Central mechanisms in phantom limb perception: The past, present and future

Melita  Giummarra; Nellie Georgiou-Karistianis

Through the influences of Descartes to Ramachandran, phantom limbs have been considered as illusory feelings caused by neural processes in the brain that are related to body representation. Extending this view to the whole body suggests that the subjective experience of one’s body even without a physical basis would be constructed by neural processes. In fact, in discussing the mechanism of phantom limbs, Ramachandran clearly stated that the whole body is a phantom constructed by the brain for convenience. This is properly called the “body-in-the-brain” view. However, a detailed examination of phantom limbs in the present paper suggests almost the opposite view, although the brain can play an important role in the phenomena. I will first explain why the experience of moving phantom limbs cannot be reduced to motor imagery but should be regarded as a part of physical body movement. Thus, phantom limbs exist as a part of a patient’s body schema. Next, I will discuss the original experience in which one’s body itself is constituted. Drawing on Husserl’s idea of “sensing,” the discussion will clarify that the constituting process of the body involves the pre-reflective sense of self being located within the body. The phantom limb phenomenon illuminates the importance of the body’s physical dimension, making it possible to locate itself within the world through sensing. This paper defends this line of thought as the “body-in- the-world” view.

Multiple sensory stimuli contribute to the conscious awareness of the body. It is well known that limb amputation can result in abnormal body awareness, but the manner in which the CNS constructs and updates a body schema after injury is largely unknown. The purpose of the present study was to systematically evaluate the effects of sensory inputs on phantom limb awareness (PLA) shortly after unilateral upper extremity amputation. The location, quality and intensity of spontaneous and tactile-evoked phantom sensations and awareness were assessed in 13 amputees who were referred sequentially for their initial post-operative rehabilitation. Subjects were tested in three visual conditions: (i) with their eyes open; (ii) with their eyes closed; and (iii) while they viewed their intact hand in a mirror, which created an illusion of their amputated hand (i.e. mirror visual illusion). The mirror illusion was also used to test the effect of combined visual and movement-related stimuli during active voluntary movement. Spontaneous PLA was reported by 12 of the 13 amputees and was not affected by normal visual inputs. Tactile stimulation of the residual limb or face evoked dual percepts in six amputees; i.e. these amputees perceived these touch stimuli as if they were being applied both to the stimulus site and also to a location on the missing limb. This mislocalization phenomenon was most prevalent in the eyes-closed condition. Thus, normal vision can strongly override the phantom component of touch-evoked dual percepts. In eight cases, the visual illusion of the missing limb transiently enhanced the spontaneous conscious awareness of the phantom limb. However, the visual illusion did not change the capacity of a tactile stimulus to induce dual percepts. These findings demonstrate that (i) phantom awareness of an amputated body part is common within the 14 months after traumatic upper extremity amputation, (ii) evoked dual percepts are less common than spontaneous PLA, (iii) visual, tactile and sensorimotor systems contribute to PLA, (iv) subtle changes in congruence of sensory information affects both evoked dual percepts and spontaneous PLA, however, (v) sensorimotor information pertaining to the state of the motor system can strongly influence spontaneous PLA, whereas the visual system can predominantly influence evoked PLA.

Recent studies of amputees reveal a remarkable diversity in the qualities of experiences that define the phantom limb, whether painless or painful. This paper selectively reviews evidence of peripheral. central and psychological processes that trigger or modulate a variety of phantom limb experiences. The data show that pain experienced prior to amputation may persist in the form of a somatosensory memory in the phantom limb. It is suggested that the length and size of. the phantom limb may be a perceptual marker of the extent to which sensory input from the amputation stump have re-occupied deprived cortical regions originally subserving the amputated limb. A peripheral mechanism involving a sympathetic-efferent somatic-afferent cycle is presented to explain fluctuations in the intensity of paresthesias referred to the phantom limb. While phantom pain and other sensations are frequently triggered by thoughts and feelings. there is no evidence that the painful or painless phantom limb is a symptom of a psychological disorder. It is concluded that the experience of a phantom limb is determined by a complex interaction of inputs from the periphery and widespread regions of the brain subserving sensory, cognitive, and emotional processes. .

B RA I N RE SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v Review Central mechanisms in phantom limb perception: The past, present and future Melita J. Giummarra a,b,⁎, Stephen J. Gibson b,c , Nellie Georgiou-Karistianis a , John L. Bradshaw a a Experimental Neuropsychology Research Unit, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Clayton VIC 3800, Australia b National Ageing Research Institute, Parkville, VIC, Australia c Caulfield Pain Management and Research Centre, Caulfield, VIC, Australia A R T I C LE I N FO AB S T R A C T Article history: Phantom limbs provide valuable insight into the mechanisms underlying bodily awareness Accepted 28 January 2007 and ownership. This paper reviews the complexity of phantom limb phenomena Available online 1 February 2007 (proprioception, form, position, posture and telescoping), and the various contributions of internal constructs of the body, or body schema, and neuromatrix theory in explaining these Keywords: phenomena. Specific systems and processes that have received little attention in phantom Phantom sensation limb research are also reviewed and highlighted as important future directions. These Phantom pain neuromatrix include prosthesis embodiment and extended physiological proprioception (i.e., the Mirror neuron extension of the body's “area of influence” that thereby extends one's innate sense of Body schema proprioception), mirror neurons and cross-referencing of the phantom limb with the intact limb (and the related phenomena of perceiving referred sensations and mirrored movements in the phantom from the intact limb). The likely involvements of the body schema and the body–self neuromatrix, mirror neurons, and cross-callosal and ipsilateral mechanisms in phantom limb phenomena all suggest that the perception of a “normal” phantom limb (that is, a non-painful phantom that has the sensory qualities of an intact limb) is more than likely an epiphenomenon of normal functioning, action understanding and empathy, and potentially may even be evolutionarily adaptive and perhaps necessary. Phantom pain, however, may be a maladaptive failure of the neuromatrix to maintain global bodily constructs. © 2007 Elsevier B.V. All rights reserved. Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . Proprioception of the phantom limb . . . . . . . . 2.1. Distorted perception of the phantom limb . 2.2. Telescoping of the phantom limb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 220 221 221 ⁎ Corresponding author. Experimental Neuropsychology Research Unit, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Clayton VIC 3800, Australia. Fax: +61 3 9905 3948. E-mail address: [email protected] (M.J. Giummarra). 0165-0173/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2007.01.009 220 B RA I N R E SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 3. 4. Prosthesis use and embodiment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The cortical origins of phantom limb phenomena . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. The body schema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The neuromatrix. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Phantom phenomena problematic for current theory . . . . . . . . . . . . . . . . . . . . . . 4.4. Mirror neurons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. Mirror neurons and action understanding . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. Mirror neurons and empathy for pain in amputees . . . . . . . . . . . . . . . . . . . 4.5. Cross referencing between the intact limb and the phantom limb . . . . . . . . . . . . . . . 4.5.1. Mirrored sensation and movement from the intact limb to the phantom limb . . . . 4.5.2. Experimentally induced sensory and motor coupling between the phantom and real 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction Phantom limbs are a seemingly curious phenomenon, nevertheless perceived by up to 98% of amputees following amputation (Ramachandran and Hirstein, 1998), nerve avulsion (Melzack, 1992), or spinal cord injury (Bors, 1951; Braun et al., 2001; Le Chapelain et al., 2001; Mikulis et al., 2002; Moore et al., 2000), and by about 20% of children with congenital limb aplasia (Melzack et al., 1997). Phantom pain is experienced by up to 80% of amputees (Kooijman et al., 2000; Sherman, 1994), with pain usually characterised as either (a) burning, tingling, or throbbing; (b) cramping or squeezing; and (c) shocking or shooting (Sherman, 1994). Phantom sensations are perceived immediately after limb loss by most amputees (Ramachandran and Hirstein, 1998); however for some, they may emerge years or even decades after limb loss. The duration of phantom limb perception also varies between individuals, and phantom sensations may be perceived for anything from a few days to weeks, months, years or even decades after limb loss before they fade completely, if at all (Kooijman et al., 2000; Machin and Williams, 1998). Phantom sensations are reported most commonly following the amputation of an arm or leg, or some part thereof (Ramachandran and Hirstein, 1998), although they have also been reported following removal of the breast (Aglioti et al., 1994; Bressler et al., 1955; Jamison et al., 1979), penis (Fisher, 1999), eye (Sörös et al., 2003), teeth (Marbach, 1993), bladder (Arcadi, 1977; Biley, 2001; Brena and Sammons, 1979) and rectum (Cherng et al., 2001; Farley and Smith, 1968; Ovesen et al., 1991). Phantom sensations following removal of visceral organs may be painful in nature (for example, menstrual pain following hysterectomy or phantom pain that resembles presurgical pain) and tend to be characterised by functional sensations; for example, sensations of urination or erection following penis removal (Fisher, 1999; Weinstein, 1998). The present paper reviews the literature on the perceived “body space” of phantom limbs, their interaction with prosthetic devices, and the evidence that the body schema (Section 4.1, below) plays an integral role in phantom limb perception. Current theories of phantom limb perception are also reviewed, including Melzack’s (1990) neuromatrix theory (Section 4.2, below), and the more recently proposed roles of the fronto-parietal mirror neuron system (Brugger, 2006; . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . limb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 223 223 224 224 225 225 225 226 226 227 228 228 228 Brugger et al., 2000), and “pain matrix” mirror system (Giummarra et al., 2006a) (Section 4.4, below). The pain matrix refers to the pain-related network that primarily includes the secondary somatosensory cortex (SII), insular regions, the anterior cingulate cortex (ACC), and the movement-related areas such as the cerebellum and supplementary motor area (Singer et al., 2004). Through the mirror neuron system, amputees with phantom sensations may have a greater “postural empathy” for others such that they are better able to match their own body schema against the observed bodies of others, and are thus potentially more likely to have a bodily experience that resembles that observed in others. The mechanisms of cross-referencing the phantom limb with the opposite limb are also considered (Section 4.5, below). This review proposes that – with the likely involvement of the body schema, mirror systems, and cross-callosal and ipsilateral projections in phantom limb phenomena – the perception of a “normal”, non-painful phantom limb is very likely to be an epiphenomenon of normal functioning, action understanding and empathy, and potentially even evolutionarily adaptive and perhaps necessary. 2. Proprioception of the phantom limb Phantom limbs are generally perceived to occupy veridical body space – being of a particular size, shape and posture – and may be perceived to be completely paralysed, or under the amputee's volitional control (Roux et al., 2001), or to move spontaneously or reflexively (Ramachandran and Hirstein, 1998). The phantom limb is generally described as adopting a “habitual” position and posture (e.g., partially flexed at the elbow with the forearm pronated), resting at the side of the body, or in a posture that resembles the posture of the limb prior to amputation (Ramachandran and Hirstein, 1998). Spontaneous changes in posture of the phantom limb are also common in amputees (Ramachandran and Hirstein, 1998) and in (normal) patients who are under anaesthesia (Bromage and Melzack, 1974; Melzack and Bromage, 1973). Henderson and Smyth (1948) reported that the phantom tends to be “correctly aligned to the stump with which it moves” (p. 90). Often, however, the phantom limb may be perceived to be stuck in a fixed position (Devor, 1997) and sometimes to B RA I N RE SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 dissociate from the stump, particularly when the latter is out of view (Fraser, 2002; Halligan, 1999; Wright et al., 1997). In one of the few studies to address phantom limb proprioception specifically, Fraser (2002) found that 63% of her sample felt that their limb remained in a fixed position when they moved other body parts. The perceived position of a limb in nonamputees (Gross and Melzack, 1978), and phantom limbs in paraplegics (Bors, 1951; Conomy, 1973; Hill, 1999) and (normal) patients under anaesthesia (Bromage and Melzack, 1974; Melzack and Bromage, 1973), may also become dissociated from the real position of that limb when it is occluded from sight. While memories of the limb immediately prior to amputation may endure in the phantom (Katz and Melzack, 1990; Ramachandran and Hirstein, 1998; Riddoch, 1941), these memories do not determine the constant or continuing posture of the phantom (Henderson and Smyth, 1948). For example, while patients are under brachial plexus nerve block for upper limb surgery (Melzack and Bromage, 1973), or epidural block for lower limb surgery (Bromage and Melzack, 1974), they experience phantom limbs that do not remain in the same position as that occupied by the limb at the time of anaesthesia. Rather, the limb was more likely to occupy one of a common repertoire of positions, in slight flexion, that would have been assumed by the limb outside of anaesthesia, and was unlikely to occupy random or unusual positions. Similarly, Fraser (2002) found that the majority of amputees in her study indicated that their phantom limb took the general shape or form of the limb prior to amputation, and many reported that parts of the amputated limb were missing (61%), had shrunken or were shortened (28%), or had become magnified (8%). Some amputees report the experience of a general awareness of the presence of a phantom limb that is without positional or sensory qualities (André et al., 2001; Fraser, 2002; Hunter et al., 2003). Phantom limb posture in some patients with spinal cord injury also mirrors the position in which the limb was last seen during the spinal cord trauma (Bors, 1951; Conomy, 1973; Ettlin et al., 1980). Furthermore, Ettlin et al. (1980) reported that phantom limb illusions were only perceived by patients who retained consciousness during the spinal cord injury. 