivacaine and morphine for post‐operative pain management. Phantom pain was assessed after one week, and 3, 6 and 12 months by a visual analogue scale (VAS). Blinding was ensured by the use of two independent investigators. One investigator was responsible for inclusion of patients and for post‐operative pain assessment and the other for randomization and pre‐and intra‐operative pain treatment. The number of patients was reduced to 28 after 1 yr, mainly because of death. After 1 week, 52% of patients in the epidural treatment group and 56% of patients in the control group had phantom pain. Incidence and intensity of phantom pain were also similar in the two groups at the later post‐operative interviews. 60 So, according to this study, it is not possible to prevent phantom pain by a epidural block of short duration.

Others have examined the effect of a post‐operative perineural analgesia on the prevention of phantom pain. Fisher and Meller (1991) introduced a catheter into the nerve sheath at the time of amputation and infused bupivacaine for 72 h post‐operatively. 23 Similar methods were used by Elizaga and colleagues 20 and Pinzur and coworkers 70 but only the study by Fisher and Meller found an effect of treatment. 23

It may not be possible to prevent phantom pain by pre‐emptive approaches. A further understanding of the mechanisms underlying pain in amputees may lead to new and rational treatments. In future, perhaps we will see the development of new drugs with fewer side effects compare with drugs we use today.

Fig 1 Pre‐amputation pain ≥20 increases the risk of phantom pain ≥20 after 1 week and 3 months (on a VAS, 0–100). Data from the 1 week interview are shown. Each dot represents one patient, n =54. P =0.04, Fishers’ exact test. (From Nikolajsen and colleagues 1997, with permission).

Fig 2 Telescoping. The phantom hand gradually approaches the residual limb and eventually becomes located inside the stump.

Incidence of phantom pain as reported in different studies

Factors that may modulate the experience of phantom pain

Treatments for phantom pain

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  • v.12(3); 2022 Mar

Unveiling the phantom: What neuroimaging has taught us about phantom limb pain

Jonathan d. browne.

1 School of Medicine, California University of Science and Medicine, Colton California, USA

Ryan Fraiser

2 Center for Pain Medicine, University of California San Diego, La Jolla California, USA

Dillon Leung

3 College of Letters and Science, University of California Berkeley, Berkeley California, USA

Albert Leung

Michael vaninetti.

Phantom limb pain (PLP) is a complicated condition with diverse clinical challenges. It consists of pain perception of a previously amputated limb. The exact pain mechanism is disputed and includes mechanisms involving cerebral, peripheral, and spinal origins. Such controversy limits researchers’ and clinicians’ ability to develop consistent therapeutics or management. Neuroimaging is an essential tool that can address this problem. This review explores diffusion tensor imaging, functional magnetic resonance imaging, electroencephalography, and magnetoencephalography in the context of PLP. These imaging modalities have distinct mechanisms, implications, applications, and limitations. Diffusion tensor imaging can outline structural changes and has surgical applications. Functional magnetic resonance imaging captures functional changes with spatial resolution and has therapeutic applications. Electroencephalography and magnetoencephalography can identify functional changes with a strong temporal resolution. Each imaging technique provides a unique perspective and they can be used in concert to reveal the true nature of PLP. Furthermore, researchers can utilize the respective strengths of each neuroimaging technique to support the development of innovative therapies. PLP exemplifies how neuroimaging and clinical management are intricately connected. This review can assist clinicians and researchers seeking a foundation for applications and understanding the limitations of neuroimaging techniques in the context of PLP.

1. INTRODUCTION

Pain is unique to individuals who experience it, and the subjective nature of pain challenges its fundamental understanding. Phantom limb pain (PLP) is one such clinical mystery for researchers, clinicians, and patients. While PLP phenomenon has been well documented in recent history, the underlying pathophysiology was poorly understood due to limitation in investigational tools. Ambroise Paré described patients feeling absent limbs following amputations he performed during the 16th century, and in the 17th century, philosopher René Descartes concluded that there might be a dissociation between nerve signals and cognitive interpretation in amputees (Finger & Hustwit, 2003 ). Later, during the American Civil War, surgeon Silas Weir Mitchell was frustrated by ineffective treatments for PLP and became notable for advocating formal scientific investigations (Finger & Hustwit, 2003 ). This mystery continues to draw curiosity and interest, and it now leverages modern technology to uncover its truth.

