- Email: [email protected]
Chapter 29 Microneurography in the assessment of neuropathic pain
Handbook of Clinical Neurology, Vol. 81 (3rd series) Pain F. Cervero, T.S. Jensen, Editors © 2006 Elsevier B.V. All rights reserved
Neurophysiology examinations in neuropathic pain Chapter 29
Microneurography in the assessment of neuropathic pain ELLEN JØRUM AND MARTIN SCHMELZ The Laboratory of Clinical Neurophysiology, The Department of Neurology, Rikshospitalet University Hospital, Oslo, Norway and Department of Anesthesiology and Operative Intensive Care, University of Heidelberg, Mannheim, Germany
29.1. Introduction
29.2. Intraneural stimulation
Microneurography is a neurophysiological method allowing microelectrode recordings of impulses in single nerve fibers in awake human subjects. The method which was developed by Swedish neurophysiologists over 35 years ago (Vallbo and Hagbarth, 1968) has been employed for recordings from afferent sensory nerve fibers, efferent sympathetic nerve fibers and proprioceptive nerve fibers (Vallbo et al., 1979). The first paper showing recordings from single afferent unmyelinated C-nociceptors in humans was published by Hallin and Torebjörk in 1970. A large number of papers have been published on the physiological properties of the human nociceptive system. Microneurography experiments in human experimental models of pain/neuropathic pain has shed important light on pathophysiological mechanisms involved in primary and secondary hyperalgesia (Torebjörk et al., 1984; Schmelz et al., 2000a; Serra et al., 2004). Over the last years, a few papers related to pathophysiological mechanisms of thick myelinated nerve fibers as well as nociceptive fibers in neuropathic pain have been published. Before considering results of studies on patients, the chapter will review the principal findings in nociceptive systems of relevance for pathology.
With the microelectrode placed in close relation to bypassing axons, they can also be used to apply low-intensity currents for intraneural microstimulation (Ochoa and Torebjörk, 1983; Schady et al., 1983a,b; Schady and Torebjörk, 1983; Torebjörk et al., 1987). For liminal stimulation of myelinated fibers, different sensory perceptions are generated (tapping, vibration, pressure) which can be correlated with the type of afferent units recorded before. Recently, the successful combination of microneurography, intraneural microstimulation and functional magnetic resonance imaging provided information about unexpectedly strong cortical activation of the primary and secondary somatosensory cortex upon stimulation of single identified myelinated afferents (Trulsson et al., 2001; McGlone et al., 2002). Cortical activations were even observed at stimulus frequencies, which did not induce any sensation. This new observation corroborates the high transmission security from primary afferents to spinal projection neurons (Rowe, 2002). As intraneural microstimulation skips activation of the receptive ending and the distal axon it can also be employed in amputees to activate afferent fibers and assess the induced sensations. Unexpectedly, intraneural microstimulation of nerves innervating amputated limbs elicited perceptions which did not differ in quality
Correspondence to: Ellen Jørum, The Laboratory of Clinical Neurophysiology, The Department of Neurology, Rikshospitalet University Hospital, Sognsvannsveien 20, 0027 Oslo, Norway. E-mail: [email protected], Tel: +47-23-07-08-34, Fax: +47-23-07-35-78.
428
E. JØRUM AND M. SCHMELZ
or location from controls, suggesting a low degree of cortical plasticity (Moore and Schady, 2000). Intraneural microstimulation has also been used to elicit unitary sensation in response to C-fiber activation. However, due to the close relation of several axons in a remak bundle it cannot be expected that a single C-afferent can be excited electrically (Wall and McMahon, 1985; Ochoa and Torebjörk, 1989). Functional clustering of axons in the peripheral nerve may explain that unitary sensations may be elicited despite activation of several axons. Anatomical segregation of axons of similar sensory characteristics and innervation territories has already been shown in myelinated fibers (Jørum et al., 1989; Hallin, 1990; Hallin et al., 1991; Wu et al., 1999; Hallin and Wu, 2001, 2002). However, the significance of functional and topographic segregation in peripheral nerves is yet unclear. 29.3. Thermoreceptors Thermoreceptors can be separated into receptors for warmth and cold detection. According to results of differential nerve blocks and response latencies, the warmth sensation has been attributed to C-fibers, whereas cold detection is a function of A-δ fibers (Erickson and Poulos, 1973; Yarnitsky and Ochoa, 1991). Microneurographic recordings from A-δ fibers are sparse and so far only few examples of human A-δ cold units have been published (Hensel, 1973, 1976; Järvilehto and Hämälainen, 1979). Data on human warm fibers have been described in several papers (Konietzny and Hensel, 1975; Hensel, 1976; Torebjörk and Hallin, 1976; Konietzny, 1984). They are mechano-insensitive and have small innervation territories. They are activated by moderate warming, but may also encode increasing temperature into the noxious range. Their low number and small receptive fields result in a sparse innervation for warmth. This may explain early impairment of warmth detection in peripheral neuropathy as compared to heat pain thresholds which may increase at a later stage of the disease. The phenomenon of paradoxical hot sensation upon mild cooling under a differential A-fiber block has provided evidence for cold specific C-fibers (Susser et al., 1999). Also, for the explanation of a heat pain illusion by a simultaneous stimulation with non-noxious warm and cold (thermal grill illusion) (Craig and Bushnell, 1994; Craig et al., 1996), the Thunberg effect (Thunberg, 1896), the existence of cold sensitive C-fibers has been suggested. Recently, recordings of C-fibers responsive to mild cooling have been identified in humans (Campero et al., 2001). Their activation thresholds were about 29°C, which is compatible with a role of this class of C-fibers in the paradoxical hot sensation.
