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PNS Origin of Phantom Limb Sensation and Pain.

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... There are also other clinical peculiarities in arm amputees such as touch of the face that is referred to the phantom hand (referred sensations, RS). While referred sensations from face to phantom hand might well reflect processes which are located centrally in the nervous system (Ramachandran 1993;Knecht et al. 1995;Vaso et al. 2014), a recent major dispute comprises whether PLP can be caused centrally in the nervous system or not (Flor et al. 2013;Devor et al. 2014;Foell et al. 2014). The dispute is echoed in the discussion of single qualities of PLP such as cramping pain with painful spasms in the phantom hand. ...
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Phantom limb pain is a restricting condition for a substantial number of amputees with quite different characteristics of pain. Here, we report on a forearm amputee with constant phantom pain in the hand, in whom we could regularly elicit the rare phenomenon of referred cramping phantom pain by touching the face. To clarify the underlying mechanisms, we followed the cramp during the course of an axillary blockade of the brachial plexus. During the blockade, both phantom pain and the referred cramp were abolished, while a referred sensation of “being touched at the phantom” persisted. Furthermore, to identify the cortical substrate, we elicited the cramp during functional magnetic imaging. Imaging revealed that referred cramping phantom limb pain was associated with brain activation of the hand representation in the primary sensorimotor cortex. The results support the hypothesis that referred cramping phantom limb pain in this case is associated with a substantial brain activation in the hand area of the deafferented sensorimotor cortex. However, this alone is not sufficient to elicit referred cramping phantom limb pain. Peripheral inputs, both, from the arm nerves affected by the amputation and from the skin in the face at which the referred cramp is evoked, are a precondition for referred cramping phantom limb pain to occur, at least in this case.
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Phantom limb pain (PLP) is commonly considered to be a result of maladaptive brain plasticity. This model proposes that PLP is mainly caused by reorganisation in the primary somatosensory cortex, presumably characterised by functional degradation of the missing hand representation and remapping of other body part representations. In the current study, we replicate our previous results by showing that PLP correlates with maintained representation of the missing hand in the primary sensorimotor missing hand cortex. We asked unilateral upper-limb amputees to move their phantom hand, lips or other body parts and measured the associated neural responses using functional magnetic resonance imaging (fMRI). We confirm that amputees suffering from worse chronic PLP have stronger activity in the primary sensorimotor missing hand cortex while performing phantom hand movements. We find no evidence of lip representation remapping into the missing hand territory, as assessed by measuring activity during lip movements in the missing hand cortex. We further show that the correlation between chronic PLP and maintained representation of the missing hand cannot be explained by the experience of chronic non-painful phantom sensations or compensatory usage of the residual arm or an artificial arm (prosthesis). Together, our results reaffirm a likely relationship between persistent peripheral inputs pertaining to the missing hand representation and chronic PLP, and emphasise a need to further study the role of peripheral inputs from the residual nerves to better understand the mechanisms underlying chronic PLP.
