maladaptive brain plasticity phantom limb

Solving phantom limb pain – science is getting closer

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After amputation of an arm, most amputees report vivid and continuous sensations of their missing limb. Some can even move their missing hand as if it were still there. For many amputees, though, these sensations are painful and, unfortunately, there are no effective treatments for this pain.

How could pain arise from a missing hand – and what can we do about it? Our brains contain a detailed map of our body that allows us to move and feel as we explore our world (see the illustration below). Our brain is also a dynamic organ, adapting and changing to experience. This flexibility is called brain plasticity – the process by which we develop from infants to adults, learn new skills and adjust to ageing.

Traditional theories suggest that phantom limb pain arises from “maladaptive plasticity”, whereby a change in the brain results in a negative, or maladaptive, outcome. According to this theory, neighbouring body parts “invade” the missing hand area, creating a signal mismatch that is interpreted as painful. For example, when you lose a hand, the representation in the brain for the missing hand is taken over by neighbouring body parts, such as the arm or the lip representation (the face neighbours the hand area). This then causes the deprived hand region to respond to sensory inputs intended for the arm or lip, and it is the mismatch between body part representations which is thought to result in an error signal that is interpreted by the brain as painful.

Treatments attempting to reverse the invasion – such as mirror therapy , where the visual reflection of the intact hand aims to reinstate the missing hand’s brain representation – have had limited success. Also, new studies have revealed that the representation of the missing hand stays in an amputee’s brain map for decades. It is not overtaken by neighbouring body parts, and this persistence is related to phantom limb pain.

Significant pain reduction

With this in mind, researchers at the University of Oxford and University College London tried to find out if a new treatment, targeted towards brain activity in the missing hand area, could lead to phantom limb pain relief. They used a technique called transcranial direct current stimulation (tDCS) to manipulate activity in the missing hand area with small electrical currents, while amputees were moving their phantom hand in an MRI scanner.

Importantly, these phantom movements differ from imaginary movements and activate the same regions in the brain that two-handed people do when they move a hand. Also, when moving the phantom hand, amputees also engage the very same nerves, or motor pathway, that previously provided sensations and movement to their missing hand. By focusing the tDCS on the missing hand’s brain area during phantom movements, researchers can direct activity, not just in the brain, but also in the damaged motor pathway.

The results of the study, published in Annals of Neurology , show that a single session of this technique led to significant phantom limb pain relief, with effects lasting up to one week, compared with sham stimulation where electrodes were placed on the scalp but no stimulation was given. After treatment, phantom limb pain relief was associated with reduced brain activity in the missing hand area.

Researchers also found that moving the phantom hand activated regions of the brain that deal with pain. The extent to which these pain regions were activated predicted the reduction of brain activity in the missing hand area as well as the pain relief experienced by the amputees after treatment. This suggests that phantom limb pain may emerge from brain activity in pain processing areas, especially when damaged motor pathways associated with the phantom hand are activated.

It is unclear whether tDCS treatment led to pain relief by regulating the processing of motor signals from the phantom hand or by altering cognitive evaluations of these signals. Despite these unanswered questions, this technique offers a cheap, safe and easy-to-use way to provide relief for many amputees who suffer from chronic, “phantom” pain.

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Phantom limb pain and maladaptive plasticity.

          Sadly, in the age of widespread use of improvised explosive devices (IEDs) during wartime, it should come as no surprise that many of our servicemembers return from a deployment missing part of a leg, a hand, or an arm. Fairly little has been conclusively determined regarding the brain’s reaction to a missing limb and most treatment options for phantom limb pain prove unsuccessful, although the increase in amputees over the course of the past decade has inspired further research among Iraq and Afghanistan war veterans, and what researchers are discovering now may turn the prevailing theory of maladaptive plasticity on its head.

            Maladaptive plasticity is the current theory that attempts to explain why up to 80% of amputees experience pain in their missing limbs (Lewis, 2013). This theory operates on the supposition that because the limb and its corresponding nerves are missing and unable to provide input to the brain, the nerve impulses from other body parts begin to take over the cortical area that the phantom limb originally occupied, thus confusing the brain and sending signals that the brain interprets as pain. In other words, in an attempt to cope with the missing limb, the brain begins to restructure itself and creates a new map, drawing from other areas of sensory input to “fill in” the missing gap. At Oxford University, however, a team of researchers led by Tamar Makin have found evidence that may prove the maladaptive plasticity theory wrong (Holzman, 2013).

According to Makin, via the use of fMRI scans, the research team discovered that amputees with stronger pain symptoms actually had stronger cortical representations of the missing limb, and that the stronger pain levels were also associated with the ability to move the phantom limb (actually stimulating the sensation of movement within the cortex, rather than simply imagining the movement) (Holzman, 2013). The fMRI scan results fly directly into the face of maladaptive plasticity, which asserts that essentially the brain no longer contains a representation of the limb and actively attempts to remap the area for use by other anatomical structures. Instead, these fMRI scans demonstrate that the brain’s cortical mapping is so strong and so ingrained that most amputees actually retain the ability to experience sensation from the missing limb, even though there are no sensory neurons being transmitted from the limb to the brain.