More than merely quenching scientific curiosity, further PLP research is needed to improve the lives of amputees. The amputee population in America is estimated to increase from 1.6 million in 2005 to 3.6 million by 2050 (Ziegler‐Graham et al., 2008 ). PLP, which is the pain of the amputated limb that is variable in timing, is experienced by up to 79.9% of amputees (Ehde et al., 2000 ; Ephraim et al., 2005 ). The severity of phantom limb sensations ranges from nonpainful to disabling and, in some instances, can be physically and psychologically debilitating (Ephraim et al., 2005 ). For surgical amputees, chronic preoperative pain and acute postoperative phantom pain are risk factors for PLP (Hanley et al., 2007 ; Larbig et al., 2019 ). Still, correlations for the severity of pain have been inconsistent (Sherman et al., 1984 ). These variations in the clinical presentation of PLP continue to burden amputees, warranting a deeper understanding of its mechanism to improve diagnosis and efficacious clinical approaches. As the demand for a conclusive understanding grows, so does the controversy among scientists and clinicians.

PLP is a particularly challenging syndrome to diagnose and treat, which may be related to the fact that, by mechanistic nature, it is challenging to understand. Nonspecific and highly varied symptoms can make diagnosing PLP difficult, requiring a comprehensive history, examination, tests, and exclusion of other possible neuropathies (Ferraro et al., 2016 ). The variety of PLP therapies, including pharmacologic, cranial stimulation, and sensory therapies, have been inconsistent (Aternali & Katz, 2019 ; Richardson & Kulkarni, 2017 ) with some potential being demonstrated among integrative approaches (Subedi & Grossberg, 2011 ). These challenges parallel the equally complex range of mechanistic explanations of PLP, which involve various combinations of cerebral, spinal, and peripheral nervous system pathologies (Flor et al., 2006 ). These mechanistic, diagnostic, and management inconsistencies underscore the importance of foundational tools for analyzing PLP. Due to the brain's role in interpreting, processing, and modulating pain, neuroimaging may fulfill this need. In addition to aiding understanding of PLP, neuroimaging may assist the development of PLP therapies.

This article will review current noninvasive imaging modalities for PLP research in mechanistic and therapeutic investigations. It will focus on diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG). Researchers and clinicians utilize each imaging modality in distinct ways to complement dynamic research involving diagnosing, characterizing, and treating PLP. By examining how DTI, fMRI, EEG, and MEG have impacted the understanding of PLP, we aim to summarize a baseline of fundamental imaging techniques to foster further research.

1.1. Background on potential pain mechanisms

In order to understand the impact of the major imaging modalities used in this field, it is helpful to briefly review the prevailing discussed potential mechanisms behind PLP. In the properly functioning human nervous system, peripheral noxious stimulus generates a sensation of pain via a cascade of neuronal events. The pathway consists of primary afferent pain fibers which carry the afferent signals from the peripheral nociceptors to the spinal cord where they synapse directly or indirectly via interneuron with the secondary neurons at the dorsal horn of the spinal cord. The afferent signals then ascend via the second‐order neurons to the brain via either spinothalamic or spinoreticular tracts (Steeds, 2009 ). Passage of this nociceptive information through the brainstem triggers modulatory signals back through the dorsal horn. These modulatory signals alter primary afferent neuron propagation which can facilitate or inhibit further peripheral nociceptive information (Renn & Dorsey, 2005 ). Additionally, supraspinal pain signal processing and modulation are important for healthy pain perception. First, the thalamus and pons relate afferent sensory signals to other supraspinal regions. Other supraspinal groups include the somatosensory cortices and inferior parietal lobe, anterior cingulate cortex (ACC) and insula (IN), and dorsolateral prefrontal cortex, which are also important sensory discriminatory, affective, and modulatory regions, respectively (Leung, 2020 ). Furthermore, supraspinal modulatory functional connectivity deficits have been associated with white matter tract deficits, emphasizing the vital role of supraspinal processing (Leung et al., 2016 , 2018 ). These normal pain mechanisms involve the intricate relationship between peripheral, spinal, and supraspinal regions.

PLP draws attention because there is still no consensus on its mechanism. Cerebral, spinal, and peripheral explanations each bear scientific evidence, perpetuating the controversy (Collins et al., 2018 ). Mechanisms within these groups are not mutually exclusive and PLP may be explained by some combination. Furthermore, researchers speculate if PLP may be a cluster of pain disorders, rather than a single disorder (Griffin & Tsao, 2014 ). Researchers have prioritized this mechanistic puzzle as it is essential for providing quality care to these patients.