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Chronic constriction injury of rat sciatic nerve promotes signs of neuropathic pain. This is associated with an increase in the levels of interleukin 1β (IL-1β) in primary afferents that peak at 7 d. This initial cytokine exposure has been proposed to trigger an enduring alteration in neuronal phenotype that underlies chronic hyper-excitability in sensory nerves that initiates and maintains chronic neuropathic pain. We have shown previously that 5-6 d exposure of rat dorsal root ganglia (DRG) to 100pM IL-1β increases the excitability of medium-sized neurons. We have now found using whole-cell recording that this increased excitability reverts to control levels within 3-4 d of cytokine removal. The effects of IL-1β were dominated by changes in K(+) currents. Thus, the amplitudes of A-current, delayed rectifier and Ca(2+) sensitive K(+) currents were reduced by ∼68%, ∼64% and ∼36% respectively. Effects of IL-1β on other cation currents were modest by comparison. There was thus a slight decrease in availability of high voltage-activated Ca(2+) channel current, a small increase in rates of activation of hyperpolarization-activated cyclic nucleotide-gated channel current (IH ), and a shift in the voltage-dependence of activation of tetrodotoxin-sensitive sodium current (TTX-S INa ) to more negative potentials. It is unlikely therefore that direct interaction of IL-1β with DRG neurons initiates an enduring phenotypic shift in their electrophysiological properties following sciatic nerve injury. Persistent increases in primary afferent excitability following nerve injury may instead depend on altered K(+) channel function and on the continued presence of slightly elevated levels IL-1β and other cytokines. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Nearly all amputees continue to feel their missing limb as if it still existed, and many experience chronic phantom limb pain (PLP). There is currently a broad consensus among investigators that the origin of these sensations is a top-down phenomenon, triggered by loss of sensory input and caused by maladaptive cortical plasticity. We tested the alternative hypothesis that PLP is primarily a bottom-up process, one due not to the loss of input but rather to exaggerated input, generated ectopically in axotomized primary afferent neurons in the dorsal root ganglia (DRG) that used to innervate the limb. In 31 amputees, the local anesthetic lidocaine was applied intrathecally and/or to the DRG surface (intraforaminal epidural block). This rapidly and reversibly extinguished PLP and also nonpainful phantom limb sensation. Control injections were ineffective. For intraforaminal block, the effect was topographically appropriate. This could also be demonstrated using dilute lidocaine concentrations that are sufficient to suppress DRG ectopia but not to block the propagation of impulses generated further distally in the nerve. PLP is driven primarily by activity generated within DRG. We recommend the DRG as a target for treatment of PLP and perhaps also other types of regional neuropathic pain. Keywords DRG; Ectopic firing; Electrogenesis; Intraforaminal; Neuropathic pain; Phantom limb pain Corresponding author contact information Corresponding author. Address: Department of Cell & Developmental Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Tel.: +972 2 6585085; fax: +972 2 6586027. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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Natural forms of stimulation were used to compare the spontaneous and evoked activity of dorsal horn neurons in three groups of rats: controls with no surgical lesion, rats with transection of the sciatic nerve and rats with transection of the dorsal roots at the same segmental level. In control rats, cells encountered in the dorsal horn were classified according to their peripheral field as tactile specific, convergent tactile and nociceptive, nociceptive, or movement driven. In 20 control animals, only 20% of the 140 cells with a peripheral field were spontaneously active. After sciatic nerve transection made on the side of recording a few days previously (18 rats), all of the 141 cells studied showed spontaneous activity, only 69 of them having a peripheral field. After dorsal root transections a few days previously (nine rats), 25 spontaneously active cells were found in the dorsal horn ipsilateral to the section, none with a peripheral field. Spontaneous activities of cells without a peripheral field were separated into three types as a function of bursting pattern, which were similar following both types of transection. The spontaneous activity shown by dorsal horn cells without peripheral fields following dorsal root transection precludes attribution of spontaneous spiking in such cells to abnormal input from the periphery, and shows that abnormal activity can develop in deafferented dorsal horn cells themselves. A possible role played by this spontaneous activity in deafferentation pain is considered.
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Examination of the relationship between pain, sensory hypersensitivity, referred sensations and involuntary muscle jerks in patients with brachial plexus injury. Fourteen patients with brachial plexus lesions were included. Spontaneous background and paroxysmal pain and mechanically and thermally evoked pain were recorded. Areas with sensory hypersensitivity and referred pain were mapped on a body chart. This was supplemented by electrophysiological analysis in three patients. Sensory hypersensitivity and areas with pinprick-induced referred phantom sensations were present in adjacent dermatomes. There was no clear relationship between chronic neuropathic pain and referred sensations, but there was a correlation between pain paroxysms and sensory hypersensitivity in dermatomes adjacent to deafferented areas. In three patients, simultaneous referred sensations and short latency motor action potentials ipsilateral to the denervated side suggested origin at subcortical sites. The study suggests a possible role of a spinal generator for sensory hypersensitivity and referred sensations following denervation.