Given the course examination of localization of function, I found this new discovery absolutely amazing! I had no idea how strongly the regions of the brain might be married to their anatomical structures or that the brain could continue to receive and interpret signals from a missing limb long after the limb has stopped sending signals. Clearly, our nervous system is far more complex than cells simply sending and receiving signals, and I look forward to reading more from Makin and her team regarding further research into phantom limb pain.

Holzman, D. (2013, March 21). A New Challenge to the Maladaptive Plasticity Theory of Phantom Limb Pain. Retrieved September 13, 2013, from Pain Research Forum: http://www.painresearchforum.org/news/25670-new-challenge-maladaptive-plasticity-theory-phantom-limb-pain

Lewis, T. (2013, March 5). New Theory Explains Why Amputees Feel Phantom Pain. Retrieved September 9, 2013, from LiveScience: http://www.livescience.com/27641-phantom-pain-linked-to-brain-mapping.html

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• Published: 01 November 2006

Phantom limb pain: a case of maladaptive CNS plasticity?

• Herta Flor 1 ,
• Lone Nikolajsen 2 &
• Troels Staehelin Jensen 3  

Nature Reviews Neuroscience volume  7 ,  pages 873–881 ( 2006 ) Cite this article

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Despite many advances in medicine, phantom limb pain — pain in a no longer existing or deafferented limb — still occurs in 50–80% of all amputees.

Pathological neuronal activity in the residual limb or the dorsal root ganglion, which can be enhanced by sympathetic activation, could be one important factor in phantom limb pain.

Spinal changes include reorganization of the body map as well as sensitization of spinal transmission neurons.

Supraspinal changes seem to be important and might have a special focus in the cortex, where maladaptive map reorganization has been found to be closely related to the magnitude of phantom pain.

Similarities of phantom limbs and phantom pain to other abnormal sensory phenomena such as somatosensory and body image-related illusions suggest that frontal and parietal brain regions might be important in the generation of phantom limbs and phantom pain.

Previous painful experience could culminate in a pain memory that might have a role in phantom pain and involve both sensory and affective components.

Behavioural interventions such as use of a mirror, imagery, sensory discrimination training or use of a myoelectric prosthesis could reduce maladaptive plastic changes and subsequently phantom limb pain; pharmacological interventions and stimulation methods might be similarly effective.

Phantom pain refers to pain in a body part that has been amputated or deafferented. It has often been viewed as a type of mental disorder or has been assumed to stem from pathological alterations in the region of the amputation stump. In the past decade, evidence has accumulated that phantom pain might be a phenomenon of the CNS that is related to plastic changes at several levels of the neuraxis and especially the cortex. Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes. We cite both animal and human studies and derive suggestions for innovative interventions aimed at alleviating phantom pain.

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Acknowledgements

This article is dedicated to the memory of T. Pons, whose work inspired many of the findings reported here. This work was supported by the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung (German Neuropathic Pain Network) and the Lundbeck Foundation, Denmark. The authors would like to thank W. Jänig for helpful comments on an earlier version of this article and M. Lotze for help with the figures.

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Department of Clinical and Cognitive Neuroscience, University of Heidelberg, Central Institute of Mental Health, Mannheim, D-68159, Germany

Department of Anesthesiology and Danish Pain Research Center, Aarhus University Hospital, Aarhus C, DK-8000, Denmark

Lone Nikolajsen

Department of Neurology and Danish Pain Research Center, Aarhus University Hospital, Aarhus C, DK-8000, Denmark

Troels Staehelin Jensen

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When a limb is severed, a terminal swelling or 'endbulb' is formed and axonal sprouting occurs. In the case of an amputation, sprouting and endbulb formation lead to a neuroma, a tangled mass that forms when the axons cannot reconnect or can only partially reconnect, as is the case in partial lesions. These neuromas generate abnormal activity that is called ectopic because it does not originate from the nerve endings.

A nodule on a dorsal root that contains cell bodies of afferent spinal neurons, which convey somatosensory input to the CNS.

An abnormal skin sensation such as tingling or itching.

Glial cells are the 'glue' of the nervous system, and support and protect the neurons. Microglia are a special form of small glial cells; they have immune functions and can be involved in inflammatory actions.

A neuropeptide that plays an important role in nociception and is released by the primary somatosensory afferents in the spinal cord.

Unmyelinated fibres, 0.4–1.2 μm in diameter, conducting nerve impulses at a velocity of 0.7–2.3 ms −1 . They conduct secondary, delayed pain.

Thinly myelinated nerve fibres with a conduction velocity of 10–30 ms −1 that convey nociceptive information to the spinal cord. These receptors convey first, sharp, pricking pain and are located mainly on hairy skin.

Large-diameter myelinated fibres that have a conduction velocity of ∼ 40 ms −1 and normally carry non-nociceptive information.

A motor-driven prosthesis that can, for example, be used for grip movements and is operated through the use of electromyographic signals from muscles.

(CRPS). A chronic neuropathic pain syndrome of two types. CRPS1 occurs most often in the arms or legs after a minor or major injury and is accompanied by severe pain, swelling, oedema, sudomotor abnormalities and increased sensitivity to touch. CRPS2 is related to an identified nerve injury.