2.1. Distorted perception of the phantom limb In rare instances, the phantom limb takes on a posture that is abnormal, distorted or disfigured. Generally, amputees report that they can move their phantom limb through normal, but usually limited, ranges; however, a small percentage report that they can move the phantom limb through anatomically impossible ranges or amplitudes (Price, 1976). Melzack (1992) described two cases of phantom limbs in abnormal postures; one where the phantom arm was extended from the shoulder at a 90° angle and the individual felt that he must walk through doorways sideways, and another where the phantom arm was stuck behind the individual's back preventing him from sleeping on his back. Henderson and Smyth (1948) also described a patient's anatomically unrealistic perception of phantom fingers that were “grossly twisted and interwoven”. Patients with spinal cord injury may also perceive their phantom sensations, particularly in 221 the lower limbs, as occupying anatomically unrealistic and unnatural postures; for example, feeling “like the toes are all turned down under the bottom of the foot”, that each digit was somehow twisted so that “each toe pointed in a different way” (Conomy, 1973), or that the legs were “twisted”, “crossed”, or “blown up” (Bors, 1951). In normals, the perception of anatomically impossible limb positions can be induced using muscle and tendon vibration; for example, when Craske (1977) vibrated and passively stretched the biceps brachii of his subjects, some reported varying degrees of hyperextension or hyperflexion of the joint, including the (non-painful) perception that the “the arm is being broken”, “it is being bent backwards”, or that “my hand is going through my shoulder”. Other studies have described illusory limb displacement, including the hand being bent back towards the dorsal surface of the forearm (Craske, 1977), or protruding down through a solid surface (Romani et al., 2005); the forearm remaining stationary while the hand continues to move downwards (Lackner and Taublieb, 1983); or extending the nose with the Pinocchio effect (Lackner, 1988). Romani et al. (2005) found that the mirror neuron system (see 4.4, below) reacts to both biomechanically possible and impossible movements, and that it is able to detect which muscle would be involved in the actual execution of the observed movement. These findings suggest that while central representations of the body are indeed able to code for anatomically impossible limb positions, the actual perception of such limb positions rarely occurs, even in a phantom limb, and is likely to be associated with the experience or anticipation of pain (Willoch et al., 2000); for example, see Armel and Ramachandran's (2003) study in which the movement of a rubber finger (using the rubber limb paradigm1) into “painful” positions, when the subjects own hidden finger was moved slightly, induced responses associated with pain. With respect to phantom limbs, Hill (1999) noted that distorted posture in a phantom limb may be more common following traumatic limb loss in which the limb had been distorted by the accident. Alternatively, André et al. (2001) suggest that phantom limbs may become seemingly deformed or dysmorphic as a result of ectopic activity in the stump (neuromas, ephapses, sprouting), or of remapping in the somatosensory cortex, the thalamus or the dorsal column nuclei. Empirical research on the mechanisms underlying distorted or disfigured phantom limbs is, however, lacking. 2.2. Telescoping of the phantom limb Phantom limbs may be perceived to be continuous and intact resembling a normal limb, or telescoped so that the proximal 1 In the rubber limb paradigm, the subject's arm is hidden from view – either behind a screen or under the table – and a life-sized rubber model of the same arm is placed on the table in front of them. The subject is instructed to fixate on the rubber limb, while two small paint brushes are used to simultaneously stroke the rubber hand and the subject's hidden hand. Within minutes, subjects report that they feel the touch on the rubber hand, not their hidden hand, as if their arm has embodied the fake rubber limb (Botvinick and Cohen, 1998; Ehrsson et al., 2004). 222 B RA I N R E SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 portion of the limb is missing or has shrunken with just the more distal portion floating near, attached to, or “within” the stump (Flor et al., 2006; Solonen, 1962; Weiss and Fishman, 1963). While telescoping is commonly reported in the literature, the definition of this phenomenon is lacking and it is ambiguous whether telescoping refers to the displacement of relative position of the components of the phantom limb over time, or whether it refers to active movement of the components of the phantom limb in accordance with the concept of actively retracting a telescope. The term appears to have been used more often to refer to the former definition; however, some authors have used the term either with the latter meaning or without clarifying the intended meaning; for example, see Poeck's (1964) case description of a child whose phantoms “gradually withdrew within the stump” when she approached the wall with her arms, which were congenitally missing both forearms and hands. Also, comments such as Melzack's (1990) report that “sometimes the limb is slowly telescoped into the stump” are ambiguous and could be interpreted either way. In this paper, discussion about telescoping of a phantom limb will refer to a phantom limb that has shortened over time with the distal portion gradually perceived to be closer to the stump. When a phantom limb becomes telescoped it usually does so in a “diffuse process, affecting most of the limb simultaneously, and not progressively, from the stump towards the periphery” (Henderson and Smyth, 1948, p. 91). Consequently, the remaining parts of the limb appear to become magnified because they maintain their original size. In some amputees telescoping may take place over a number of years, or may change from moment to moment or day to day. The phantom limb is perceived to be telescoped in between 49 and 63% of cases, and this process generally begins within the first few weeks post-amputation (Carlen et al., 1978). The distal portion of the phantom limb may subsequently disappear (Shukla et al., 1982), or remain “dangling” from the stump in about 50% of cases (Ramachandran and Hirstein, 1998). Phantom limbs apparently do not telescope in patients with spinal cord transection, brachial plexus avulsion or in cases with preexisting peripheral nerve injury (Katz, 1992; Ramachandran and Hirstein, 1998), perhaps because there are conflicting representations of the deafferented body part according to visual and somatosensory afferents. It is widely accepted that phantom limbs become telescoped because the distal portion of any limb is more strongly represented in the cortex relative to the more proximal regions of the limb (Ramachandran and Hirstein, 1998). The upper limbs, compared with the lower limbs, are more diffusely represented throughout the cortex as they are integral in fine unimanual and bimanual motor schemata, and this disparity manifests in more rapid telescoping of the lower compared with upper limbs (Henderson and Smyth, 1948; Jones, 1988; Ramachandran and Hirstein, 1998). Over time, the more weakly represented regions of the limb may “fade from consciousness” while the distal portion of the limb becomes attached to the stump, perhaps as a result of changes in receptive fields, cortical reorganisation or changes in stump sensitivity (Hill, 1999). Katz (1992) suggested that the perceived distance between the phantom and the stump may be a function of the distance separating their respective representations in the somatosensory homunculus. While telescoping was originally thought to be a sign of adaptive plasticity, it tends to be related to increased levels of phantom pain (Flor et al., 2006). Telescoping of the phantom appears to be associated with remapping of the distal portion of the phantom limb onto nearby regions of the cortex; for example, movement of a completely telescoped phantom arm corresponds to activity in the cortical region that represents the shoulder, partially telescoped phantoms to activity