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Despite the amount of research that has been conducted on phantom limb pain (PLP), the etiology of the condition remains unknown, and treatment options are limited. After an individual loses a limb, the brain continues to detect the presence of the missing limb even though it is no longer attached to the body, likely through proprioceptive signals. The majority of patients with amputations either report the feeling of volitional control over their phantom or a phantom limb that is frozen in a specific position. Many patients also experience PLP. Here we propose a new theory, termed "proprioceptive memory," which may explain some of the unique experiences amputees encounter. We also suggest that memories of the limb's position prior to amputation remain embedded within an individual's subconscious, and pain memories that may be associated with each limb position contribute not only to PLP, but to the experience of a fixed or frozen limb. We suspect that there are memory networks for pain--and other sensations, either positive or negative--that are associated with each limb position, and propose that these memories evolved to protect our bodies from repeated injury. A discussion of mirror therapy as a treatment option for PLP is also provided, as well as an explanation for the efficacy of mirror therapy. The paper offers a unique insight into how and why amputees experience these unusual phenomena.
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Although axons within neuromas have been shown to produce inappropriate spontaneous ectopic discharges, the molecular basis for pain in patients with neuromas is still not fully understood. Because sodium channels are known to play critical roles in neuronal electrogenesis and hyperexcitability, we examined the expression of all the neuronal voltage-gated sodium channels (Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9) within human painful neuromas. We also examined the expression of two mitogen-activated protein (MAP) kinases, activated p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are known to contribute to chronic pain, within these human neuromas. We used immunocytochemical methods with specific antibodies to sodium channels Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9, and to activated MAP kinases p38 and ERK1/2 to study by confocal microscopy control and painful neuroma tissue from five patients with well-documented pain. We demonstrate upregulation of sodium channel Nav1.3, as well as Nav1.7 and Nav1.8, in blind-ending axons within human painful neuromas. We also demonstrate upregulation of activated p38 and ERK1/2 MAP kinases in axons within these neuromas. These results demonstrate that multiple sodium channel isoforms (Nav1.3, Nav1.7, and Nav1.8), as well as activated p38 and ERK1/2 MAP kinases, are expressed in painful human neuromas, indicating that these molecules merit study as possible therapeutic targets for the treatment of pain associated with traumatic neuromas.
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Previously we reported that the cuff model of peripheral neuropathy, in which a 2 mm polyethylene tube is implanted around the sciatic nerve, exhibits aspects of neuropathic pain behavior in rats similar to those in humans and causes robust hyperexcitation of spinal nociceptive dorsal horn neurons. The mechanisms mediating this increased excitation are not known and remain a key unresolved question in models of peripheral neuropathy. In anesthetized adult male Sprague-Dawley rats 2-6 weeks after cuff implantation we found that elevated discharge rate of single lumbar (L(3-4)) wide dynamic range (WDR) neurons persists despite acute spinal transection (T9) but is reversed by local conduction block of the cuff-implanted sciatic nerve; lidocaine applied distal to the cuff (i.e. between the cuff and the cutaneous receptive field) decreased spontaneous baseline discharge of WDR dorsal horn neurons approximately 40% (n=18) and when applied subsequently proximal to the cuff, i.e. between the cuff and the spinal cord, it further reduced spontaneous discharge by approximately 60% (n=19; P<0.05 proximal vs. distal) to a level that was not significantly different from that of naive rats. Furthermore, in cuff-implanted rats WDR neurons (n=5) responded to mechanical cutaneous stimulation with an exaggerated afterdischarge which was reversed entirely by proximal nerve conduction block. These results demonstrate that the hyperexcited state of spinal dorsal horn neurons observed in this model of peripheral neuropathy is not maintained by tonic descending facilitatory mechanisms. Rather, on-going afferent discharges originating from the sciatic nerve distal to, at, and proximal to the cuff maintain the synaptically-mediated gain in discharge of spinal dorsal horn WDR neurons and hyperresponsiveness of these neurons to cutaneous stimulation. Our findings reveal that ectopic afferent activity from multiple regions along peripheral nerves may drive CNS changes and the symptoms of pain associated with peripheral neuropathy.