Cerebral mechanisms consist of cortical reorganization, alterations in sensory and motor feedback, and pain memory (Flor et al., 2006 ). PLP is commonly correlated with reorganization and furthermore related to the self‐perception of one's own body (Subedi and Grossberg, 2011) . In support of cerebral mechanisms, a 1998 study found hemispheric differences in cortical representation in traumatic amputees absent in subjects with congenital absence of limb (Montoya et al., 1998 ).

Spinal mechanisms relate to amputation‐related nerve injury causing spinal cord hypersensitization and further reorganization of spinal cord areas formerly occupied by functioning afferent nerves (Flor et al., 2006 ). Connections between the proximal sections of amputated nerves can form disruptive connections with receptive spinal nerves. Additionally, distorted neuronal activity, hyperexcitability, and central nociceptive neuron firing pattern changes may also contribute to PLP (Subedi and Grossberg, 2011) .

The peripheral mechanisms involve nerve ending and dorsal root ganglion reorganization following amputations (Flor et al., 2006) . Efficacious pre‐ and postoperative peripheral interventions for PLP support this explanation. Patients receiving peripheral nerve interfaces before surgery have had lower rates of peripheral neuromas and PLP (Kubiak et al., 2019 ). Additionally, minimally invasive percutaneous peripheral nerve stimulation programs improved functionality in patients with chronic pain postamputation (Gilmore et al., 2019 ). Peripheral nervous system treatment has addressed PLP functionality and pain, which validates this mechanism.

Cerebral, spinal, and peripheral PLP mechanisms have each endured scientific evaluation with no distinct victor. These are also not mutually exclusive and PLP may be a product of a combination of these mechanisms. Makin and Flor further expand upon the multifactorial nature through a review of factors beyond remapping that may come together to contribute to PLP (Makin & Flor, 2020 ). Broad consideration of mechanism and dynamic changes warrants a comprehensive analysis of this complex disease. Investigators continue to explore this scientific question using several specialized neuroimaging techniques.

A literature search was conducted using the PubMed database between January 2020 and August 2021. The literature search was organized using the following keywords/keyword combinations: “phantom limb pain and diffusion tensor imaging (DTI),” “phantom limb pain mechanism,” “phantom limb pain and electroencephalography (EEG),” “phantom limb pain and functional magnetic resonance imaging (fMRI),” “phantom limb pain and amputation,” “phantom pain,” “phantom limb pain and mirror therapy,” “phantom limb pain and magnetoencephalography (MEG),” “phantom limb pain and therapeutics,” “diffusion tensor imaging (DTI),” “electroencephalography (EEG),” “magnetoencephalography (MEG),” “functional magnetic resonance imaging (fMRI).” The articles generated from the search were then screened and additional articles referenced by the searched articles were also utilized. Articles were selected based on the inclusion of amputees with PLP or phantom sensations along with the utilization of DTI, fMRI, EEG, or MEG to investigate mechanism or response to therapy.

3.1. Diffusion tensor imaging

DTI is a variant of conventional MRI that has become a standard tool in researching PLP. As a general MRI principle, tissue microstructure determines water diffusion, which translates into an image. Anisotropy describes water diffusion that is directionally dependent while isotropy describes unrestricted water diffusion; white matter is more anisotropic than gray matter, while cerebrospinal fluid is isotropic (Hagmann et al., 2006 ; Pierpaoli et al., 1996 ). DTI capitalizes on white matter tracts to assess structural integrity and connectivity (Bandettini, 2009 ). In PLP, DTI has become the most common tool for evaluating anatomical changes.

Important DTI scalars include axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA). AD and RD characterize rates of diffusion in principal and perpendicular directions, respectively, while MD is the net displacement of water molecules (Feldman et al., 2010 ). FA is a ratio that describes the degree of anisotropic diffusion (Feldman et al., 2010 ). These scalars allow DTI to interpret structural changes within the brain. A 2019 study employed DTI to determine a connection between PLP and white matter changes. Interestingly, these researchers found symmetrically increased white matter AD bilaterally, but a stronger white matter RD association with visual analog scale (VAS) score in the corpus callosum and hemisphere associated with the amputated limb (Seo et al., 2019 ). Guo et al. ( 2019 ) studied changes in FA following upper‐limb amputation using DTI and positively correlated contralateral middle temporal gyrus nodal strength with the magnitude of PLP. In contrast, Jiang et al. studied lower‐limb amputees using DTI and described ipsilateral decreased FA in the superior corona radiata, sub‐temporal lobe white matter, and inferior fronto‐occipital fasciculus. Additionally, they noted contralateral reduced FA in the left premotor cortex. Utilizing tractography in the premotor cortices, they also found altered interhemispheric fibers (Jiang et al., 2015 ).