in the region of the arm and non-telescoped phantoms to activity in the hand region (Flor et al., 2006). Flor et al. (2006) proposes that the continued perception of an extended (i.e., nontelescoped) phantom limb might reverse maladaptive cortical changes, as the phantom continues to provide sensory feedback to the area that previously represented the amputated limb. Telescoped phantoms, on the other hand, activate areas remote from the limb representation (Flor et al., 2006), and such cortical reorganisation is strongly correlated with phantom pain. 3. Prosthesis use and embodiment Amputees commonly feel that their phantom limb embodies and thus becomes one with the prosthesis, and they often confound their phantom limb with the prosthesis (André et al., 2001). Such embodiment may be associated with a twoway interaction between prosthesis use and phantom limb perception. Initially, the pre-existing representation of the amputated limb in the body schema – which also likely provides the template for phantom limb perception – may come to provide a valuable neural template for prosthesis use. Repeated use of the prosthetic limb may, in turn, reinforce the representation of the missing limb and thus reinforce the perception of phantom limb sensations. This hypothesis is supported by Lotze et al. (1999) who found that upper limb amputees who use myoelectric prostheses do not show cortical reorganisation, or phantom limb pain, compared with those who use either a cosmetic prosthesis or no prosthesis. Amputees who use a prosthesis extensively retain a different functional representation of the amputated limb compared to non-prosthesis users, and the endpoint of the amputated limb is perceived to be more distal than it actually is (McDonnell et al., 1989). These findings suggest that prostheses become embodied in the same way that a habitually employed tool does (Lewis, 2006; Yamamoto and Kitazawa, 2001), and preserve the biological representation of the amputated limb; that is, the bimodal neurons in the posterior parietal cortex that code peripersonal space appear to be recoded to represent space accessible to a handheld tool – e.g., rake or screwdriver – in monkeys (Iriki et al., 1996) and neurologically intact humans (Maravita et al., 2003; Yamamoto and Kitazawa, 2001; Yamamoto et al., 2005). Essentially, it appears that the prosthesis is incorporated into the body schema and becomes part of a coherent internal model of the body (Murray and Fox, 2002), and this contributes to the relative facility and rapidity with which amputees can learn to control a prosthesis (André et al., 2001; Murray, 2004). While using a prosthesis, the amputee's bodily experience is generally one of being whole, such that the prosthesis is felt B RA I N RE SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 to be a “part of them” (Murray, 2004), and they phenomenologically have a normal and intact body (André et al., 2001; Giummarra et al., 2006b). The prosthesis may be described as being embodied by, or fused with, the phantom limb (Gow et al., 2004). The perceived convergence between phantom limb and prosthesis helps to coordinate movement and maintain fluid and natural motor control over the prosthesis (MacLachlan et al., 2004a). For some amputees, when the phantom limb is itchy, scratching the corresponding locus on the embodied prosthesis can relieve the itch (Giummarra et al., 2006b; Gow et al., 2004), suggesting that the prosthesis is represented in the contralateral somatosensory cortex in the same region as the phantom limb, and that the visual feedback that parts of the prosthesis are being stimulated is centrally processed and thus perceived as if the phantom limb is being stimulated. Future research. The relationship between phantom limb sensations, prosthesis use and embodiment is still not well understood. There is limited research to inform us of whether and how phantom sensations and phantom pain differ according to the use of a prosthesis, or the type of prosthesis used. Our understanding of tool embodiment and extended physiological proprioception – that is, the extension of the body's “area of influence” that also extends one's innate sense of proprioception (Gow et al., 2004) – could benefit greatly from research on prosthesis embodiment. Experimental research could adopt the rubber limb paradigm (Botvinick and Cohen, 1998) to explore prosthesis embodiment. Studies should examine prosthesis embodiment within a body schema framework, and determine whether amputees with phantom sensations (particularly those with complex sensations) differ in adaptation to prosthesis use compared with other amputees without phantom sensations. Additionally, it is unknown whether prosthesis embodiment varies between upper limb and lower limb amputees, whose missing limbs biologically do (upper limb) and do not (lower limb) habitually use tools. These studies could also investigate whether amputees' perceptions of prosthesis embodiment vary according to voluntary versus passive movement of the prosthesis. Investigation of the interaction between phantom sensations and a prosthesis may provide valuable insight into the interaction between internal constructs of the body and the embodiment of a tool as a functional extension of the body. 4. The cortical origins of phantom limb phenomena 4.1. The body schema Many authors have highlighted the distinction between the concepts of body image and the body schema (Gallagher, 1986; Maravita, 2006). Recently, Schwoebel and Coslett (2005) highlighted that there are at least three distinct types of body representations. First, the body image is the lexical–semantic representation of the body including the names and functions of body parts and relations between body parts and external objects. Second, the body structural description is a topological map of body part locations. These body part locations are 223 monitored by visual input and defined by the boundaries of body parts and their proximity to other body parts and objects. Finally, the body schema, in brief, is the internal, dynamic representation of the spatial and biomechanical properties of one's body, and is derived from multiple sensory and motor inputs that interact with motor systems in the generation of actions. It is the body schema that is implicated in providing a template for the perception of phantom limbs following amputation or deafferentation. Ongoing bodily experience is brought about by the “body schema”, the plastic and dynamic representation of the body that is constantly being modified and updated. Head and Holmes (1911–1912) are often credited for coining the term “body schema”; however, Maravita (2006), and Holmes and Spence (2006) highlighted that Münk, in 1890, had previously considered the concept of an organised spatial representation of the body with respect to the world, and Bonnier, in 1905, had introduced the term schema to this concept. The main systems that contribute to the properties of the body schema include: (a) proprioceptive and somatosensory systems, (b) vestibular system, (c) visual system, and (d) movement systems and efference copy—that is, the neural copy of a movement command that is sent to the parietal cortex to be mapped onto the body schema to generate expected sensory outcomes (McGonigle et al., 2002), and to the premotor cortex in preparation for rapid corrective adjustment of movements when errors between the expected and actual sensory outcomes are detected (Helmholtz, 1995; Lewis, 2006; Rinehart et al., in press). The body schema is fundamentally generated in the parietal cortex – particularly the multimodal cells in the superior parietal lobule (Lewis, 2006), parieto-insular region (Ventre-Dominey et al., 2003) and the temporo-parietal junction (Blanke and Arzy, 2005) – together with inputs and outputs to various other cortical and subcortical regions. Neurons in the parietal cortex are involved in mapping “real space” relative to the body – that is, coding egocentric frames of reference – based on the convergence of retinal, somaesthetic, proprioceptive, vestibular, and auditory signals relating to the self and space, together with information about movements of the