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Flor, H., Nikolajsen, L. & Staehelin Jensen, T. Phantom limb pain: a case of maladaptive CNS plasticity?. Nat Rev Neurosci 7 , 873–881 (2006). https://doi.org/10.1038/nrn1991

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Pain, Emotion and Cognition pp 189–207 Cite as

Phantom Pain: The Role of Maladaptive Plasticity and Emotional and Cognitive Variables

• Xaver Fuchs 3 ,
• Robin Bekrater-Bodmann PhD 3 &
• Herta Flor PhD 3  
• First Online: 01 January 2015

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Phantom pain is a frequent sequel of the amputation of a limb or another body part and must be differentiated from residual limb pain, postoperative pain, and other chronic pain problems such as back pain that may occur simultaneously. In this chapter, we first discuss how maladaptive plasticity of the central nervous system in interaction with peripheral variables may contribute to phantom pain and then examine how emotional and cognitive variables modulate the phantom pain experience. We show that anxiety, depression, stress experiences, body representation, and memory processes as well as psychosocial variables are associated with both the development of phantom limb pain and its maintenance. In examining this issue, pain and disability-related emotional and cognitive factors must be differentiated. An integration of the described physiological changes with the psychological variables is still missing. We propose a model that integrates psychological and physiological variables in phantom limb pain and discuss implications for both pain assessment and treatment.

• Phantom limb pain
• Residual limb pain
• Brain plasticity

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Acknowledgment

This research was supported by the European Research Council Advanced Grant “Phantom phenomena: A window to the mind and the brain (PHANTOMMIND)” (FP7/2007–2013)/230249 to HF.

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Xaver Fuchs, Robin Bekrater-Bodmann PhD & Herta Flor PhD

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Fuchs, X., Bekrater-Bodmann, R., Flor, H. (2015). Phantom Pain: The Role of Maladaptive Plasticity and Emotional and Cognitive Variables. In: Pickering, G., Gibson, S. (eds) Pain, Emotion and Cognition. Springer, Cham. https://doi.org/10.1007/978-3-319-12033-1_12

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Phantom limb pain: thinking outside the (mirror) box

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Tamar R Makin, Phantom limb pain: thinking outside the (mirror) box, Brain , Volume 144, Issue 7, July 2021, Pages 1929–1932, https://doi.org/10.1093/brain/awab139

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It has long been established that phantom limb pain is a real physiological condition. Why then do we tolerate mystery and myth when it comes to phantom limb pain treatment?

Following amputation, individuals generally report experiencing vivid sensations of their missing limb, which for the majority of people may also feel painful. Phantom limb pain (PLP) is a curious phenomenon; we find it interesting because it raises challenging questions relevant to what it means for us to live inside our bodies, and has thus been a source of wonder and curiosity throughout modern culture. René Descartes liked to use PLP as a cautionary example for why the human senses cannot be trusted. Admiral Nelson, who lost his arm in 1797, took his phantom sensations as evidence for the existence of his eternal soul. More recently, millions of viewers sympathized with the struggles of patients with PLP and their medical teams on hit TV shows, such as Grey’s Anatomy and House , and PLP has even been the topic of an action-adventure stealth video game. Alongside popular culture, PLP has also inspired a plethora of clinical speculation and research.

PLP was first clinically characterized in 1551 by one of the forefathers of modern surgery, Ambroise Paré:

‘Verily it is a thing wondrous strange and prodigious, and which will scarce be credited, unless by such as have seen with their eyes, and heard with their ears the Patients who have many months after the cutting away of the Leg, grievously complained that they yet felt exceeding great pain of that leg so cut off’.

Silas Weir Mitchell, a US Civil War surgeon, coined the term ‘phantom pain’, which he described as: ‘ these hallucinations … so vivid so strange ’.

But for a person suffering from PLP, these sensations are tangible. One amputee, who lost her arm to cancer, describes her sensations:

‘ To anyone looking at me, I have no arm. But I can feel the entirety of my phantom hand and arm. Imagine you are wearing an elbow length evening glove … everywhere the glove touches your skin it’s crushing your arm constantly. … On top of it you get pains like burning pains. It’s like when you burn yourself on the grill. Your instinct is to pull your hand away, but with this pain you can’t. It's a nerve sensation and it stays there, until “it” decides to pull away ’.

Although originally considered to be rare, 1 most recent accounts estimate the incidence of PLP among those who have undergone limb amputation at ∼63% [95% confidence interval (CI): 58.23–67.05]. 2 Despite being very common, PLP is notoriously difficult to treat with conventional medicine. 3 The unusual challenge we are faced with is that the body part to be treated is not physically present. A mechanistic understanding of the neural basis of PLP is thus needed to treat it successfully.

Why do people experience PLP? Early observations showing that PLP can be evoked by applying pressure to the stump led to the theory that it may relate to the peripheral nerves. This was elegantly demonstrated using intraneural recordings from the residual limb of people who had undergone an amputation: even though the receptors of the peripheral nerve are missing, the residual axons still generate and transmit action potentials. Importantly, both spontaneous and evoked PLP are reflected in the electrical activity of the residual nerve.

This finding inspired a simple mechanistic explanation for PLP: as these peripheral nerves normally provide information about touch and pain originating from the hand, inputs provided by these nerves will be interpreted by the CNS as arising from the missing hand. Clinical attempts to use local anaesthesia to block this ectopic electrical activity proved difficult to implement, 4 potentially due to the challenges associated with long-term blocking of nociceptive C-fibres. However, blocking any peripheral signals to the CNS by applying local anaesthesia to the cell body, produced rapid and reversible attenuation—and often complete elimination—of PLP. This provides a powerful demonstration that PLP originates in the periphery.