Structural analysis is useful for understanding physical changes due to PLP and potentially planning for interventions. The properties of DTI have propelled it to become a standard tool for such structural analysis. Corpus callosum changes identified via DTI provide clues regarding the connection between phantom sensations and sensorimotor cortex inhibition (Simões et al., 2012 ). Furthermore, Owen et al. ( 2007 ) utilized DTI tractography to guide deep brain stimulation in an amputee experiencing stump pain. DTI applications and key findings are summarized in Table  1 .

Diffusion tensor imaging (DTI) and phantom limb pain (PLP)

Note : Study sample size reflects amputees with phantom limb pain unless otherwise noted.

a Amputees with “painless” phantom sensations.

Despite its growing prevalence in neuroimaging, DTI maintains technical issues such as subject motion, eddy currents, and low resolution (Bandettini, 2009) . A review of DTI imaging by Alexander et al. found that its measure of FA was sensitive for finding microstructure changes, but this alone was less useful for characterizing such changes. They emphasized the importance of utilizing additional DTI scalars in concert for comprehensive cerebral pathology classification (Alexander et al., 2007 ). Hakulinen et al. caution the acceptance of FA, considering it to be nonspecific to various pathologies. They also note the variation in the DTI technique, potentially compromising different reports’ comparability without a validated method. The review concludes that the circular method has better repeatability, while the freehand method has less variation; these characteristics may be advantageous for studying distinct aspects of the brain (Hakulinen et al., 2012 ). Furthermore, Soares et al. ( 2013 ) address the technical components of DTI interpretation at each stage of data collection and propose conformity that may serve to reduce variability among researchers.

In summary, DTI exploits water diffusion due to tissue microstructures to reveal critical structural changes due to PLP. As depicted in Figure  1 , analysis of these structural changes can contribute to studying cerebral mechanisms of PLP. Technical aspects limit this imaging technique and may compromise data collection and interpretation. DTI should continue to be used to characterize how particular structural changes relate to the presence and severity of PLP in correlation with functional changes.

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Flowchart of imaging modalities within the context of phantom limb pain.

3.2. Functional magnetic resonance imaging

fMRI employs many of the same concepts as DTI. However, in contrast to DTI structural imaging, fMRI is an essential functional imaging technique utilized in PLP research. Magnetic forces create particular arrangements of water molecules. Additionally, oxyhemoglobin and deoxyhemoglobin have different magnetic properties (Bunge & Kahn, 2009 ). Thus, fMRI can measure tissue perfusion and changes in oxygen that are interpreted to create a functional activity map (Logothetis, 2008 ). It is a commonly used neuroimaging technique due to logistic factors such as availability, low cost, and low risks (Bunge and Kahn, 2009) . Compared to the other functional imaging techniques discussed in this review (EEG and MEG), fMRI has more substantial spatial resolution but lower temporal resolution (Meyer‐Lindenberg, 2010 ).

Simoes et al. ( 2012 ) combined fMRI and DTI to study cortical and colossal plasticity and found that neuroplastic modifications were present in subjects who reported PLP and those who reported only phantom limb sensations . Pasaye et al. ( 2010 ) also utilized fMRI to show activation of distinct areas within the brain upon stump stimulation. Andoh et al. ( 2017 ) identified inter‐ and intrahemispheric differences in amputees via fMRI in addition to bilateral SI and intraparietal sulcus activation upon phantom sensation evocation. In a later study, Andoh et al. (2020) also utilized fMRI during a virtual reality (VR) task to demonstrate that motor cortex activity was positively related to PLP intensity.