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The activity of myelinated primary afferents was recorded from the dorsal roots 1-3 days after creation of a painful peripheral neuropathy in rats. The effects on spontaneous discharge of acute transections at various points along the injured sciatic nerve and the dorsal root were determined, as were the effects of K+ channel blockers applied topically to two putative sites of impulse origin: the injured region of the nerve and the dorsal root ganglion (DRG). Transections just proximal to the nerve injury and just distal to the DRG failed to halt the discharge, but spontaneous discharge disappeared when the transection was made just proximal to the DRG (i.e. between the DRG and recording electrode). K+ channel blockers (4-aminopyridine and gallamine triethiodide) applied to the DRG increased the frequency of spontaneous discharge or initiated activity from silent fibers. Applications of K+ channel blockers to the injured region of the nerve were without effect. Thus, the spontaneous discharge and the sensitivity to K+ channel blockade seen in A beta and A delta primary afferents at the time of the onset of the neuropathic pain syndrome appear to originate in the DRG.
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e of amputation. Furthermore, there was precise one-to-one correspondence between these points and those on the phantom limb. (3). (ii) Sensations were referred most often to the hand, especially to the digits with an overrepresentation of the thumb and "pinky." This may reflect the high cortical magnification of these areas. (iii) The referred sensations were modality-specific; for example, a drop of warm water trickling down the face was felt as "warm water trickling down"in the phantom hand. (iv) Reference fields were somatotopically organized. we suggest that this is a direct consequence of the remapping observed by physiologists (1). (v) There was a vivid persistence of short-term "memory" of complex sensations; when we gripped and released the finger adjacent to the amputated finger the patient felt the phantom finger being "gripped," and this sensation persisted for 7 or 8 seconds in the phantom. (v1) Reorganization was relatively rapid. In one patient, our study was carried out
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Previous studies of relationships between surface EMG of the residual limb and phantom pain have not shown which changed first. Thus, predictive relationships could not be demonstrated. 24 male (20) and female (4) amputees between the ages of 33 and 71 who reported either burning (3), cramping (8), shocking-shooting-stabbing (6), or a combination of these descriptions of phantom pain (7) participated in one or two recording sessions. Raw surface EMG from the major muscles of the residual limb was recorded while subjects activated an event marker to indicate changes in pain. All eight subjects with cramping phantom pain reported changes in pain after the recording showed sharply demarcated increases in EMG. Subjects reporting either shocking-shooting or burning pain did not show any consistent relationships between EMG and pain. Three of the four subjects reporting experiencing both shocking-shooting and cramping phantom pain simultaneously during recordings showed changes in EMG preceding changes in pain. Sensations of cramping phantom pain were preceded by increases in muscle tension in the residual limb in almost every instance for each of our subjects showing changes in cramping phantom pain. Thus, changes in muscle tension in the residual limb are likely to either be causes or close intermediaries for the cause of cramping phantom pain but not necessarily of other common descriptors.
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Systemic application of lidocaine in rats suppressed ectopic impulse discharge generated both at sites of experimental nerve injury and in axotomized dorsal root ganglion (DRG) cells. ED50 for DRGs was significantly lower than for the injury site. Lidocaine doses effective at blocking ectopic discharge failed to block the initiation or propagation of impulses by electrical stimulation, and only minimally affected normal sensory receptors. This selectivity may account for the effectiveness of systemic local anesthetics and other drugs that share the same mechanism of action (notably certain anticonvulsants and antiarrhythmics), in the management of neuropathic paresthesias and pain. In addition, it may account for the prolonged analgesia sometimes obtained using regional local anesthetic block.
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This paper reviews reports of phantom limb sensations which resemble somatosensory events experienced in the limb before amputation. It also presents descriptions of this phenomenon in 68 amputees who took part in a series of clinical studies. These somatosensory memories are predominantly replicas of distressing pre-amputation lesions and pains which were experienced at or near the time of amputation, and are described as having the same qualities of sensation as the pre-amputation pain. The patients who experience these pains emphasize that they are suffering real pain which they can describe in vivid detail, and insist that the experience is not merely a cognitive recollection of an earlier pain. Reports of somatosensory memories are less common when there has been a discontinuity, or a pain-free interval, between the experience of pain and amputation. Among the somatosensory memories reported are cutaneous lesions, deep tissue injuries, bone and joint pain and painful pre-amputation postures. The experience of somatosensory memories does not appear to be related to the duration of pre-amputation pain, time since amputation, age, gender, prosthetic use, level of amputation, number of limbs amputated, or whether the amputation followed an accident or illness. The results suggest that somatosensory inputs of sufficient intensity and duration can produce lasting changes in central neural structures which combine with cognitive-evaluative memories of the pre-amputation pain to give rise to the unified experience of a past pain referred to the phantom limb. Implications for pre- and post-operative pain control are discussed.