eyes, neck, trunk and limbs (Stein, 1992). Damage within the various sensory systems that contribute to maintaining, updating or evoking templates of the body schema can result in various perceptual aberrations, including denial of limb ownership in somatoparaphrenia (Aglioti et al., 1996; Halligan et al., 1995b; Ramachandran, 1996), perceived absence of body parts in asomatognosia (Arzy et al., 2006; Schiff and Pulver, 1999), supernumerary phantom limbs (Brugger, 2003; Mazzoni et al., 1997; Miyazawa et al., 2004; Sakagami et al., 2002), disembodiment and autoscopic phenomena in out-of-body experiences (Blanke, 2004; Blanke and Arzy, 2005; Brugger et al., 1997), and magnification and shrinking of various body parts, or Alice in Wonderland illusions, in somaesthetic aura (Kew et al., 1998). The body schema consists of innate representations of the biological, evolutionary design and function of the human body and a repertoire of motor templates (e.g., hand–mouth coordination) designed to promote survival in infancy (Gallagher et al., 1998). It also provides a neural platform for understanding and interacting with others throughout life (Brugger et al., 2000; Melzack, 1989). Phantom limb perception 224 B RA I N R E SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 following congenital limb deficiency suggests that the brain may be genetically predisposed to represent a prototypical human body, regardless of the correspondence or lack thereof between the ideal model and the actual body (Berlucchi and Aglioti, 1997). The innate body schema is then retained and modified throughout life experience (Melzack et al., 1997; Weinstein and Sersen, 1961; Weinstein et al., 1964). The range of triggers that evoke or modify phantom sensations and pain provide evidence for the complex involvement of the various systems likely involved in bodily awareness and perception in phantom limb phenomena, including stimulation of the vestibular system (André et al., 2001; Le Chapelain et al., 2001), visual illusions of phantom limb embodiment using the mirror box [also see 4.5.2, below] (Ramachandran et al., 1995) and tactile or somatosensory inputs from the stump and/or remaining portion of the amputated limb (Melzack et al., 1997; Saadah and Melzack, 1994; Wilkins et al., 2004). Additionally, “forgetting” the limb loss and the performance of automatic motor schemas with the phantom limb (e.g., attempts to answer the telephone or fend off a blow with the missing limb) can trigger phantom sensations and pain (Giummarra et al., 2006a; Hill, 1999; Price, 1976; Ramachandran and Hirstein, 1998). The complex nature of phantom limbs suggests that the same systems responsible for maintaining, updating and evoking internal representations of the body are responsible for maintaining templates of the phantom limb. These sensory systems are further accounted for in Melzack's (1989, 1990, 1992, 1996) neuromatrix theory of phantom limb perception. further proposes that cramping pain and shooting phantom pain may arise from similar origins from spontaneous activity associated with intention to move muscles; however, there is also evidence that cramping phantom pain is related to muscle tension in the residual limb (Sherman, 1994). Continued sensory input through stimulation and functional sensitivity of the residual limb and stump, however, may preserve a “normal”, non-painful representation of the amputated limb in the body schema (Bittar et al., 2005; Lotze et al., 1999); for example, by providing continued sensory input via sensory discrimination training (the discrimination between the frequency and/or location of sensory inputs, such as electrical impulses (Flor et al., 2001)), myoelectric prosthesis use, Transcutaneous Electrical Nerve Stimulation (TENS), or vibration. The neuromatrix theory provides a valuable model for the perception of phantom phenomena, and particularly phantom pain, which, unlike sources of pain triggered by injury or lesion, is often triggered by supraspinal (e.g., affective, emotional, and cognitive factors), peripheral (e.g., from the residual limb/stump, or other sites) and environmental (e.g., changes in barometric pressure) experiences, as well as by spontaneous ectopic activity at central, spinal or peripheral levels. A major limitation of the neuromatrix theory, however, is that while it can broadly account for the various aspects of phantom phenomena, it is possibly too broad and difficult to be tested empirically, particularly with respect to painless phantom sensations. 4.3. 4.2. Phantom phenomena problematic for current theory The neuromatrix Melzack's (1989, 1990, 1992, 1996) neuromatrix theory of phantom limb perception extends theories of the body schema, and proposes that conscious awareness and perception of the body and self are primarily generated within the brain via patterns of activity (or neurosignatures) that can be triggered or modulated by various perceptual inputs. These inputs primarily include (a) somatosensory inputs (cutaneous, visceral and other somatic receptors), (b) visual and other sensory inputs that influence the cognitive interpretation of the situation, (c) phasic and tonic cognitive and emotional inputs from other areas of the brain, (d) intrinsic neural inhibitory modulation inherent in all brain function, and (e) the activity of the body's stress regulation systems, including cytokines as well as the endocrine, autonomic, immune and opioid systems (Melzack, 1999). These inputs thus generate the body–self neuromatrix primarily through the somatosensory, limbic and thalamocortical systems. While multiple sensory inputs are integrated to create the body–self neuromatrix, amputation and deafferentation are commonly associated with cortical reorganisation, and spontaneous bursts of activity that produce output patterns that resemble activity associated with pain and thus lead to the conscious experience of phantom pain (Melzack, 1999). For example, according to Melzack (1996) high-frequency bursts of activity associated with deafferentation may be interpreted as hot or burning pain, although there is evidence that burning pain is associated with vascular mechanisms (i.e., a reduction in blood flow in the stump) (Sherman, 1994). Melzack (1996) There are many aspects of phantom limb experience that current theory of phantom limb phenomena do not explain, or which cannot be tested under current models. First, why do some amputees with similar circumstances of limb loss experience no phantom sensations, some only painless phantom sensations, and some only phantom pain (as amputees in our studies have reported)? Second, how do internal representations of the self (that is, templates of the body schema) interact with specific sensory afferents (e.g., visual, proprioceptive, motor, vestibular) in relation to phantom limb sensations? Third, how and why do phantom limbs telescope actively? Fourth, why do phantom sensations continue to be perceived by some amputees, while for others phantom sensations diminish, telescope or disappear over time? Fifth, why do some congenital and childhood amputees feel phantom sensations as adults, even when they have never experienced a limb (e.g., absence of all four limbs as reported by Brugger et al., 2000)? Sixth, why do people who desire amputation of a healthy body part (Body Integrity Identity Disorder; BIID (Bayne and Levy, 2005; First, 2005)) perceive a conflict in the body–self neuromatrix such that their physical body does not converge with their phenomenological experience? Would people with BIID perceive a phantom limb following amputation and if so, would this differ from other amputees without BIID? Seventh, why do some amputees experience phantom pain when they observe another person in pain (i.e., “empathic pain”), and does this relate to how empathic one is? Finally, why do some amputees B RA I N RE SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 perceive sensations in the phantom limb that mirrors those in the intact limb? While the neuromatrix theory may be a very adequate model for the complexity of phantom limb pain, non-painful phantom sensations are likely to also be related to other complex central processes involved in bodily perception, beyond the body schema. The latter include mirror neuron systems – particularly those involving movement (fronto-parietal mirror system), pain (anterior cingulate cortex and anterior insula), and touch (somatosensory and posterior parietal cortices) – and mechanisms of cross-referencing between the phantom limb and intact limb (Giummarra et al., 2006a). 