When characterizing the efficacy of PLP rehabilitative techniques, researchers often utilize fMRI. Foell et al. focused on fMRI to identify physical changes in response to mirror therapy, which involved movement of the intact limb in front of a mirror to create the perception of movement in the amputated limb. They report decreased inferior parietal cortex activity and the reversal of maladaptive cortical reorganization (Foell et al., 2014 ). In a case report about using chronic motor cortex stimulation to treat PLP, researchers used fMRI for precise surgical electrode placement and monitored the patient's response to therapy (Roux et al., 2008 ). A study of 13 upper limb amputees utilized fMRI that showed reduced cortical reorganization in PLP patients following mental imagery therapy by contrasting pretraining diffuse cortical activation upon motor tasks, such as a lip purse, with post‐training isolated lip area activation. This 6‐week training additionally correlated reductions in pain intensity with a decrease in cortical reorganization (MacIver et al., 2008 ). fMRI applications and key findings are summarized in Table  2 .

Functional magnetic resonance imaging (fMRI) and phantom limb pain (PLP)

Logothetis explains that fMRI interpretation requires caution as this neuroimaging technique may not make key distinctions, such as top‐down versus bottom‐up, excitation versus inhibition, or regional differences (Logothetis, 2008 ). Another recent review of 10 fMRI investigations from 2001 to 2015 found that this imaging technique did not comprehensively support maladaptive brain plasticity, including the relationship between pain intensity and reorganization (Jutzeler et al., 2015 ). In studying fMRI during a VR movement task, Andoh et al. (2020) found that fMRI findings for PLP may vary based on methodology. These findings suggest that fMRI is inconsistent in evaluating changes due to PLP, or perhaps there are gaps in understanding of plasticity in PLP. This principle reiterates the importance of the link between PLP and neurologic adaptation and the need for collaborative techniques.

fMRI measures functional changes with strong spatial resolution but is prone to certain ambiguities in interpretation. The lack of critical distinctions may be why fMRI studies have shown mixed results in PLP research. fMRI has utility in supplementing studies of PLP therapies and interventions (Figure  1 ).

3.3. Electroencephalography

EEG is a temporal‐functional imaging technique that is useful in PLP research. EEG interprets electrical flow across membranes as neurons depolarize. It is distinct from the other imaging techniques discussed in this review by recording real‐time measurements in varying cognitive states (Bunge and Kahn, 2009) . By measuring perpendicular electrical flow, EEG can analyze gyri and deep sulci pyramidal cells (Bunge and Kahn, 2009) . EEG has been further touted, along with MEG, as a method of analyzing cortical reorganization due to advantageous temporal and spatial resolution (Wiech et al., 2004 ). Other researchers have challenged EEG and MEG for truly assessing signal sources, and suggest employing fMRI as a tertiary, complementary component for signal localization (Bunge and Kahn, 2009 ; Cottereau et al., 2015 ). EEG, along with MEG, has higher temporal resolution but lower spatial resolution than fMRI (Meyer‐Lindenberg, 2010 ). The unique ability to perform EEG simultaneously with fMRI further distinguishes this tool as a select method for capturing nonrepeatable events (Bandettini, 2009) .

A case report of a subject with a congenitally absent limb found EEG signatures during attempted movements of the phantom limb to be similar to a cohort of healthy volunteers (Walsh et al., 2015 ). Another study analyzed a cohort of 22 right‐hand amputees via EEG showed distinct global and local network changes in alpha and beta bands (Lyu et al., 2016 ). An investigation of the connection between pain catastrophizing and PLP using EEG showed that these patients had an increased response at the N/P135 dipole of the affected side, suggesting that attention to stimuli may be associated with PLP (Vase et al., 2012 ).

Mirror therapy has been studied as a potential PLP treatment, but recent developments in VR have enabled inventive therapeutic techniques. One such VR investigation utilized EEG and observed PLP alleviation and alpha wave coherence during stimulation of referred sensation areas (Osumi et al., 2020 ). EEG presents a safe and practical way to monitor the forefront of therapeutic techniques for PLP. It allows researchers to gather robust functional change data during therapies. EEG applications and key findings are summarized in Table  3 .

Electroencephalography (EEG) and phantom limb pain (PLP)

While it has many applications and strengths, EEG is limited by lower spatial resolution than fMRI (Meyer‐Lindenberg, 2010) . The spatial resolution has important utility in the investigation of cerebral PLP mechanisms. If only certain superficial regions are reliably captured, deeper cortical reorganization may be missed. Additionally, a review of the EEG technique concluded that EEG deflections are challenging to interpret, and this tool should be one of many used in conjunction (Jackson & Bolger, 2014 ). EEG alone therefore may not provide adequate information about functional changes due to PLP.