And yet this simple mechanism has been largely marginalized in comparison to more ambiguous explanations based on psychopathology or cortical neural mechanisms.

Many theories dominating the early 20th century assumed that PLP was neurotic in nature, manifested by ‘denial’ or even ‘hysteria’. 1 For example, R.D. Langdale Kelham, a pioneer in post-amputation rehabilitation concluded that the typical patient with a phantom limb was, more often than not, someone with an ‘unsatisfactory personality’:

‘ It may be he is an anxious, introspective, dissatisfied, ineffective [sic] who, becoming obsessed by his symptoms, and brooding upon them and his disability, tends to dramatise their degree, using undoubted exaggerations in his description of his sufferings ’.

Theories relying on psychopathology or other psychogenic mechanisms to explain PLP have been conclusively debunked. Cognitive behavioural therapy, however, is a common tool for helping amputees cope with the consequences of PLP. 3

Others have considered the anatomical origins of PLP to lie in the sensorimotor CNS. This possibility paved the way for a flurry of surgical interventions in the latter half of the 20th century, ranging from antero-lateral chordotomy to ablation of the postcentral gyrus, with relatively poor clinical outcomes ( Fig. 1 ).

PLP treatments. Reproduced with permission from Sherman et al . 4

Since the end of the 20th century, the prevailing theory for the development of PLP has been that of maladaptive brain plasticity. This idea is based on an observation in monkeys where loss of input to the brain’s hand area (e.g. following arm deafferentation) leads to redistribution of brain resources, termed brain plasticity, or reorganization. Simply put, the cortical resources of the (now missing) hand become freed up, and subsequently get taken over by a new body part. Intuitively, you might expect that the brain’s ability to reassign resources across body parts based on altered demand should be helpful, and perhaps even allow people who have lost a limb to better adapt to their disability. An example of adaptive plasticity would be early-blind individuals, where the visual cortex becomes involved in non-visual processing for perception and language.

However, according to the maladaptive plasticity theory of PLP, reorganization in the adult brain can be harmful. This idea is rooted in an observation that a relatively crude measure of brain reorganization in amputees correlates with PLP. 5 Consequently, cortical reorganization was proposed to trigger pain in the phantom hand as a result of the cortical area corresponding to the missing limb becoming activated by the invading inputs. This input mismatch was thought to generate an ‘error’ signal that is interpreted by the brain as pain arising from the missing hand. This theory provides clear predictions on how to treat PLP: if pain is caused by maladaptive reorganization, then we need to reverse the reorganization to alleviate PLP.

Presently, some of the most widely used treatments for PLP aim to reverse maladaptive plasticity by ‘reinstating’ the representation of the missing hand to its original territory. 3 Mirror box therapy uses illusory visual information about the missing hand (by reflecting an image of the intact hand via a mirror), in an effort to restore the missing hand representation in primary somatosensory cortex ( Fig. 2 ). A related approach, using implicit and explicit motor imagery, aims to gradually ‘reawaken’ the motor representation of the missing hand. Building on these ideas, virtual reality approaches aim to improve phantom motor execution in an attempt to ‘normalize’ the sensorimotor representation of the missing hand. Common to these and other techniques is the ambition to exploit neuroplasticity mechanisms to reinstate normal sensory and motor representations.

Mirror box treatment aims to reinstate the representation of the missing hand in order to reverse maladaptive brain plasticity. Modified from ‘Motor homunculus' by Ralf Stephan, [email protected], https://commons.wikimedia.org/wiki/File:Motor_homunculus.svg (22 March 2021, date last accessed) licensed under CC BY-SA 4.0, https://creativecommons.org/licenses/by-sa/4.0 , via Wikimedia Commons.

Although the idea of a neuroscientific mechanism may be compelling, it is important to remember that we should not infer causation from a correlation, such as that observed between reorganization and PLP. A closer examination of the maladaptive theory and its ensuing therapies reveals a number of unsupported assumptions and a consistent lack of efficacy, respectively.

Consider some of the key hypotheses underlying the maladaptive theory. First, the notion that input loss ‘erases’ the representation of the missing hand, leading to cortical reorganization, has been negated. 6 Recent human studies using advanced neuroimaging techniques fail to find invasion of foreign inputs into the cortical territory of the missing hand. 7 Instead, multiple lines of evidence demonstrate that the brain retains the representation of the missing hand despite the fact that the hand is physically absent. In other words, there is no need to ‘reinstate’ the representation of the hand, which persists after amputation. As a side note, you cannot trick somatosensory cortex into reorganizing with visual information, simply because visual input is not a powerful modulator of this particular brain area.

Second, the idea that a foreign input causes pain by triggering an error signal in the cortex representing the missing hand has also long been refuted. 6 For example, researchers have artificially stimulated the somatosensory hand territory in a deafferented patient, by injecting very small currents directly into the brain. According to the maladaptive theory, this should result in an ‘error’ signal, potentially giving rise to pain. But instead, this procedure triggers tactual and non-painful sensations on the insensate hand. Therefore, consistent with other results from studies using stimulation in amputees’ motor cortex, displaced inputs to the missing hand territory do not cause pain. Instead, pain sensations are better linked to a set of brain areas with a connectome distinct from that of the sensorimotor network.