4.4. Mirror neurons 4.4.1. Mirror neurons and action understanding Mirror neurons have an integral role in the observation and understanding of goal-directed actions between an agent and an object (Gallese, 2001; Rizzolatti et al., 1988). Mirror neurons were initially identified by Rizzolatti et al. (1988) in the ventral premotor cortex in the macaque monkey. These neurons fired not only while the monkey executed a goal-directed action, but also when it observed another monkey, or the human experimenter, perform the same goal-directed motor action. Essentially, in order to understand the actions of others one must match the action against one's own motor system, simulating cortical activity in the same neurons that are responsible for performing that action (Buccino et al., 2004; Fadiga et al., 2005; Rizzolatti et al., 2002). Following the discovery of mirror neurons in monkeys, similar mirror neuron systems were identified in humans and were found to result not only in action simulation in the motor cortex, but also sub-threshold activity in muscles engaged in the observed action (Fadiga et al., 2005). Essentially, activity in mirror neuron systems enables the observer to embody the other's motivational system. Amputees with phantom sensations may provide evidence that efficient action understanding requires a mirror neuron system that retains a representation of an intact and functioning body. Amputees may experience “somatic” or “postural” empathy during mirror neuron activity when observing others using their limbs (Price, 2006). This process may evoke phantom limb perception, or even the perceived embodiment of another's movements without apparent phantom limb perception (Frank, 1986). Mirror neuron activity may thus both require and reinforce the representation of the body and its functions within the body schema—even if a limb has been amputated, in which case activation of mirror neurons may reinforce the representation of the phantom limb. Phantom limb perception in cases of congenital limb loss supports the possible role of mirror neurons in the retention of a representation of the missing limb within the body schema (Brugger, 2006; Brugger et al., 2000; Funk et al., 2006; Price, 2006). For example, the case of a 44-year-old amputee who was born missing all four limbs, but who perceived vivid phantom limbs (Brugger et al., 2000), suggests that phantom limb perception may have evolved, at least in part, from the habitual observation of other people moving their limbs, and the continued activation of the innate body schema. While these mechanisms may explain phantom limb perception 225 following congenital limb absence (Brugger, 2006; Brugger et al., 2000; Price, 2006), we propose that they are also likely to be central to the perception of phantom limbs following acquired limb loss. Future research. The role of mirror neurons in phantom limb perception is only just beginning to receive attention, and much work is required to clarify its role in congenital and acquired limb loss. In particular, research should examine the relationship between action understanding and phantom limb perception and movement. For example, do amputees differ with respect to action perception and embodiment of another's motor system (i.e., mirror system activity) according to (a) whether they perceive phantom pain, phantom sensations, or neither phantom pain or sensations; (b) whether they perceive a “moveable” phantom limb compared with those who perceive a phantom limb that is “paralysed”; and (c) whether they use a prosthesis, the type of prosthesis used and the perceived embodiment of the prosthesis. 4.4.2. Mirror neurons and empathy for pain in amputees In addition to action understanding, mirror neurons are involved in other domains of perception and perceptual understanding, including emotion (Ruby and Decety, 2004), disgust (Wicker et al., 2003), touch (Keysers et al., 2004), and pain (Jackson et al., 2005; Morrison et al., 2004; Singer et al., 2004). For example, mirror neurons are likely to be responsible for the instinct to cringe or shudder when observing another person in pain (Miller, 2005). We propose that the mirror neuron systems for touch and pain may be involved in maintaining the representation of a phantom limb, and in some cases triggering phantom pain. Mirror systems for touch, in the secondary somatosensory cortex, were identified by Keysers et al. (2004) in people who were touched or observed another person or non-biological object being touched. Synaesthesia for touch has also been described in a single case study (Blakemore et al., 2005): using functional Magnetic Resonance Imaging (fMRI), Blakemore et al. (2005) investigated the neural networks involved in the perception of touch in their synaesthete subject (C), and a group of control subjects. Activations in the somatosensory cortex were significantly higher in C, compared with controls, when she observed touch. An area in the left premotor cortex was activated in C to a greater extent than in the nonsynaesthetic group and the anterior insula cortex (AIC) was bilaterally activated in C, but there was no evidence of such activation in the non-synaesthetic group. The evidence suggests that in C the mirror system for touch is disinhibited and involves activity that exceeds the threshold for conscious tactile perception. When observing another person in pain, we not only consciously comprehend that the other is in pain, but we also automatically interpret the experience throughout the same cortical networks that mediate personal experience of pain. There is strong evidence that the AIC and the ACC are involved in both the personal experience of pain and its empathic experience (Jackson et al., 2005; Morrison et al., 2004; Singer et al., 2004). These same areas, associated with processing physical pain, also process feelings of “emotional pain”, such as social rejection (Eisenberger et al., 2003) or frustration (Abler et al., 2005). The level of activity in the ACC is strongly 226 B RA I N R E SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 correlated with an observer's ratings of the intensity of another's pain (Jackson et al., 2005). The ACC receives projections from the superior temporal areas, which play a role in semantic visual processing, and is probably involved in the affective components of the “pain matrix” during empathy for pain. The ACC has extensive outputs to the premotor and motor areas (Morrison et al., 2004), and there are similar motor action responses to a painful stimulus when it is either personally experienced, or observed to be experienced by another person (Avenanti et al., 2005). These findings suggest that there is empathic inference of the sensory qualities of another's pain, automatic embodiment of the observer's motor system, and empathic activity in the autonomic nervous system's “flight” mechanism during empathy for pain. Bradshaw and Mattingley (2001) reported the first clinical case of feeling mirrored pain when observing another person in pain. This hyperalgesic man reported that he felt pain that was immediate and intense, and appeared to be qualitatively similar to his own hypersensitivity to touch, when he saw his wife hurt. Giummarra et al. (2006a) have described eight cases who reported that their phantom pain is triggered by observing, thinking about, or inferring that another person is in pain. The neuromatrix theory may suggest that this is due to triggering pain memories, or heightened activity in the limbic system due to emotional distress. However, we propose that it is also probable that empathically perceived pain in the phantom limb involves mirror system activity within the “pain matrix”, which maps the observed pain onto the body schema (Giummarra et al., 2006a). This is a novel hypothesis