EEG is one of the two main techniques for identifying functional changes with temporal resolution. It measures changes in electrical potential perpendicular to the direction of neuronal signal propagation. While EEG is limited by a lack of spatial resolution, its inherent design allows it to be easily used alongside other tools to provide comprehensive results. EEG is a practical way to monitor functional changes while developing PLP therapies (Figure  1 ).

3.4. Magnetoencephalography

MEG is another temporal‐functional imaging technique used in PLP research. It functions by measuring the small magnetic fields created by electrical currents involved in neuronal signaling. The measured magnetic dipole is 90° off phase with the electrical one. The electrical and magnetic fields detected by EEG and MEG are generated by extracellular and intracellular currents, respectively (Singh, 2014 ). Both of these measured phenomena occur at directions perpendicular to that of neuronal signal propagation. Because it assesses magnetic activity at and parallel to the brain's surface, MEG is limited to the analysis of superficial sulci pyramidal cells (Bunge & Kahn, 2009) . As mentioned before, EEG and MEG share a common caveat as they both have difficulty localizing signal sources (Bunge & Kahn, 2009) . MEG also has a higher temporal resolution but lower spatial resolution compared to fMRI (Meyer‐Lindenberg, 2010) .

In a 2001 study, researchers induced acute left thenar pain in healthy non‐PLP patients through capsaicin injections. MEG analysis revealed increased proximity between hand and lip representation, suggesting an acute reorganization in response to the stimulus (Sörös et al., 2001 ). Blume et al. later utilized MEG and identified lip and hand cortical reorganization following an amputated limb replantation. In contrast to other reports, they also found a negative correlation between pain and cortical reorganization (Blume et al., 2014 ).

Kringelbach et al. employed MEG to investigate the effect of deep brain stimulation on a PLP patient. The researchers found changes in mid‐anterior orbitofrontal and subgenual cingulate activity after stimulation was stopped and associated these regions of the brain with pain relief. Their results demonstrate that MEG is useful for identifying response to therapy and potential surgical targets for pain relief (Kringelbach et al., 2007 ). Another investigation of brain–machine interface training integrated MEG reading with a robotic hand. Interestingly, they found this training to intensify pain when used with the phantom limb. At the same time, it reduced pain during dissociative prosthetic‐phantom hand training, further suggesting a link between plasticity and pain (Yanagisawa et al., 2016 ). MEG applications and key findings are summarized in Table  4 .

Magnetoencephalography (MEG) and phantom limb pain (PLP)

Despite its usefulness and safety, MEG has sensitivity to artifacts. Ray et al. addressed the challenge of deep brain stimulation artifact when using MEG by focusing on the occipital lobe following a visual stimulus (Ray et al., 2009 ). The study shows that this tool can provide relevant information if researchers account for its limitations.

MEG is another primary technique for identifying functional changes with temporal resolution. In contrast to EEG, MEG detects magnetic activity parallel to the brain surface. This imaging modality is mostly limited by potential artifacts, which an adapted approach may control. MEG has promising future use for studying robotic and interventional therapy in PLP research (Figure  1 ).

4. DISCUSSION

Neuroimaging has proven paramount in the study of PLP (Figure  1 ). DTI readily outlines structural changes and has potential for surgical applications but is frequently cited for technical limitations, such as subject motion and resolution. Additionally, DTI has often been criticized for variation in measuring technique and data interpretation. fMRI captures functional changes with spatial resolution in various PLP therapies, but cannot make critical neurologic distinctions, which limits data interpretation without behavioral or structural correlation. EEG and MEG are notable for identifying functional changes with a strong temporal resolution and are differentiated by perpendicular electric and parallel magnetic activity, respectively. EEG is significant for spatial limitations, while both EEG and MEG are limited by artifact. Overall, all four imaging techniques provide unique perspectives that have shaped the modern understanding of PLP.

Accessibility and practicality are common barriers that limit PLP neuroimaging. The study scale is often resource dependent, which has restricted how much imaging data can be collected. Limited reproducibility of neuroimaging findings may also hinder the analysis of PLP in certain cases. Consistent techniques and collaboration may alleviate the burden on groups studying PLP. Additionally, the automation of imaging analysis using artificial intelligence and machine learning algorithms may generate uniformity among data interpretation (Hu et al., 2019 ; Vieira et al., 2017 ). These advancements enable the synthesis of data sets to help map neural changes. Robust data collection illustrates the key intersection of imaging and analytical technology, especially in the context of clinical disease. As this field evolves, researchers will continue to utilize neuroimaging aiming to provide fundamental insight into PLP's pathogenesis and treatment.