Interestingly, these fibers not only differed in their receptive properties, but also their axonal characteristics clearly distinguished them from C-nociceptors. Activity-dependent hyperpolarization of axons which leads to slower conduction velocities was much less pronounced in C-cold fibers as compared to the nociceptors.
29.4. Nociceptors 29.4.1. A-δ Nociceptors Thinly myelinated nociceptors with a conduction velocity of about 20 m/s have been recorded in human radial nerve (Adriaensen et al., 1983). According to their receptive properties they can be separated into a highthreshold mechanoreceptive class and a mechano-heat sensitive class. Activation of A-δ nociceptors underlies the sharp pricking pain inflicted in noxious mechanical and heat stimulation. In monkeys also mechano-insensitive A-δ chemonociceptors have been found which have a chemical response pattern similar (Ringkamp et al., 1997) to that of mechano-insensitive C-fibers (Schmelz et al., 2000a). Moreover, differentiation between A-δ and C-fibers in the periphery can be complicated by the fact that A-δ fibers can have surprisingly long unmyelinated distal branches in the skin of up to 5 cm (Peng et al., 1999). 29.4.2. C-nociceptors 29.4.2.1. Polymodal C-nociceptive afferent fibers Microneurographic recordings have shown that the human skin has a rich supply of polymodal nociceptors which respond to mechanical, thermal and chemical painful stimuli (Torebjörk, 1974). Properties of polymodal C-nociceptive fibers have been well described. In recordings from a total of 118 C-afferent units responding to mechanical stimuli (Schmidt et al., 1995), C-units which were activated by both mechanical stimuli and heat (CMH) were in the majority (66%) (45% of all afferent C-fibers) compared to those only responding to mechanical stimuli (CM). Thresholds of activating CM were from 14 to 360 mN and 3.4 to 750 mN for CMH (Fig. 29.1, example of a CMH unit). Six of the units responded to heating with thresholds from 45° to 48°C. A subpopulation of C-polymodal nociceptors may also be activated by low temperatures between 19° and 0°C, which is in the noxious range and which may contribute to the determination of cold pain (Campero et al., 1996). It has been suggested that the same group of C-nociceptor fibers may play a role in cold hyperalgesia in patients with peripheral nerve lesions (Campero et al., 1996).
C-fiber
C-fiber
Mechanoinsensitive C-fiber
Mechano- and heatLarge and insensitive C-nociceptors irregular (CMiHi )
Large
Small and large C-fiber (variation)
Itch fibers
Low threshold C-fibers
C-fiber
Small
Small
Cold Nociceptors
A-δ fiber
Polymodal C-nociceptors (CM and CMH)
Small
Cold Receptors
C-fiber
A-δ fiber
Small
Warm Receptors
Nerve Fiber
A-δ nociceptors
Receptive Field
Receptor Type
Properties of A-δ and C-fiber receptors
Table 29.1
Accurate stimulus localization of pain
Sharp pricking pain
Cold pain
Cold
Warm
Sensation
Light stroking
Histamine
Pleasant touch?
Itch
Not activated by Plays a role in heat- or mechanical pathophysiology? stimuli
CM: 14–360 mN CMH: 3.4–750 mN Heat 45°–48°C
1. High-threshold mechanical 2. Mechanical and heat
Mechanical Heating Cooling 19°–0°C
Cooling 28°–30°C
Moderate heating
Stimulus
Mean 0.87 m/s
Mean 1.01 m/s
Conduction Velocity
Role in Flare
Yes
Present, but less No pronounced than for CMiHi
ActivityDependent Slowing of Conduction
High: average 60 mA Pronounced
Low: 2.0–5.5 mA (lower and upper quartile)
Transcutaneous Electrical Threshold
E. JØRUM AND M. SCHMELZ
430
These units, which also have been referred to as “silent nociceptors”, have been studied in detail and are suggested to play a particular role in the pathophysiology of pain. For this reason and as a prerequisite for an understanding of alterations observed in patients with chronic pain, the properties of these fibers will be presented.