Perhaps the most compelling evidence against the maladaptive plasticity theory is its poor clinical outcomes. As stated, over the past three decades, the maladaptive theory has become assertively dominant. For example, the original paper reporting a correlation between cortical plasticity and PLP has been cited almost 2000 times. 5 Consequently, its therapeutic derivatives have dominated clinical practice—according to a recent international survey, four of the six most widely recommended PLP treatments (including both pharmacological and non-pharmacological options) are based on reversing maladaptive plasticity. 3 Yet, PLP is still a common condition, and the overwhelming consensus across clinical trials, systematic reviews and meta-analyses is that there is no strong evidence that these clinical approaches provide consistent and long-lasting PLP relief, beyond a placebo control. 8

Then why are we continuing to use these unsuccessful therapies? The limited efficacy of these therapies is exhasperated by the fact that much of the first-level evidence supporting these treatments is compromised. To begin with, PLP and its relief are ultimately measured by subjective report, which is fundamentally susceptible to suggestion and biases. Without a direct comparison to a double-blind placebo-controlled study arm, any observed changes in PLP reports should be treated with scepticism. Yet, this gold standard is rarely adopted in PLP research.

A further challenge is that PLP phenomenology is diverse, and therefore studies aimed at tracking PLP tend to use multiple pain scales. This becomes a problem when researchers ‘cherry-pick’ a particular outcome measure post hoc , without accounting for the multiple potential comparisons that have been performed.

A third problem relates to the mechanisms of pain alleviation. Some of the newest virtual/augmented reality treatments use principles from gamification to make the therapy more engaging, but attentional distraction is known to have pain-relieving benefits. 9 Let’s consider an ongoing clinical trial, where phantom movements are used to control a video game in a virtual/augmented environment. 10 This intervention is compared to a control condition where participants are asked to imagine moving the phantom but not engage in or control the game. Any benefits incurred by the main treatment might be attributable to distraction arising from this increased engagement.

Considering that no effective PLP treatment is currently available, one might argue that there is no harm in providing patients with suboptimal treatments. Indeed, the placebo effect is extremely powerful, and could be harnessed to ease the suffering of individuals struggling with intractable pain. But we should also consider the consequences of deliberately developing and using suboptimal treatments. From an ethical standpoint, if we know the treatment is not more effective than a placebo, we should make this explicitly clear to the patient and the clinical team. This is especially true when the treatment might be expensive or time consuming for the patient.

From a policy perspective, the development and assessment of mirror box-like treatments has consumed an enormous share of the resources available to the small community tasked with developing targeted PLP treatments. This leaves very few research and innovation opportunities for identifying alternative and potentially more successful treatments, which we desperately need. Rather than rehashing unsuccessful treatments, we should instead work towards practical methods to suppress the PLP generators that have been identified.

In their very detailed and comprehensive account of phantom limbs from 1948, Henderson and Smyth concluded:

‘ To put the matter briefly, that which still exists is working in harmony with that which has ceased to exist   except as a pattern in the cortex ’ [emphasis in original text].

It appears that despite our best efforts over the past 70 years, our mechanistic conceptualization of PLP and its treatment have not advanced much beyond this vague notion. Unfortunately, at this point, we still don’t have a consensus understanding of the neural drivers of PLP. We don’t even know if this condition is mechanistically any different from other more common, and arguably less romanticized, chronic pain conditions, such as joint pain. But considering how futile our focus on maladaptive brain plasticity has been so far, it is time for us to shed our romantic prenotions around this pain condition, and start thinking outside the (mirror) box.

Tamar Makin is a Professor of Cognitive Neuroscience at UCL and leader of the London Plasticity Lab https://plasticity-lab.com/

Figures were modified by Dani Code. Marshall Devor and Joel Katz provided helpful comments on a preliminary draft of the essay.

T.R.M. is funded by a Wellcome Trust Senior Research Fellowship (215575/Z/19/Z).

The author reports no competing interests.

Henderson WR , Smyth GE. Phantom limbs . J Neurol Neurosurg Psychiatry . 1948 ; 11 ( 2 ): 88 – 112 .

Google Scholar

Limakatso K , Bedwell GJ , Madden VJ , Parker R. The prevalence of phantom limb pain and associated risk factors in people with amputations: A systematic review protocol . Syst Rev . 2019 ; 8 ( 1 ): 1 – 5 .

Limakatso K , Parker R. Treatment recommendations for phantom limb pain in people with amputations: An expert consensus Delphi study . PM R . Published online 18 January 2021 . https://onlinelibrary.wiley.com/doi/epdf/10.1002/pmrj.12556

Sherman RA , Sherman CJ , Gall NG. A survey of current phantom limb pain treatment in the United States . Pain . 1980 ; 8 ( 1 ): 85 – 99 .

Flor H , Elbert T , Knecht S , et al.  Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation . Nature . 1995 ; 375 ( 6531 ): 482 – 484 .