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1. Multiple microelectrode maps of the hand representation within and across the borders of cortical area 3b were obtained before, immediately after, or several weeks after a period of behaviorally controlled hand use. Owl monkeys were conditioned in a task that produced cutaneous stimulation of a limited sector of skin on the distal phalanges of one or more fingers. 2. Analysis of microelectrode mapping experiment data revealed that 1) stimulated skin surfaces were represented over expanded cortical areas. 2) Most of the cutaneous receptive fields recorded within these expanded cortical representational zones were unusually small. 3) The internal topography of representation of the stimulated and immediately surrounding skin surfaces differed greatly from that recorded in control experiments. Representational discontinuities emerged in this map region, and "hypercolumn" distances in this map sector were grossly abnormal. 4) Borders between the representations of individual digits and digit segments commonly shifted. 5) The functionally defined rostral border of area 3b shifted farther rostralward, manifesting either an expansion of the cutaneous area 3b fingertip representation into cortical field 3a or an emergence of a cutaneous input zone in the caudal aspect of this normally predominantly deep-receptor representational field. 6) Significant lateralward translocations of the borders between the representations of the hand and face were recorded in all cases. 7) The absolute locations--and in some cases the areas or magnifications--of representations of many skin surfaces not directly involved in the trained behavior also changed significantly. However, the most striking areal, positional, and topographic changes were related to the representations of the behaviorally stimulated skin in every studied monkey. 3. These experiments demonstrate that functional cortical remodeling of the S1 koniocortical field, area 3b, results from behavioral manipulations in normal adult owl monkeys. We hypothesize that these studies manifest operation of the basic adaptive cortical process(es) underlying cortical contributions to perception and learning.
Article
Damaged nerves attempt to regenerate. The nerve membrane changes its properties, becomes spontaneously active and may be the source of pain. These impulse generators have unusual properties. They become silent after high frequency activity. This silence may partially explain the effect of counterstimulation as a pain therapy.
Article
Spontaneous discharges arising within lumbar dorsal root ganglia that had been isolated from the periphery by section of the corresponding spinal nerves were recorded in dorsal spinal nerve rootlets in cats and rabbits. Those dorsal rootlet fibers that were individually isolated had conduction velocities of less than 22 meters/second, i.e., they were Aδ fibers. The chronic preparations had been kept alive for between 1 and 21 days, and spontaneous activity was present in each of them. In acute preparations in which hemorrhage was minimal, spontaneous activity first appeared three to three and one-half hours after section of the spinal nerve. Spontaneous activity in the dorsal rootlets continued for approximately 25 minutes after physical separation, by dissection, of the active nervous tissue from the remainder of the preparation. The activity was not recorded in either the distal parts of sectioned ventral rootlets or the portion of a sectioned spinal nerve that remained in continuity with its dorsal root ganglion. It is suggested that the occurrence of these discharges could partly explain the observed differences in the extent and reactivity of cutaneous sensory areas between animals in which dorsal spinal nerve rootlets were sectioned close to the spinal cord and animals in which the corresponding spinal nerves were sectioned distal to their dorsal root ganglia.