CMH u. t.
Mech. Stim.
i. t.
Mustard Oil
Heating
29.5. Properties of mechano-insensitive C-units
60 s
420
440
460 Latency ms
Fig. 29.1. CMH unit (top panel) responding to mechanical stimuli (second panel) and to heating (third panel). Notice the irregular increases in latency of this unit during topical application of mustard oil (bottom panel), implying chemosensitivity. (From Schmidt et al., 1995.)
29.4.2.2. Mechano-insensitive Before their identification in humans, animal experiments revealed the existence of mechano-insensitive nociceptors in addition to the mechanoresponsive (Meyer and Campbell, 1981; Garell et al., 1996). Within the last few years, mechano-insensitive C-fibers were discovered in human skin (Schmidt et al., 1995). They were identified following a change in the experimental protocol from the traditional mechanical search stimuli to a search procedure employing electrical stimuli to recruit units independently of their sensitivity to natural stimulation. A computerized version of a method utilizing interactions between naturally and electrically evoked discharges (Hallin and Torebjörk, 1974; Torebjörk, 1974; Torebjörk and Hallin, 1976) allowed reliable testing of responsiveness of individual C-units in multiunit recordings frequently encountered in microneurography. The basis for this technique is the characteristic slowing of impulse conduction in thin fibers that is observed after repetitive firing induced either by electrical or natural skin stimulation, or by sympathetic reflex activation. The method is sensitive enough to allow detection of one or a few extra impulses elicited by any maneuver, which is the basis of the marking technique, and which will be referred to in recordings from patients.
The mechano-insensitive units are not excited by von Frey hairs of 750 mN. The units (24 % of the afferent C-units), as described in detail in Schmidt et al. (1995), did not respond to mechanical stimulation with von Frey filaments up to 1.6 N (far beyond the threshold of CMH) nor to heating with temperatures of 48°C and above. Because of their unresponsiveness to both mechanical and heat stimuli, these units were termed CMiHi (C-mechano-insensitive and heat-insensitive units). Four of the 15 CMiHi units in this material were sensitized to physical stimuli after treatment with mustard oil. Two CMiHi units became sensitized to mechanical and heat stimuli following topical application of capsaicin (Schmidt et al., 1995). One-third of the units responded to mustard oil and were regarded as chemonociceptors (Fig. 29.1). The “marking technique” as explained in the above section has made it possible to classify C-units in relation to responsiveness, threshold determinations and extensions of innervation territories and to compare differences between CMH and CMi units. There are large differences between the two classes of C-units, which have significance for their function both in a normal state and in a pathophysiological setting. 29.5.1. Conduction velocities, transcutaneous electrical threshold and slowing activity Electrical properties of the two classes of C-fibers are different (Weidner et al., 1999). In this study, it was demonstrated that both conduction velocities and transcutaneous thresholds differed between the two groups. Conduction velocities of CMiHi were lower (mean of 0.87 m/sec) than those of the CMH (mean of 1.01 m/s), while the transcutaneous electrical threshold was higher for the mechano-insensitive nerve fibers (average of 60 mA) than for the CMH fibers (2.0 and 5.5, lower and upper quartile, respectively). The two classes of afferent C-units have a different activity-dependent slowing of conduction which was much more pronounced in mechano-insensitive than in mechano-sensitive nerve fibers. Repetitive electrical stimulation at 0.125, 0.25 and 0.5 Hz gradually increased the response latencies in C-fibers. The slowing of mechano-insensitive units exceeded by far the slowing of mechanoresponsive
MICRONEUROGRAPHY IN THE ASSESSMENT OF NEUROPATHIC PAIN b
c
d
that mechano-insensitive C-units in human skin are equipped with tetrodotoxin TTX-R sodium channels with an elevated activation threshold, which would explain their high activation thresholds for transcutaneous electrical stimuli (Weidner et al., 1999). The finding that mechano-insensitive C-nociceptors have distinct membrane characteristics opens up possibilities for selective pharmacological interventions tailored for these C-fibers, which may be of particular importance for the treatment of inflammatory pain and hyperalgesia (Weidner et al., 1999).
e
1/4 Hz
Traces 1/8 Hz
a
431
1/2 Hz
29.5.2. Role in sensitization following tonic pressure
1/4 Hz
With reference to the above-mentioned results, functional differences in relation to pathophysiological mechanisms have been studied. It has been shown that tonic pressure induced increased pain responses (sensitization), matching the discharges of the mechano-insensitive nerve fibers, and that this class of C-afferent units thereby play an important role in static mechanical hyperalgesia, whereas the polymodal C-nociceptors only displayed a strong initial excitation followed by adaptation (Schmidt et al., 2000).