FUNDING INFORMATION

Conflict of interest.

The authors declare no conflict of interest.

PEER REVIEW

The peer review history for this article is available at https://publons.com/publon/10.1002/brb3.2509

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IMAGES

  1. Origin of phantom limb pain: A dynamic network perspective

    phantom limb pain pathophysiology

  2. Phantom-limb pain: characteristics, causes, and treatment

    phantom limb pain pathophysiology

  3. JCI

    phantom limb pain pathophysiology

  4. Intro to phantom limb pain

    phantom limb pain pathophysiology

  5. Phantom Limb Pain

    phantom limb pain pathophysiology

  6. Phantom-limb pain: characteristics, causes, and treatment

    phantom limb pain pathophysiology

VIDEO

  1. Pain.phantom limb pain treatment

  2. Module D : Referred pain (Anatomy) 3/4

  3. Phantom Limb Pain

  4. The pathophysiology and management of Phantom Limb Pain

  5. Phantom sensation and Phantom Limb Pain 😓 #phantompain #amputee

  6. Treating 'phantom limb pain' with mirror therapy

COMMENTS

  1. Phantom Limb Pain

    Phantom limb pain is the perception of pain or discomfort in a limb that is no longer there. PLP most commonly presents as a sequela of amputation. The underlying pathophysiology remains poorly understood.

  2. Phantom Limb Pain: Mechanisms and Treatment Approaches

    The concept of phantom limb pain (PLP) as being the pain perceived by the region of the body no longer present was first described by Ambrose Pare, a sixteenth century French military surgeon [ 1 ].

  3. Phantom Limb Pain: What is It, Causes, Treatment & Outcome

    The phantom part refers to the location of the pain: the missing limb or part of the limb (such as fingers or toes). Phantom limb pain ranges from mild to severe and can last for seconds, hours, days or longer. It may occur after a medical amputation (removing part of a limb with surgery).

  4. Pathophysiology and treatment of phantom limb pain☆ : Colombian Journal

    Pathophysiology and treatment of phantom limb pain☆ : Colombian Journal of Anesthesiology Introduction: Phantom limb pain may be present in up to 80% of patients subjected to amputation b Pathophysiology and treatment of phantom limb pain☆ : Colombian Journal of Anesthesiology

  5. Phantom limb pain: A literature review

    Phantom pain is pain sensation to a limb, organ or other tissue after amputation and/or nerve injury. 5 In podiatry, the predominant cause of phantom limb pain is after limb amputation due to diseased state presenting with an unsalvageable limb.

  6. Phantom-limb pain: characteristics, causes, and treatment

    Phantom-limb pain is a common sequela of amputation, occurring in up to 80% of people who undergo the procedure. It must be differentiated from non-painful phantom phenomena, residual-limb pain, and non-painful residual-limb phenomena.

  7. Pathophysiology and treatment of phantom limb pain

    Phantom limb pain may be present in up to 80% of patients subjected to amputation because of trauma or peripheral vascular disease. Several factors have been associated with its occurrence, including pre-amputation pain, the etiology, and the amputation level. Objective

  8. Phantom limb pain: mechanisms and treatment approaches

    Abstract The vast amount of research over the past decades has significantly added to our knowledge of phantom limb pain. Multiple factors including site of amputation or presence of preamputation pain have been found to have a positive correlation with the development of phantom limb pain.

  9. Phantom Limb Pain: A Systematic Neuroanatomical-Based Review of

    Introduction. Historically, phantom sensations (PLS) and phantom limb pain (PLP) were widely believed to be psychogenic .With recent advances, we now know that pathological changes occur in both the peripheral and central nervous system after amputation .PLS are characterized by cortical sensory perception of an amputated body part.

  10. Phantom Limb Pain

    Phantom limb pain (PLP) is defined as "pain that is localised in the region of the removed body part" [2]. It is a poorly understood clinical phenomenon that remains the subject of intense research due to the acute and chronic nature of the condition.

  11. Phantom-limb pain: characteristics, causes, and treatment

    The amputation of a limb is commonly followed by the sensation that the deafferented body part is still present. These non-painful phantom sensations may include a specific position, shape, or movement of the phantom, feelings of warmth or cold, itching, tingling, or electric sensations, and other paraesthesias. 1 Pain in the body part that is no longer present occurs in 50-80% of all ...