Article
Ectopically generated and antidromically conducted nerve impulses were recorded in 5 patients with tungsten microelectrodes inserted into skin nerve fascicles. All patients had mainly positive sensory symptoms and reported paresthesiae which could be provoked by different maneuvers which suggested increased mechanosensitivity of the primary sensory neurons at different anatomic levels. Ectopic multiunit nerve activity correlating in intensity and time course to the positive sensory symptoms was recorded: when Tinel's sign was elicited in a patient with entrapment of the ulnar nerve at the elbow, when paresthesiae were provoked by elevation of the arm in a patient with symptoms consistent with a thoracic outlet syndrome, when paresthesiae were evoked by straining during chin-chest maneuver in a patient with an S1 syndrome due to a herniated lumbar disc, when a painful Lasegue's sign occurred during the straight-leg raising test in a patient with an S1 syndrome due to root fibrosis, and when Lhermitte's sign was elicited by neck flexion in a patient with multiple sclerosis. The sites for the ectopic impulse generation in these cases are suggested to be peripheral nerve, brachial plexus, dorsal root or dorsal root ganglion and dorsal columns. The paresthesiae were non-painful except in the patient with Lasegue's sign and the ectopic impulses were probably recorded from large myelinated afferent fibers.
Article
Single units were recorded in dorsal roots or in the sciatic nerve of anaesthetised rats. It was shown by making sections, by stimulation and by collision that some ongoing nerve impulses were originating from the dorsal root ganglia and not from the central or peripheral ends of the axons. In a sample of 2731 intact or acutely sectioned myelinated sensory fibres, 4.75% +/- 3.7% contained impulses generated within the dorsal root ganglia. In 2555 axons sectioned in the periphery 2-109 days before, this percentage rose to 8.6% +/- 4.8%. There was a considerable variation between animals; 0-14% in intact and acutely sectioned nerves and 1-21% in chronically sectioned nerves. The conduction velocity of the active fibres did not differ significantly from the conduction velocity of unselected fibres. The common pattern of ongoing activity from the ganglion was irregular and with a low frequency (about 4 Hz) in contrast to the pattern of impulses originating in a neuroma which usually have a higher frequency with regular intervals. Slight mechanical pressure on the dorsal root ganglion increased the frequency of impulses. Unmyelinated fibres were also found to contain impulses originating in the dorsal root ganglion. In intact or acutely sectioned unmyelinated axons, the percentage of active fibres 4.4% +/- 3.5% was approximately the same as in myelinated fibres but there were no signs of an increase following chronic section. Fine filament dissection of dorsal roots and of peripheral nerves and collision experiments showed that impulses originating in dorsal root ganglia were propagated both orthodromically into the root and antidromically into the peripheral nerve. It was also shown that the same axon could contain two different alternating sites of origin of nerve impulses: one in the neuroma or sensory ending and one in the ganglion. These observations suggest that the dorsal root ganglion with its ongoing activity and mechanical sensitivity could be a source of pain producing impulses and could particularly contribute to pain in those conditions of peripheral nerve damage where pain persists after peripheral anaesthesia or where vertebral manipulation is painful.
Article
Intraneural microelectrode recordings were made from the nerve supplying the phantom area in two patients suffering from phantom limb pain. Spontaneous activity was prominent in both cutaneous and muscle fascicle of the nerves. Tapping the neuromata which accentuated the phantom limb pain, induced afferent discharges with both short and long latencies, the latter from fibres with a conduction velocity of only 0.5 m/sec. Blocking the neuromata with lidocaine completely abolished the tap-induced afferent discharges and the tap-induced accentuation of the phantom pain. The spontaneous pain was, however, unchanged, as was the spontaneous activity recorded.
Article
After upper limb deafferentation, adult macaques exhibit substantial reorganization of cortical somatosensory topography with enlargement of cortical areas responsive to facial stimuli. In the present study non-invasive magnetic source imaging technology has been used to map in detail the bilateral somatosensory homunculi in four neurologically normal controls and two upper arm amputees. Bilateral homuncular maps of normals and of the unaffected hemisphere of both amputees showed a wide hand area. The affected hemisphere of both amputees showed marked intrusion of facial representations into the digit and hand area consistent with the earlier observations in macaques. Our findings provide the first evidence of massive somatosensory plasticity in human adults and suggest a mechanism for post-amputation perceptual changes.
Article
Phantom limb pain has been reported as a transient phenomenon in patients with lower limb amputations during subsequent spinal anaesthesia. In order to determine its incidence and to define any predisposing factors we prospectively studied 23 spinal anaesthetics in 17 patients with previous lower limb amputation. Only one patient developed clinically significant phantom limb pain and we were unable to define any predisposing factors. Given the low incidence of recurrent phantom limb with spinal anaesthesia, its transient nature, and the fact that it can be treated if it occurs, we conclude that spinal anaesthesia is not contraindicated in patients with previous lower limb amputation.