c
b
d
e
750 mN
a
450
470
490
Response Latency, ms
29.5.3. Role of mechano-insensitive C-fibers in flare response
Fig. 29.2. Slowing of conduction velocity during repetitive stimulation. Specimen obtained during the electrode stimulation protocol applied to a group of five C-units recorded simultaneously. After a 2-min recovery period, the nerve terminals were stimulated by intracutaneous impulses at 0.125, 0.25 and 0.5 Hz and then again at 0.25 Hz. Subsequent traces are shown from top to bottom. The top trace provides an amplified and unfiltered view of the recording also shown in the first trace of the following sequence. For the standard protocol, 20 stimuli were applied at 0.125 and 0.25 Hz and 30 stimuli at 0.5 Hz. In this specimen record, only 20 stimuli at 0.5 Hz are shown. In the bottom, responses of the five units to mechanical stimuli with a stiff von Frey bristle are shown (750 mN; arrow). Unit (b) was mechano-insensitive. Units (a, c–e) showed pronounced marking responses to mechanical stimulation. (From Weidner et al., 1999.)
There is evidence for the mechano-insensitive C-nociceptors and not the polymodal C-units being responsible for the mediation of the axon reflex flare in human skin (Schmelz et al., 2000b). Electrical stimulation of the skin with an intensity of 10 mA, selectively recruiting the mechanoresponsive C-units, produced only a weak and small flare reaction. Following stimulation with an intensity of 25 mA (an intensity known to recruit mechano-insensitive C-units), a persistent and large flare response was produced exceeding the mean receptive field size of 15 mm of the mechanoresponsive units (Schmidt et al., 1997). The findings support the idea that the mechano-insensitive nerve fibers play an important role in both the physiology and especially in the pathophysiology of human skin, by supporting neurogenic vasodilatation.
units at each stimulus frequency and as shown in Fig. 29.2. Differences in activation-dependent slowing between mechanoresponsive C-nociceptors and non-nociceptive C-cold units have also been shown (Serra et al., 1999). Altogether the findings strongly suggest differences in basic membrane properties of different classes of C-units. The details are far from yet known, but one possibility which has been suggested has been
29.5.4. Innervation territories of mechanosensitive and mechano-insensitive C-fibers Innervation territories of CMi units are larger and more irregular compared to those of CMH units and exceeding the latter by a factor of approximately 3 (Schmidt et al., 2002) (see Fig. 29.3). This finding suggests that the CMH are the C-units responsible for an accurate stimulus localization,
432
E. JØRUM AND M. SCHMELZ
A
extensive arborization of the nerve terminals) which again would suggest these units being responsible for large areas of axon reflex flare induced by capsaicin injection, highintensity electrical stimulation or histamine. 29.5.5. Sensitization of mechano-insensitive C-fibers induced by capsaicin
B
C
Fig. 29.3. The “marking method” used for mapping the electroreceptive field (eRF). A: Intracutaneous needles were inserted for regular 0.25-Hz electrical stimulation. Conditioning transcutaneous electrical pulses (pen) delivered in the vicinity of the needles were interposed between regular pulses for mapping the eRF. B: Regular pulses through intracutaneous needles within the receptive field every 4 s (stimulus artifacts under straight arrow) evoked responses of the unit at a stable latency. When additional electrical pulses through a surface probe were applied within the eRF, additional action potentials (left curved arrow) were generated, causing delayed responses to the regular pulses and a slow recovery (right curved arrow). C: Schematic drawing of an electroreceptive field; 50-mA square-wave pulses were applied to the skin (shown by arrows). Points where the unit was activated are marked with filled circles, and points where A was tested but not activated are marked with open circles. (From Schmidt et al., 2002.)