Makin TR , Bensmaia SJ. Stability of sensory topographies in adult cortex . Trends Cogn Sci . 2017 ; 21 ( 3 ): 195 – 204 .

Muret D , Makin TR. The homeostatic homunculus: Rethinking deprivation-triggered reorganisation . Curr Opin Neurobiol . 2020 ; 67 : 115 – 122 .

Aternali A , Katz J. Recent advances in understanding and managing phantom limb pain . F1000Research . 2019 ; 8 : 1167 .

Matheve T , Bogaerts K , Timmermans A. Virtual reality distraction induces hypoalgesia in patients with chronic low back pain: A randomized controlled trial . J Neuroeng Rehabil . 2020 ; 17 ( 1 ): 55 .

Lendaro E , Hermansson L , Burger H , et al.  Phantom motor execution as a treatment for phantom limb pain: Protocol of an international, double-blind, randomised controlled clinical trial . BMJ Open . 2018 ; 8 ( 7 ): e021039 .

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Cortical plasticity as a basis of phantom limb pain: Fact or fiction?

Affiliations.

• 1 Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, D-68159 Mannheim, Germany. Electronic address: [email protected].
• 2 Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, D-68159 Mannheim, Germany.
• 3 Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA; Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, TN, USA; Department of Neurology, Memphis Veterans Affairs Medical Center, Memphis, TN, USA.
• 4 Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, D-68159 Mannheim, Germany. Electronic address: [email protected].
• PMID: 29155276
• DOI: 10.1016/j.neuroscience.2017.11.015

Cortical reorganization has been proposed as a major factor involved in phantom pain with prior nociceptive input to the deafferented region and input from the non-deafferented cortex creating neuronal activity that is perceived as phantom pain. There is substantial evidence that these processes play a role in neuropathic pain, although causal evidence is lacking. Recently it has been suggested that a maintenance of the cortical representation of the former hand area is related to phantom pain. Although interesting, evidence for this process is so far scarce. In addition, peripheral factors have been proposed as important for phantom limb pain. Although often introduced as contradictory, we suggest that cortical reorganization, preserved limb function and peripheral factors interact to create the various painful and nonpainful aspects of the phantom limb experience. In addition, the type of task (sensory versus motor), the interaction of injury- and use-dependent plasticity, the type of data analysis, contextual factors such as the body representation and psychological variables determine the outcome and need to be considered in models of phantom limb pain. Longitudinal studies are needed to determine the formation of the phantom pain experience.

Keywords: context dependency; cortical reorganization; peripheral input; phantom limb pain; preserved limb.

Copyright © 2017 IBRO. All rights reserved.

Publication types

• Research Support, Non-U.S. Gov't
• Cerebral Cortex / physiology*
• Neuralgia / complications
• Neuralgia / physiopathology*
• Neuronal Plasticity / physiology*
• Phantom Limb / complications
• Phantom Limb / physiopathology*

Grants and funding

• 230249/ERC_/European Research Council/International

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Phantom limb pain: thinking outside the (mirror) box

Tamar r makin.

Institute of Cognitive Neuroscience, University College London, London, UK

Despite our best efforts over the past century, our mechanistic understanding of phantom limb pain and our ability to treat it have remained limited. Tamar Makin invites readers to think more critically about some of the most popular approaches to understanding and treating this condition.

It has long been established that phantom limb pain is a real physiological condition. Why then do we tolerate mystery and myth when it comes to phantom limb pain treatment?

Following amputation, individuals generally report experiencing vivid sensations of their missing limb, which for the majority of people may also feel painful. Phantom limb pain (PLP) is a curious phenomenon; we find it interesting because it raises challenging questions relevant to what it means for us to live inside our bodies, and has thus been a source of wonder and curiosity throughout modern culture. René Descartes liked to use PLP as a cautionary example for why the human senses cannot be trusted. Admiral Nelson, who lost his arm in 1797, took his phantom sensations as evidence for the existence of his eternal soul. More recently, millions of viewers sympathized with the struggles of patients with PLP and their medical teams on hit TV shows, such as Grey’s Anatomy and House , and PLP has even been the topic of an action-adventure stealth video game. Alongside popular culture, PLP has also inspired a plethora of clinical speculation and research.

PLP was first clinically characterized in 1551 by one of the forefathers of modern surgery, Ambroise Paré:

‘Verily it is a thing wondrous strange and prodigious, and which will scarce be credited, unless by such as have seen with their eyes, and heard with their ears the Patients who have many months after the cutting away of the Leg, grievously complained that they yet felt exceeding great pain of that leg so cut off’.

Silas Weir Mitchell, a US Civil War surgeon, coined the term ‘phantom pain’, which he described as: ‘ these hallucinations … so vivid so strange ’.

But for a person suffering from PLP, these sensations are tangible. One amputee, who lost her arm to cancer, describes her sensations:

‘ To anyone looking at me, I have no arm. But I can feel the entirety of my phantom hand and arm. Imagine you are wearing an elbow length evening glove … everywhere the glove touches your skin it’s crushing your arm constantly. … On top of it you get pains like burning pains. It’s like when you burn yourself on the grill. Your instinct is to pull your hand away, but with this pain you can’t. It's a nerve sensation and it stays there, until “it” decides to pull away ’.