Article
Reorganization of somatosensory cortex after peripheral nerve damage typically has been attributed to cortical plasticity. Here we provide evidence that much of the large-scale cortical reorganization that occurs after a major loss of peripheral inputs reflects the sprouting or expansion of afferents from the remaining forelimb into deprived territories of the spinal cord and brainstem. We examined sensory afferent terminations in the spinal cord and brainstem, and determined the somatotopic organization of cortical area 3b in three adult monkeys with previous hand or forearm amputation, as veterinary treatment of forelimb injuries. In each monkey, the distribution of labeled sensory afferent terminations from the remaining parts of the fore-limb was much more extensive than the normal distribution of inputs from the forelimb, and extended into portions of the dorsal horn of the spinal cord and the cuneate nucleus of the brainstem related to the amputated hand. In the same animals, tactile stimulation of the forelimb activated much of the deprived hand representation in area 3b of cortex; the lateral portion of the deprived region in area 3B appeared to be reactivated by inputs from the face. These data provide important new evidence that one of the mechanisms subserving large scale reorganization in cortex is a relay of topographic changes that occur subcortically. Presumably, the expanded primary sensory inputs activate postsynaptic neurons that are normally driven by inputs from the hand so that the neurons now have receptive fields on the forearm. Since the topographic representation of the body is greatly magnified in the relay to cortex, the subcortical changes can result in dramatic cortical map changes.
Article
Systemic lidocaine has been reported to be effective in treating several neuropathic pain syndromes. Few reports relate plasma lidocaine concentration to analgesia and the available studies have been complicated by labile plasma lidocaine concentrations. We used a computer-controlled infusion pump (CCIP) to target and maintain stable plasma lidocaine concentrations and study the effect of intravenous lidocaine on (1) pain scores, (2) current perception thresholds, (3) side effects, and (4) pain distribution in patients suffering from peripheral nerve injury pain. This study used a randomized double-blind placebo-controlled design. Eleven patients suffering from neuropathic pain after peripheral nerve injury received both a lidocaine and saline infusion in separate study sessions. The order of the study sessions was randomized and separated from each other by 1 week. The CCIP was programmed to target plasma lidocaine concentrations of 0.5, 1, 1.5, 2, and 2.5 micrograms/ml, each held for 10 min. Pain scores and pain distribution were assessed in the painful area, and electrical current perception thresholds (CPT) of the ring finger were measured using a cutaneous perception threshold neurometer (Neurometer CPT, Neurotron, Baltimore, MD). Side effects were recorded at fixed intervals. Plasma lidocaine concentrations were measured at 4 and 9 min after each step increase in infusion and correlated with the observed effects. Saline infusion had no effect. However, with lidocaine there was a significant plasma concentration-dependent decrease in pain scores starting at 1.5 micrograms/ml. This effect typically corresponded with a decrease in the size of the receptive field to which the pain was referred. For the electrical stimulus, there was no significant effect on cutaneous perception at 2000-Hz stimulation at the highest concentration examined; however, there was a significant increase in thresholds at 250-Hz (starting at 1.5 micrograms/ml) and 5-Hz (starting at 1.0 micrograms/ml) stimulation. There were no serious side effects. In all, 54.5% of patients reported lightheadedness (average plasma lidocaine concentration: 1.5 micrograms/ml) and one patient reported nausea (2.3 micrograms/ml). The computer-controlled delivery of intravenous lidocaine results in relatively stable plasma concentrations which allows a more thorough evaluation of the relationship between plasma concentration and patient response. This administration methodology for intravenous lidocaine may prove to be a valuable clinical and research tool.