supporting previous findings that localization of noxious events from pure C-fiber stimulation is fairly precise from the foot and the hand (Jørum et al., 1989; Koltzenburg et al., 1993). The innervation territories of the CMi displayed a considerable expansion (several square centimeters) which could only be explained by an
Mechano-insensitive nerve fibers have been shown to be sensitized following application of capsaicin (Schmelz et al., 2000a). Capsaicin-induced primary and secondary hyperalgesia has been regarded as a model of chronic pain. Microneurographic recordings were obtained from a total of 12 mechanoresponsive and 20 mechanoinsensitive C-fibers before and after intracutaneous injection of capsaicin in the innervation territory of the cutaneous branch of the peroneal nerve. All mechanoresponsive and 17 of the 20 mechano-insensitive C-units were activated by the capsaicin, but the duration of the responses in the mechano-insensitive units was much longer than for the mechanosensitive units (median 170 s versus 8 s), matching the duration of the capsaicininduced pain responses. Eight of the total 17 mechanoinsensitive units became sensitized to mechanical stimulation of the receptive field, evidence of a sensitization of the units. The differential capsaicin sensitivity adds to the accumulating evidence for the existence of two categories of functionally different nociceptors in human skin and with a special role for mechanoinsensitive fibers in sensitization and hyperalgesia (Schmelz et al., 2000a). 29.6. Itch fibers About 10% of the mechano-insensitive nociceptors show lasting activation by histamine which parallels the itch sensation in humans (Schmelz et al., 1997). Supporting the view of “itch selective” neurons only the histaminepositive fibers were also excited by intracutaneous injection of the weak pruritogen prostaglandin E2, whereas histamine-negative mechano-insensitive nociceptors and polymodal nociceptors were not activated (Schmelz et al., 2003a). “Itch selective” spinal neurons have been identified in the cat (Andrew and Craig, 2001), which strengthens the concept of a labeled line also for the central processing of itch. Recently, spontaneous activity of “itch selective” neurons in a patient with chronic itch have been published (Schmelz et al., 2003b), supporting a clinical relevance for this fiber class. 29.7. Low-threshold C-fibers Traditionally afferent C-fiber function has been restricted to nociception and warmth detection. Therefore, the
MICRONEUROGRAPHY IN THE ASSESSMENT OF NEUROPATHIC PAIN
finding of C-fibers which can be activated by slightly stroking the skin and discharge at high frequencies was surprising (Nordin, 1990; Vallbo et al., 1993, 1995, 1999), as no obvious sensory correlate for this activity was known. This class of afferent C-fibers has been hypothesized to have a role in grooming behavior. Recently, touch-evoked activation of the insular cortex, but not primary and secondary somatosensory cortex, combined with a faint sensation of pleasant touch, has been described in a patient without myelinated fibers (Olausson et al., 2002). This result strengthens the view that these fibers have a role in emotional or limbic touch as suggested before (Bolanowski et al., 1999; Essick et al., 1999). Although impaired function of these fiber classes is problematic to quantify in neuropathy patients, it might well considerably affect their social life.
29.8. Studies with microneurography in patients 29.8.1. Paresthesias and spontaneous activity in myelinated fibers In healthy nerves spontaneous activity can be generated by hyperventilation, and ischemia, but it is also observed upon reperfusion and following long impulse trains (Mogyoros et al., 2002). Microneurographic recordings have verified irregular bursting discharges in A-fibers under these conditions (Ochoa and Torebjörk, 1980). As underlying mechanism for the generation of spontaneous activity observed in hyperventilation, high-pHinduced activation of persistent axonal Na channels have been proposed, which might be of more significance as compared to lowering of free Ca concentration (Mogyoros et al., 2000). Under ischemic conditions the impaired electrogenic Na–K pump and accumulation of extracellular K facilitate spontaneous activity (Mogyoros et al., 2000). It is yet unclear as to whether the same mechanisms leading to paresthesias in healthy subjects also play a critical role under pathophysiological conditions. Spontaneous and abnormal evoked activity in myelinated afferents corresponding to paresthesia has been recorded by microneurography in neuropathy patients (Campero et al., 1998), in patients recovering from Guillain–Barré syndrome (Mackel et al., 1994) and also in amputees (Nyström and Hagbarth, 1981). In some patients the generating site of the spontaneous activity was investigated by proximal and distal local anesthesia. As anesthesia of the nerve proximal to the recording site stopped on-going activity in one patient (Campero et al., 1998) the origin was either along the central path of the axon or the dorsal root ganglion cell. Similarly local anesthesia of the neuroma in an amputee did not abolish spontaneous activity (Nyström and Hagbarth, 1981),
433