  12. An Algorithm Approach to Phantom Limb Pain

    Phantom limb pain (PLP) is a common condition that occurs following both upper and lower limb amputation. First recognized and described in 1551 by Ambroise Pare, research into its underlying pathology and effective treatments remains a very active and growing field.

  13. Phantom Limb Pain

    Pathophysiology. Despite, the phantom limb sensation was described by French military surgeon Ambroise Pare (1510-1590) in the sixteenth century, even today we do not have a clear explanation of this complex phenomenon and, therefore, the pathophysiology is explained by a wide range of mechanisms. ... Phantom limb pain can often develop into ...

  14. Phantom Limb Pain

    2023 Aug 4. Authors 1 , Marco Cascella 2 , Matthew Varacallo 3 Affiliations 1 Ochsner Health 2 3 Penn Highlands Healthcare System 28846343 Bookshelf ID: NBK448188 Excerpt In the United States (U.S.), 30,000 to 40,000 amputations are performed each year.

  15. Phantom-limb pain: characteristics, causes, and treatment

    Phantom-limb pain is a common sequela of amputation, occurring in up to 80% of people who undergo the procedure. It must be differentiated from non-painful phantom phenomena, residual-limb pain, and non-painful residual-limb phenomena. Central changes seem to be a major determinant of phantom-limb p …

  16. A review of current theories and treatments for phantom limb pain

    Ortiz-Catalan M, et al. Phantom motor execution facilitated by machine learning and augmented reality as treatment for phantom limb pain: a single group, clinical trial in patients with chronic intractable phantom limb pain. Lancet. 2016;388(10062):2885-2894.

  17. Phantom limb pain

    The development of phantom pain was unpredictable. 77. It has been claimed that severe phantom pain may recur in lower‐limb amputees undergoing spinal anaesthesia. Tessler and Kleiman prospectively investigated 23 spinal anaesthetics in 17 patients. Only one patient developed phantom pain, which resolved in 10 min. 88.

  18. Clinical updates on phantom limb pain

    Phantom limb pain (PLP) is defined as a painful sensation referring to the missing limb, but is also described after loss of an eye, breast, or tooth. 6, 10, 24, 28, 122, 123, 138 The prevalence can be estimated right up to 80% of all patients after limb amputation, depending on study design and study population. 107.

  19. Phantom limb pain: pathophysiology and treatment

    The pathophysiology of phantom limb pain is complex and includes changes in the peripheral nerve, the dorsal root ganglia, spinal cord and cerebral cortex, and just a few treatments have good quality studies to support its use. Phantom limb pain is a common complication after amputation of a limb, its pathophysiology is complex and includes ...

  20. What is phantom pain? Examples, cause, and treatment

    Phantom pain is a feeling of pain in a body part that is no longer present, such as an amputated limb. The pain can range from occasional or mild to constant or severe. For most people,...

  21. Phantom-limb pain: characteristics, causes, and treatment

    Phantom-limb pain is a common sequela of amputation, occurring in up to 80% of people who undergo the procedure. It must be differentiated from non-painful phantom phenomena, residual-limb pain, and non-painful residual-limb phenomena. Central changes seem to be a major determinant of phantom-limb pain; however, peripheral and psychological factors may contribute to it.

  22. Teesside researchers trial phantom limb pain device

    Researcher Sarah Oatway hopes the device will improve people's quality of life. An app-controlled device which could help amputees reduce phantom limb pain is being trialled nationally. The yet-to ...

  23. Recent advances in understanding and managing phantom limb pain

    Post-amputation phantom limb pain (PLP) is highly prevalent and very difficult to treat. The high-prevalence, high-pain intensity levels, and decreased quality of life associated with PLP compel us to explore novel avenues to prevent, manage, and reverse this chronic pain condition.

  24. Investigations into the Etiology of Phantom Limb Sensations and Phantom

    Investigations into the Etiology of Phantom Limb Sensations and Phantom Limb Pain. Project Number. 5R01HD094588-04. Agency/Funding Organization. NICHD. Funding Year. 2022. View Full Project Details for Investigations into the Etiology of Phantom Limb Sensations and Phantom Limb Pain.

  25. Unveiling the phantom: What neuroimaging has taught us about phantom

    Phantom limb pain (PLP) is a complicated condition with diverse clinical challenges. It consists of pain perception of a previously amputated limb. ... the underlying pathophysiology was poorly understood due to limitation in investigational tools. Ambroise Paré described patients feeling absent limbs following amputations he performed during ...