Although originally considered to be rare, 1 most recent accounts estimate the incidence of PLP among those who have undergone limb amputation at ∼63% [95% confidence interval (CI): 58.23–67.05]. 2 Despite being very common, PLP is notoriously difficult to treat with conventional medicine. 3 The unusual challenge we are faced with is that the body part to be treated is not physically present. A mechanistic understanding of the neural basis of PLP is thus needed to treat it successfully.

Why do people experience PLP? Early observations showing that PLP can be evoked by applying pressure to the stump led to the theory that it may relate to the peripheral nerves. This was elegantly demonstrated using intraneural recordings from the residual limb of people who had undergone an amputation: even though the receptors of the peripheral nerve are missing, the residual axons still generate and transmit action potentials. Importantly, both spontaneous and evoked PLP are reflected in the electrical activity of the residual nerve.

This finding inspired a simple mechanistic explanation for PLP: as these peripheral nerves normally provide information about touch and pain originating from the hand, inputs provided by these nerves will be interpreted by the CNS as arising from the missing hand. Clinical attempts to use local anaesthesia to block this ectopic electrical activity proved difficult to implement, 4 potentially due to the challenges associated with long-term blocking of nociceptive C-fibres. However, blocking any peripheral signals to the CNS by applying local anaesthesia to the cell body, produced rapid and reversible attenuation—and often complete elimination—of PLP. This provides a powerful demonstration that PLP originates in the periphery.

And yet this simple mechanism has been largely marginalized in comparison to more ambiguous explanations based on psychopathology or cortical neural mechanisms.

Many theories dominating the early 20th century assumed that PLP was neurotic in nature, manifested by ‘denial’ or even ‘hysteria’. 1 For example, R.D. Langdale Kelham, a pioneer in post-amputation rehabilitation concluded that the typical patient with a phantom limb was, more often than not, someone with an ‘unsatisfactory personality’:

‘ It may be he is an anxious, introspective, dissatisfied, ineffective [sic] who, becoming obsessed by his symptoms, and brooding upon them and his disability, tends to dramatise their degree, using undoubted exaggerations in his description of his sufferings ’.

Theories relying on psychopathology or other psychogenic mechanisms to explain PLP have been conclusively debunked. Cognitive behavioural therapy, however, is a common tool for helping amputees cope with the consequences of PLP. 3

Others have considered the anatomical origins of PLP to lie in the sensorimotor CNS. This possibility paved the way for a flurry of surgical interventions in the latter half of the 20th century, ranging from antero-lateral chordotomy to ablation of the postcentral gyrus, with relatively poor clinical outcomes ( Fig. 1 ).

PLP treatments. Reproduced with permission from Sherman et al . 4

Since the end of the 20th century, the prevailing theory for the development of PLP has been that of maladaptive brain plasticity. This idea is based on an observation in monkeys where loss of input to the brain’s hand area (e.g. following arm deafferentation) leads to redistribution of brain resources, termed brain plasticity, or reorganization. Simply put, the cortical resources of the (now missing) hand become freed up, and subsequently get taken over by a new body part. Intuitively, you might expect that the brain’s ability to reassign resources across body parts based on altered demand should be helpful, and perhaps even allow people who have lost a limb to better adapt to their disability. An example of adaptive plasticity would be early-blind individuals, where the visual cortex becomes involved in non-visual processing for perception and language.

However, according to the maladaptive plasticity theory of PLP, reorganization in the adult brain can be harmful. This idea is rooted in an observation that a relatively crude measure of brain reorganization in amputees correlates with PLP. 5 Consequently, cortical reorganization was proposed to trigger pain in the phantom hand as a result of the cortical area corresponding to the missing limb becoming activated by the invading inputs. This input mismatch was thought to generate an ‘error’ signal that is interpreted by the brain as pain arising from the missing hand. This theory provides clear predictions on how to treat PLP: if pain is caused by maladaptive reorganization, then we need to reverse the reorganization to alleviate PLP.

Presently, some of the most widely used treatments for PLP aim to reverse maladaptive plasticity by ‘reinstating’ the representation of the missing hand to its original territory. 3 Mirror box therapy uses illusory visual information about the missing hand (by reflecting an image of the intact hand via a mirror), in an effort to restore the missing hand representation in primary somatosensory cortex ( Fig. 2 ). A related approach, using implicit and explicit motor imagery, aims to gradually ‘reawaken’ the motor representation of the missing hand. Building on these ideas, virtual reality approaches aim to improve phantom motor execution in an attempt to ‘normalize’ the sensorimotor representation of the missing hand. Common to these and other techniques is the ambition to exploit neuroplasticity mechanisms to reinstate normal sensory and motor representations.

Mirror box treatment aims to reinstate the representation of the missing hand in order to reverse maladaptive brain plasticity. Modified from ‘Motor homunculus' by Ralf Stephan, [email protected], https://commons.wikimedia.org/wiki/File:Motor_homunculus.svg (22 March 2021, date last accessed) licensed under CC BY-SA 4.0, https://creativecommons.org/licenses/by-sa/4.0 , via Wikimedia Commons.

Although the idea of a neuroscientific mechanism may be compelling, it is important to remember that we should not infer causation from a correlation, such as that observed between reorganization and PLP. A closer examination of the maladaptive theory and its ensuing therapies reveals a number of unsupported assumptions and a consistent lack of efficacy, respectively.