suggesting a central origin. However, microneurography results will not provide more specific information about the ional mechanism leading to spontaneous activity. In diabetic patients low-threshold mechanoreceptors showed pronounced fatigue slowly adapting units (SA I), and lower discharge rates (SA), which may correspond to impaired tactile function in the patients (Mackel, 1989). More specifically, diabetes patients had shorter refractory periods despite unchanged conduction velocity and action potential duration (Mackel and Brink, 2003). Pronounced fatigue in low-threshold mechanoreceptors was also described in regenerating fibers following nerve transection (Mackel, 1985; Mackel et al., 1985), whereas spinal injury did not substantially change sensory characteristics of the primary afferents (Thomas and Westling, 1995). 29.8.2. Pathological C-fibers in patients with a chronic painful condition If mechano-insensitive afferent C-units might be sensitized in the capsaicin model, a natural question was whether sensitization of afferent C-units could be demonstrated in patients with chronic pain. One previous study has demonstrated sensitization of C-nociceptive afferents in a patient with chronic, possibly nociceptive pain (Cline et al., 1989). To further address this question, microneurographic recordings were performed in patients with the painful condition of erythromelalgia. Erythromelalgia is a rare condition characterized by painful, red, hot extremities. Characteristically the symptoms are aggravated by heat and patients find relief from their symptoms by cooling the affected limbs (Mørk et al., 2000). Most patients report pain only during attacks provoked by increased environmental temperature, physical activity, alcohol or sleeping. According to the definition of neuropathic pain, erythromelalgia is not a neuropathic pain syndrome. However, recent studies have unmasked alterations in function of both the efferent sympathetic nervous fibers (Sandroni et al., 1999) as well as afferent myelinated and unmyelinated nerve fibers (Ørstavik et al., 2004), raising the question of a neuropathic component. Microneurographic recordings were made from a total of 103 C-units from eight patients (Ørstavik et al., 2003). The mean conduction velocity was reduced (0.81 m/s) compared with 96 units from a study on healthy subjects (Weidner et al., 1999). A total of 24 units not responding to mechanical stimulation and not characterized as sympathetic units were classified as mechano-insensitive C-nociceptive fibers (Ørstavik et al., 2003). These mechano-insensitive afferents had substantially reduced conduction velocity (mean of 0.67 m/s) compared to mechano-insensitive C-afferent units in
E. JØRUM AND M. SCHMELZ
434 70 m/s
Total Slowing
60 EM Patients
50
Control
40 30 20 10 0 1.1
in healthy subjects. Their transcutaneous electrical thresholds were within the range normally restricted to mechano-insensitive units and two of the units exhibited a long-lasting response to histamine iontophoresis, a finding which previously only has been seen exclusively in mechano-insensitive itch fibers in healthy subjects (Schmelz et al., 1997). A pathological mechanoresponsiveness in several C-nociceptors is demonstrated here for the first time, which by previously established criteria would be classified as mechano-insensitive units (Fig. 29.5). This finding, in addition to the demonstration of spontaneous activity of one afferent mechano-insensitive
m/s 1.0 Conduction Velocity
Control
EM Patient
0.9 0.8 0.125 Hz 0.7
0.25 Hz
0.6 0.5 Hz 0.5 Mechanoinsensitive
Mechanoresponsive
Sympathetic 0.25 Hz
Unit Class
Fig. 29.4. Altered conductive properties only in afferent fibers of erythromelalgia patients. Conduction velocity (lower panel) and total slowing (upper panel), obtained with a standardized protocol, differed significantly ( P < 0.05) between healthy subjects and erythromelalgia patients. (From Ørstavik et al., 2003.)
healthy subjects (mean of 0.86 m/s). They also displayed a higher degree of activity-dependent slowing (Fig. 29.4). Decreased conduction velocity and increased activitydependent slowing are possible features of a small-fiber neuropathy. One of the mechano-insensitive units showed spontaneous activity, with two bursts of action potentials in a patient with only a slightly elevated temperature of 31.5°C on the dorsum of the foot. The unit was classified in detail and had a high degree of total slowing, low conduction velocity, an electrical threshold of 60 mA and a heat threshold of > 46.7°C. It did not respond to sympathetic arousal provocations. Seven other C-units showed on-going activity, but reliable classification of their properties was not obtained. Three mechanoresponsive units were identified and they were all activated by mechanical stimulation with von Frey < 750 mN. Three mechanoresponsive fibers in the patients showed a total slowing that previously has never been observed
530
560
590 500
530
560
Response Latency, ms
Fig. 29.5. Left panel: sensitization of a mechano-insensitive nociceptor. Simultaneous recording of three afferent C-fibers in a healthy subject. The first trace is shown as the original nerve signal; for all successive traces, action potentials are symbolized by rhombi at their appropriate latencies. Two fibers (filled symbols) developed pronounced activity-dependent slowing of conduction velocity on increasing stimulus frequency; slowing was much less for the third fiber (open symbols). The marking response induced by stimulation with a 750 mN von Frey hair (arrow) proved this fiber to be mechanoresponsive. The two fibers with pronounced activity-dependent slowing were not activated (mechano-insensitive fibers). Right panel: a fiber recorded from a patient, showing a slowing of conduction velocity similar to that observed in mechano-insensitive fibers of healthy subjects. However, the mechanical stimulation induced a clear and reproducible marking response. (From Ørstavik et al., 2003.)