and requires further research; for example, using the methodology of past studies that have examined mirror system activity for observed and perceived pain (Singer et al., 2004). Through mirror system activity, the sensory and affective qualities of the other's pain would be embodied and mapped onto the observer's body schema (Schwoebel et al., 2002), leading to an empathic motivational state of readiness for action (Avenanti et al., 2005). It is of significance that only lower limb amputees have reported “mirror pain” (Giummarra et al., 2006a). The experience of mirror pain only in the lower limb suggests heightened activity of the autonomic nervous system, as a result of embodiment of the other's fight or flight dilemma, which is more likely to involve (a) the lower limbs in readiness for flight from danger, and (b) the urogenital system through the increased reflex urge to empty the bladder or bowels for more efficient evasion of danger. Cortical reorganisation of the lower limb onto the homuncular-adjacent genitals is also associated with heightened phantom pain (Flor, 2002; Flor and Birbaumer, 2000). The genitals are highly involved in emotional perceptual processes (Both et al., 2003; van der Velde and Everaerd, 2001), while the face – which is localised close to the upper limbs in the somatosensory homunculus – plays an emotionally expressive role. In summary, while there may be mirror neuron activity in the pain matrix of non-amputees and other healthy people without actual perception of pain, it appears that the mirror neuron system in some people, particularly lower limb amputees, may be disinhibited, leading to empathically perceived pain when another is in pain. In amputees, mirrored pain may be perceived to be localised in the stump and/or phantom limb, which has been pre- sensitised, by trauma, to pain. While the possible mirror system activity for the lower limbs is not well understood, there is nevertheless some limited evidence for mirrorneuron-like activity in the lower limbs (Buccino et al., 2005; Bach and Tipper, 2007), despite the fact that they do not have a repertoire of meaningful or operant activities that could be involved in communicating, or understanding another's intentions, which seems to be a major role for mirror neurons. Future research. An important area of research includes investigating the role of mirror systems for pain in amputees who empathically feel phantom pain when observing another person in pain. Experimental research should examine the factors that predispose amputees towards experiencing empathically triggered pain; for example (a) aspects of traumatic experience; (b) whether sensitisation to pain is generalised or specific to the amputated limb; or (c) whether the other's pain is generalised or specific to the amputee's past pain experiences. It is not clear whether amputees who have observed injuries incurred by another person are more likely to experience phantom pain in general. Empathically triggered pain is likely to be present in other populations who have experienced recent trauma, such as childbirth or third-degree burn victims. For example, consider the case of a woman who experienced a long painful childbirth, resulting in emergency caesarean section delivery, who experiences shooting pain from the groin that radiates down the legs when she is told of another person's traumatic experience (unpublished case). 4.5. Cross referencing between the intact limb and the phantom limb 4.5.1. Mirrored sensation and movement from the intact limb to the phantom limb While remapping and cortical reorganisation have received considerable attention in the phantom pain literature (for example, see reviews by Flor, 2002; Flor et al., 2006), the role of transcallosal cross-referencing between the phantom limb and the intact limb has received somewhat less attention. The present review will focus on the perception of mirrored sensation and movement from the intact to the phantom limb. Giummarra et al. (2006a) reported that 13% of their patients experienced phantom sensations that mirrored sensations from the intact limb, including: ache, pain or injury; neuropathy or disability; posture/form; temperature; touch and exteroception; itching and the ability to ease itch, discomfort or pain in the phantom by scratching or rubbing the contralateral limb; and mirror movements. Mirror movements have been described in an upper limb amputee during passive and active movement of the intact hand (Halligan et al., 1995a), and in one patient with a supernumerary “alien” limb subsequent to callosal lesion during active movement only (Hari et al., 1998; McGonigle et al., 2002). Haigh et al. (2003) examined the phantom sensations in amputees who had been diagnosed with rheumatoid arthritis (RA) prior to amputation. These patients described sensations in the phantom that mirrored the RA symptoms perceived in the intact leg, including stiffness and limited ability to move the joints freely, clawing of the toes, swelling in the ankle and/or knee, and a desire to exercise the limb. Franz and Ramachandran (1998) provide evidence that the phantom hand remains B RA I N RE SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 spatially coupled with the intact hand following amputation, as long as the amputee can conduct voluntary movements in the phantom. Animal studies have shown that deafferentation is followed by rapid cortical reorganisation contralateral to the deafferented limb (Donoghue et al., 1990; Sanes et al., 1988). These findings have been replicated in human studies (BrasilNeto et al., 1993; Ziemann et al., 1998), together with evidence that the motor cortex ipsilateral to the deafferented limb undergoes cortical reorganisation (Schwenkreis et al., 2003). Cortical reorganisation following deafferentation is thought to be based on various mechanisms, including unmasking of preexisting synapses by removal of local inhibition, strengthening of existing synapses in processes such as long-term potentiation, changes in neuronal membrane excitability, and axonal sprouting with the formation of new synapses (Schwenkreis et al., 2003). Amputees who use a functional prosthesis (Cruz et al., 2003; Hamzei et al., 2001), particularly a myoelectric prosthesis (Lotze et al., 2001), exhibit less cortical reorganisation, highlighting that cortical reorganisation may be use-dependent. Cross-referencing mechanisms, either at the spinal or supraspinal level, clearly continue to function even after deafferentation, particularly in amputees who can execute voluntary phantom limb movements. The peripheral pathways involved in bimanual motor coupling endure in amputees, such that movement of a phantom limb corresponds to the activation of motor neurons that once served the missing hand, which reinnervate the stump muscles (Mercier et al., 2006). Centrally, cross-referencing of the phantom limb to the intact, contralateral limb may be related to the disinhibition and strengthening of pre-existing commissural connections between the cortical representation of the two limbs. Ordinarily, these neural pathways are recruited to enhance performance of bimanual movements, and recruit local inhibitory interneurons during unimanual or antiphase movements (Carson, 2005). Unilateral movements – particularly movements that are rapid and repetitive or involve force and effort – are associated with an increase in the regional cerebral blood flow in the ipsilateral motor cortex (Carson, 2005; Kew et al., 1994), and enhanced interhemispheric interaction of the nondominant hemisphere onto the dominant hemisphere (Kobayashi et al., 2003). Following amputation or deafferentation, the perception of “referred” or mirrored sensation from the intact to the phantom limb may be related to altered inhibitory mechanisms in these ipsilateral pathways, particularly during high-threshold somatosensory or motor afferents. 