Consider some of the key hypotheses underlying the maladaptive theory. First, the notion that input loss ‘erases’ the representation of the missing hand, leading to cortical reorganization, has been negated. 6 Recent human studies using advanced neuroimaging techniques fail to find invasion of foreign inputs into the cortical territory of the missing hand. 7 Instead, multiple lines of evidence demonstrate that the brain retains the representation of the missing hand despite the fact that the hand is physically absent. In other words, there is no need to ‘reinstate’ the representation of the hand, which persists after amputation. As a side note, you cannot trick somatosensory cortex into reorganizing with visual information, simply because visual input is not a powerful modulator of this particular brain area.

Second, the idea that a foreign input causes pain by triggering an error signal in the cortex representing the missing hand has also long been refuted. 6 For example, researchers have artificially stimulated the somatosensory hand territory in a deafferented patient, by injecting very small currents directly into the brain. According to the maladaptive theory, this should result in an ‘error’ signal, potentially giving rise to pain. But instead, this procedure triggers tactual and non-painful sensations on the insensate hand. Therefore, consistent with other results from studies using stimulation in amputees’ motor cortex, displaced inputs to the missing hand territory do not cause pain. Instead, pain sensations are better linked to a set of brain areas with a connectome distinct from that of the sensorimotor network.

Perhaps the most compelling evidence against the maladaptive plasticity theory is its poor clinical outcomes. As stated, over the past three decades, the maladaptive theory has become assertively dominant. For example, the original paper reporting a correlation between cortical plasticity and PLP has been cited almost 2000 times. 5 Consequently, its therapeutic derivatives have dominated clinical practice—according to a recent international survey, four of the six most widely recommended PLP treatments (including both pharmacological and non-pharmacological options) are based on reversing maladaptive plasticity. 3 Yet, PLP is still a common condition, and the overwhelming consensus across clinical trials, systematic reviews and meta-analyses is that there is no strong evidence that these clinical approaches provide consistent and long-lasting PLP relief, beyond a placebo control. 8

Then why are we continuing to use these unsuccessful therapies? The limited efficacy of these therapies is exhasperated by the fact that much of the first-level evidence supporting these treatments is compromised. To begin with, PLP and its relief are ultimately measured by subjective report, which is fundamentally susceptible to suggestion and biases. Without a direct comparison to a double-blind placebo-controlled study arm, any observed changes in PLP reports should be treated with scepticism. Yet, this gold standard is rarely adopted in PLP research.

A further challenge is that PLP phenomenology is diverse, and therefore studies aimed at tracking PLP tend to use multiple pain scales. This becomes a problem when researchers ‘cherry-pick’ a particular outcome measure post hoc , without accounting for the multiple potential comparisons that have been performed.

A third problem relates to the mechanisms of pain alleviation. Some of the newest virtual/augmented reality treatments use principles from gamification to make the therapy more engaging, but attentional distraction is known to have pain-relieving benefits. 9 Let’s consider an ongoing clinical trial, where phantom movements are used to control a video game in a virtual/augmented environment. 10 This intervention is compared to a control condition where participants are asked to imagine moving the phantom but not engage in or control the game. Any benefits incurred by the main treatment might be attributable to distraction arising from this increased engagement.

Considering that no effective PLP treatment is currently available, one might argue that there is no harm in providing patients with suboptimal treatments. Indeed, the placebo effect is extremely powerful, and could be harnessed to ease the suffering of individuals struggling with intractable pain. But we should also consider the consequences of deliberately developing and using suboptimal treatments. From an ethical standpoint, if we know the treatment is not more effective than a placebo, we should make this explicitly clear to the patient and the clinical team. This is especially true when the treatment might be expensive or time consuming for the patient.

From a policy perspective, the development and assessment of mirror box-like treatments has consumed an enormous share of the resources available to the small community tasked with developing targeted PLP treatments. This leaves very few research and innovation opportunities for identifying alternative and potentially more successful treatments, which we desperately need. Rather than rehashing unsuccessful treatments, we should instead work towards practical methods to suppress the PLP generators that have been identified.

In their very detailed and comprehensive account of phantom limbs from 1948, Henderson and Smyth concluded:

‘ To put the matter briefly, that which still exists is working in harmony with that which has ceased to exist   except as a pattern in the cortex ’ [emphasis in original text].

It appears that despite our best efforts over the past 70 years, our mechanistic conceptualization of PLP and its treatment have not advanced much beyond this vague notion. Unfortunately, at this point, we still don’t have a consensus understanding of the neural drivers of PLP. We don’t even know if this condition is mechanistically any different from other more common, and arguably less romanticized, chronic pain conditions, such as joint pain. But considering how futile our focus on maladaptive brain plasticity has been so far, it is time for us to shed our romantic prenotions around this pain condition, and start thinking outside the (mirror) box.

Acknowledgements

Figures were modified by Dani Code. Marshall Devor and Joel Katz provided helpful comments on a preliminary draft of the essay.

Tamar Makin is a Professor of Cognitive Neuroscience at UCL and leader of the London Plasticity Lab https://plasticity-lab.com/

T.R.M. is funded by a Wellcome Trust Senior Research Fellowship (215575/Z/19/Z).

Competing interests

The author reports no competing interests.