MICRONEUROGRAPHY IN THE ASSESSMENT OF NEUROPATHIC PAIN
fiber, shows some principal alterations which may occur in patients with chronic pain. 29.8.3. On the relation between efferent sympathetic nerve fibers and afferent C-nociceptive nerve fibers in neuropathic pain For many years, there have been controversies regarding the role of the sympathetic nervous system in the generation of pain. Sympathetically maintained pain has been the term used for pain which is relieved by sympathetic blocks. In spite of the many questions related to the effect of sympathetic blockades, the fact that some patients obtain pain reduction indicates that the sympathetic nervous system is involved in the generation of pain. This is supported by the fact that application of norepinephrine (NE) in the painful skin area may aggravate pain (Torebjörk et al., 1995; Wallin et al., 1976; Ali et al., 2000). Sympathetic arousal may increase the pain in patients with complex regional pain syndrome (CRPS) (Drummond and Finch, 2004) but the question still remains how the activity in the sympathetic nervous system may affect activity in afferent nociceptive neurons. The role of the sympathetic nervous system in neuropathic pain has also been studied with the use of microneurography in humans. Microneurographic recordings from a patient with reflex sympathetic dystrophy (CRPS type 1) and with pain, sensory abnormalities and signs of sympathetic hyperactivity as evidenced by low skin temperature, showed no increase in sympathetic neural discharge (Casale and Elam, 1992). This finding coincides with previous results from microneurography (Wallin et al., 1976). Since there is no evidence for increased sympathetic outflow in patients with CRPS, no increase in venous concentration of NE in the affected limb (Drummond et al., 1991) and no increase in reflex vasoconstrictor response in the sympathetic extremity (Christensen and Henriksen, 1983; Rosen et al., 1988), α-adrenergic receptor supersensitivity to cathecholamines has been postulated as a likely mechanism for both the hyperalgesia and autonomic disturbances associated with sympathetically maintained pain (SMP) (Raja, 1995). Another hypothesis has been a coupling of afferent and efferent axons via ephaptic interactions (McMahon, 1991; Jänig et al., 1996). Attempts have been made to study possible coupling between efferent sympathetic nerve fibers and afferent C-units in an experimental hyperalgesia model in healthy volunteers (Elam et al., 1999). Microneurographic recordings on C-mechano- and heat-sensitive nerve fibers were performed before and after chemical sensitization of receptive fields by topical application of
435
mustard oil. The aim of the study was to see whether intense excitation of the sympathetic nervous system could affect the firing properties of the afferent C-units. As a consequence of sympatho-excitation of the patient, sympathetic nerve traffic increased considerably, but there was no alteration in the firing of the afferent units and there were similar results before and after sensitization of cutaneous receptive fields. The authors could not show any abnormal coupling between efferent sympathetic activity and the activity in the polymodal C-fibers. One may argue that the question of whether the firing of mechano-insensitive nerve fibers would be altered following sympatho-excitation in this experimental model still remains to be answered. Microneurographic recordings from low-threshold cutaneous mechanoreceptors were performed on healthy subjects (Elam and Macefield, 2004). Recordings from 17 rapidly adapting and 20 slowly adapting units revealed no increase in the firing rates of these afferents as a consequence of sympathetic arousal. However, a modest reduced afferent firing was observed, which could be argued to have consequences for sympathetically elicited vascular changes, but which could not explain any worsening of pain following sympathetic activation. 29.9. Future perspectives of microneurography Although microneurography has provided unique information about neural encoding in humans, functional electrophysiological data provided by this technique were basically isolated from developments in cellular biology on a molecular level. As microneurography does not allow recording directly from the sensory endings or of the membrane potential, molecular mechanisms of transduction cannot be investigated directly. However, axonal mechanisms of membrane potential modulation, such as post-excitatory hyperpolarization, are also currently being identified on a molecular level (Cordoba-Rodriguez et al., 1999). The time course of post-excitatory hyperpolarization can be assessed by microneurography and, thus, there is an exciting perspective to finally bridge the gap between the cellular and systemic approach. Moreover, the unexpected segregation of axonal and sensory properties in C-fibers might also help to link the electrophysiological data to analysis using immunohistochemistry, as has been successfully shown in cold-sensitive units (Koltzenburg and Koerber, 2002). Despite many limitations the microneurographic approach provides unique data from healthy human subjects and patients and has a mediative position between clinical science and basic research.