4.5.2. Experimentally induced sensory and motor coupling between the phantom and real limb Illusions of touch and movement can be evoked in a phantom limb, inducing somatosensory and/or motor coupling between the phantom and real limb, using the additional sense of vision with mirror feedback (Ramachandran, 1996; Ramachandran et al., 1995). In the mirror box paradigm, a mirror is positioned vertically in the centre of a box, the amputated limb and “phantom” are placed on one side out of view, and the intact limb is placed so that the amputee can see its reflection. During mirror therapy, the amputee observes the 227 reflection of his normal limb moving in the mirror in order to induce the visual illusion that he has two intact limbs and that the intact limb is superimposed onto the felt position of his phantom limb (Ramachandran, 1996). Ramachandran et al. (1995) reported that upper limb amputees who used this technique feel their phantom arm move when they observe their own arm, or the arm of the experimenter, move in the mirror. Four out of five of the amputees tested who had “clenching” spasms in their phantom limbs found instant relief upon looking into the mirror and opening “both” hands simultaneously. Ramachandran and Rogers-Ramachandran (1996) examined intermanual referral in 10 upper limb amputees using the mirror box paradigm, and found that (a) three amputees perceived referred sensation that was topographically organised such that touching the intact thumb elicited referred touch in the phantom thumb; (b) the referral of touch, but not temperature or pain; (c) enhanced effects when mirror feedback was used to give the illusion of touching the phantom hand; (d) movements of the real hand – either passively or actively – were referred to the phantom hand in six amputees; and (e) referral was reported from the intact hand and forearm up to a level corresponding to the amputation of the other arm. Sathian (2000) also reported the intermanual referral of sensation to a hand rendered anaesthetic by stroke or surgery using the mirror box paradigm; however, these patients perceived “referred” sensation as pressure in the hidden, anaesthetic hand, regardless of the type of stimulation of the good hand, which included pain, cold, vibration or joint movement. Sathian (2000) proposed that following decreased somatosensory input from the anaesthetic hand, the neurons that correspond to the anaesthetic hand may become disinhibited and responsive to input from the ipsilateral hand, input which, during moderately intense tactile stimulation, exceeds perceptual threshold resulting in the perception of referred sensation. Mirror box therapy has now been successfully used in both upper (Oakley et al., 2002; Ramachandran, 1996) and lower limb (Brodie et al., 2003; MacLachlan et al., 2004b) amputees to assist in voluntary movement of the phantom limb and alleviation of phantom pain, and in some cases apparently causing the phantom limb to telescope (Ramachandran et al., 1995). Perceived illusions in the phantom limb are reported to be so realistic that amputees claim they can see and feel their phantom limb moving as if it was under their volitional control (Ramachandran, 1996). Mirror box therapy has also been used by patients in the early and intermediate stages of Complex Regional Pain Syndrome (CRPS, type 1) to reduce pain associated with movement of the affected limb (McCabe et al., 2003). Conversely, Acerra and Moseley (2005) found that pain and paraesthesia could be induced in the affected limb of patients with CPRS (type 1) when corresponding areas of the unaffected limb were passively stimulated and observed in the mirror as if superimposed onto the affected limb. These findings suggest that pain – at least pain associated with amputation and CRPS (type 1) – may be related to (a) mapping observed stimulation onto the body schema, already modified by disease or pain, and (b) a mismatch or reafference (efference copy) between intention to move the phantom limb and the lack of proprioceptive feedback from the deafferented limb. Creating the illusion of convergence between sensory systems 228 B RA I N R E SE A R CH RE V I EW S 54 ( 20 0 7 ) 2 1 9–2 3 2 and efference copy may restore sensory and motor schemas of the body (Harris, 1999; McCabe et al., 2003; Ramachandran and Rogers-Ramachandran, 1996). Viewing a mirror reflection of one's hand conducting unilateral finger–thumb opposition movements, in normals, facilitates activity in the ipsilateral motor cortex (Garry et al., 2005) and may indicate that commissural pathways are involved in evoking visual “capture” through mirror reflection, probably via reduced intracortical inhibition. Illusory “phantom” movements in the paretic arm of right-brain stroke patients have been reported during mirror feedback of the normal right limb (Zampini et al., 2004), again suggesting that the visual capture phenomenon is related to the dominance of vision over somatic senses such as proprioception. This technique has important treatment implications not only for reducing levels of phantom pain in amputees, and movementrelated pain in CRPS (type 1), but also for restoring motor function following stroke. When stroke patients view the mirror reflection of the good limb superimposed onto the paretic limb, they would not only perceive the illusion of enhanced movement of the impaired limb, but could also trigger and restore neural activity in the deafferented motor cortex. Future research. The investigation of cross-referencing the phantom limb with other parts of the body is an area of research that has received little attention to date, but could be both theoretically and clinically invaluable. Future research should investigate the relative role of internal global constructs of the body (the body schema), cross-callosal and ipsilateral pathways on the perception of mirrored sensations and movement in the phantom limb. Research on crossreferencing of movement execution and perception could examine (a) motor overflow (Addamo et al., 2007; Hoy et al., 2004) from the intact limb to the residual portion of the amputated limb measured by EMG (Dennis, 1976; Green, 1967) or overflow of force (Armatas and Summers, 2001); (b) motor overflow from the intact limb to the phantom limb measured by fMRI; (c) mirror movements perceived in the phantom limb following movement of the intact limb; or (d) motor overflow from imagined phantom movement to the intact limb measured by EMG or force overflow. 5. Conclusions Research on non-painful phantom limbs provides valuable insight to the mechanisms underlying bodily awareness and embodiment. The body schema most likely provides the template for phantom limb perception, particularly considering the complexity of phantom limb sensations (notably, proprioception, kinaesthesia, and kinetics), the nature of the triggers of phantom sensations and pain (e.g., referred sensations, vestibular stimulation, and visual capture through the mirror box paradigm), and the likely role of phantom limb perception in prosthesis use and embodiment. The neuromatrix – which inter-relates sensory-discriminative, affectivemotivational and evaluative-cognitive dimensions of bodily experience – provides a functional model for phantom limb perception, and phantom pain. We propose that specific central processes beyond the body schema and neuromatrix are also involved in phantom limb perception, and require further research. First, the activation and disinhibition of various mirror neuron systems – including systems involved in action understanding, and empathy for touch and empathy for pain – may both reinforce and require the representation of the phantom limb in the body schema. Second, the potential mechanisms underlying the interaction between the phantom limb and the intact limb require clarification; in particular, the relative roles of the global body schema, transcallosal and ipsilateral projections. With the likely involvement of the body schema and neuromatrix, mirror neuron systems, and transcallosal and ipsilateral cross-referencing in phantom limb phenomena, the perception of a “normal” (non-painful) phantom limb is in the very least an epiphenomenon of normal functioning, action understanding and empathy, and potentially even evolutionarily adaptive and perhaps necessary. Phantom pain, on the other hand, may be a maladaptive failure of the neuromatrix to maintain global bodily constructs. 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