Article
1. We have studied the characteristics of the abnormal properties of damaged myelinated fibers (conduction velocity > 2.0 m/ s) after peripheral nerve injury in a novel in vitro model of the rat sciatic nerve/dorsal root ganglion/dorsal root (L4-5) preparation removed from control naíve or sham-operated rats and animals that had received sciatic neurectomy 12-24 days before the in vitro study. A total of 122-245 filaments were recorded in each dorsal root. The proportion of A alpha, beta and A delta fibers were not significantly different between control, sham-operated, and axotomized nerves. Spontaneous activity was recorded in 3.4% (A alpha, beta) and 4.6% (A delta) of fibers in comparison with 0.4% (A alpha, beta) and 0.3% (A delta) in naíve controls. 2. A sporadic, irregular, low-frequency (< 1 Hz) firing was seen in 26% of the fibers with spontaneous activity. Periodical (irregular) bursting pattern was observed in 43% of spontaneously active fibers, whereas a relatively stable, ongoing firing pattern (median frequency: 7.1 Hz) was displayed by 31% of active fibers. 3. Mechanosensitivity of the neuroma/peripheral nerve was displayed in preparations from lesioned [axotomized: 18.2% (A alpha, beta) and 14.1% (A delta), sham operated: 2% (A alpha, beta) and 0% (A delta)], but not control naíve animals. There was no correlation between the presence of spontaneous activity and mechanosensitivity in single fibers. 4. The principal site of spontaneous activity generation was the dorsal root ganglion. Transection of the peripheral nerve (or removal of the neuroma), while recording from dorsal root filaments, produced a cessation of firing in 21% of fibers firing with ongoing discharge. The remaining active fibers continued firing until the DRG was removed. A sustained injury discharge was observed in damaged fibers but not control, undamaged fibers from naíve animals after acute peripheral nerve transection. 5. We present an in vitro model for the study of abnormal primary sensory activity in peripheral neuropathy. Although our data are consistent with in vivo electrophysiological findings in published reports, the proportion of damaged afferent fibers displaying spontaneous activity was significantly lower under in vitro conditions. This model may serve as a valuable tool for further physiological and pharmacological studies of peripheral neuropathy.
Article
The occurrence of cortical plasticity during adulthood has been demonstrated using many experimental paradigms. Whether this phenomenon is generated exclusively by changes in intrinsic cortical circuitry, or whether it involves concomitant cortical and subcortical reorganization, remains controversial. Here, we addressed this issue by simultaneously recording the extracellular activity of up to 135 neurons in the primary somatosensory cortex, ventral posterior medial nucleus of the thalamus, and trigeminal brainstem complex of adult rats, before and after a reversible sensory deactivation was produced by subcutaneous injections of lidocaine. Following the onset of the deactivation, immediate and simultaneous sensory reorganization was observed at all levels of the somatosensory system. No statistical difference was observed when the overall spatial extent of the cortical (9.1 +/- 1.2 whiskers, mean +/- SE) and the thalamic (6.1 +/- 1.6 whiskers) reorganization was compared. Likewise, no significant difference was found in the percentage of cortical (71.1 +/- 5.2%) and thalamic (66. 4 +/- 10.7%) neurons exhibiting unmasked sensory responses. Although unmasked cortical responses occurred at significantly higher latencies (19.6 +/- 0.3 ms, mean +/- SE) than thalamic responses (13. 1 +/- 0.6 ms), variations in neuronal latency induced by the sensory deafferentation occurred as often in the thalamus as in the cortex. These data clearly demonstrate that peripheral sensory deafferentation triggers a system-wide reorganization, and strongly suggest that the spatiotemporal attributes of cortical plasticity are paralleled by subcortical reorganization.
Article
Pain without accompanying tissue pathology poses a classic puzzle, presented in extreme form by phantom pain in a non-existent amputated limb. A clue to the origin of such pain is given by the recent discovery of a region of cortex active in response to incongruence between motor intention, awareness of movement, and visual feedback. Phantom-limb sensation, and repetitive strain injuries or focal hand dystonias in writers, musicians, or keyboard operators, are accompanied by plastic changes in sensorimotor cortex and by pathological pain. Disorganised or inappropriate cortical representation of proprioception may falsely signal incongruence between motor intention and movement, which results in pathological pain in the same way that incongruence between vestibular and visual sensation results in motion sickness.