436
E. JØRUM AND M. SCHMELZ
References Adriaensen H, Gybels J, Handwerker HO, Van HJ (1983). Response properties of thin myelinated (A-delta) fibers in human skin nerves. J Neurophysiol 49: 111–122. Ali Z, Raja SN, Wesselmann U, Fuchs PN, Meyer RA, Campbell JN (2000). Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Pain 88: 161–168. Andrew D, Craig AD (2001). Spinothalamic lamina 1 neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 4: 72–77. Bolanowski SJ, Verrillo RT, McGlone F (1999). Passive, active and intra-active (self) touch. Somatosens Mot Res 16: 304–311. Campero M, Serra J, Ochoa JL (1996). C-polymodal nociceptors activated by noxious low temperature in human skin. J Physiol 497: 565–572. Campero M, Serra J, Marchettini P, Ochoa JL (1998). Ectopic impulse generation and autoexcitation in single myelinated afferent fibers in patients with neuropathy and positive sensory symptoms. Muscle Nerve 21: 1661–1667. Campero M, Serra J, Bostock H, Ochoa JL (2001). Slowly conducting afferents activated by innocuous low temperature in human skin. J Physiol 535: 855–865. Casale R, Elam M (1992). Normal sympathetic nerve activity in a reflex sympathetic dystrophy with marked skin vasoconstriction. J Auton Nerv Syst 41: 215–220. Christensen K, Henriksen O (1983). The reflex sympathetic dystrophy syndrome. An experimental study of sympathetic reflex control of subcutaneous blood flow in the hand. Scand J Rheumatol 12: 263–267. Cline M, Ochoa J, Torebjörk HE (1989). Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain 112: 621–647. Cordoba-Rodriguez R, Moore KA, Kao JP, Weinreich D (1999). Calcium regulation of a slow post-spike hyperpolarization in vagal afferent neurons. Proc Natl Acad Sci USA 96: 7650–7657. Craig AD, Bushnell MC (1994). The thermal grill illusion: unmasking the burn of cold pain. Science 265: 252–255. Craig AD, Reiman EM, Evans A, Bushnell MC (1996). Functional imaging of an illusion of pain [see comments]. Nature 384: 258–260. Drummond PD, Finch PM (2004). Persistence of pain induced by startle and forehead cooling after sympathetic blockade in patients with complex regional pain syndrome. J Neurol Neurosurg Psychiatry 75: 98–102. Drummond PD, Finch PM, Smythe GA (1991). Reflex sympathetic dystrophy: the significance of differing plasma catecholamine concentrations in affected and unaffected limbs. Brain 114: 2025–2036. Elam M, Macefield V (2004). Does sympathetic nerve discharge affect the firing of myelinated cutaneous afferents in humans? Auton Neurosci 111: 116–126. Elam M, Olaussen B, Skarphedinsson JO, Wallin BG (1999). Does sympathetic nerve discharge affect the firing of polymodal C-fiber afferents in humans? 122: 2237–2244.
Erickson RP, Poulos DA (1973). On the qualitative aspect of the temperature sense. Brain Res 61: 107–112. Essick GK, James A, McGlone FP (1999). Psychophysical assessment of the affective components of non-painful touch. Neuroreport 10: 2083–2087. Garell PC, McGillis SL, Greenspan JD (1996). Mechanical response properties of nociceptors innervating feline hairy skin. J Neurophysiol 75: 1177–1189. Hallin RG, Torebjörk HE (1970). Afferent and efferent C units recorded from human skin nerves in situ. A preliminary report. Acta Soc Med Uppsala 75: 277–281. Hallin RG (1990). Microneurography in relation to intraneural topography: somatotopic organisation of median nerve fascicles in humans. J Neurol Neurosurg Psychiatry 53: 736–744. Hallin RG, Torebjörk HE (1974). Methods to differentiate electrically induced afferent and sympathetic C unit responses in human cutaneous nerves. Acta Physiol Scand 92: 318–331. Hallin RG, Wu G (2001). Fitting pieces in the peripheral nerve puzzle. Exp Neurol 172: 482–492. Hallin RG, Wu G (2002). Novel information on peripheral tactile mechanisms in man acquired with concentric needle electrode microneurography. Behav Brain Res 135: 11–18. Hallin RG, Ekedahl R, Frank O (1991). Segregation by modality of myelinated and unmyelinated fibers in human sensory nerve fascicles. Muscle Nerve 14: 157–165. Hensel H (1973). Cutaneous thermoreceptors. In: Iggo A (Ed.) Handbook of Sensory Physiology. Springer Verlag, Berlin, p. 79. Hensel H (1976). Correlations of neural activity and thermal sensation in man. In: Zotterman Y (Ed.) Sensory Functions of the Skin in Primates. Pergamon Press, Oxford, pp. 331–352. Jänig W, Levine JD, Michaelis M (1996). Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma. Prog Brain Res 113: 161–184. Järvilehto T, Hämälainen H (1979). Touch and thermal sensations: psychophysical observations and unit activity in human skin nerves. In: Kenshalo DR (Ed.) Sensory Functions of the Skin in Humans. Plenum Publishing, New York, p. 279. Jørum E, Lundberg LER, Torebjörk HE (1989). Peripheral projections of nociceptive unmyelinated axons in the peroneal nerve. J Physiol 416: 291–301. Koltzenburg M, Koerber RH (2002). Diversity of nociceptors – which are important for the generation of clinically relevant persistent pains? In: Proceedings of 10th World Congress on Pain. IASP, Seattle, WA, p. 710. Koltzenburg M, Handwerker HO, Torebjörk HE (1993). The ability of humans to localise noxious stimuli. Neurosci Lett 150: 219–222. Konietzny F (1984). Peripheral neural correlates of temperature sensations in man. Hum Neurobiol 3: 21–32. Konietzny F, Hensel H (1975). Letters and notes: warm fiber activity in human skin nerves. Pflugers Arch 359: 265–267. Mackel R (1985). Human cutaneous mechanoreceptors during regeneration: physiology and interpretation. Ann Neurol 18: 165–172.
MICRONEUROGRAPHY IN THE ASSESSMENT OF NEUROPATHIC PAIN Mackel R (1989). Properties of cutaneous afferents in diabetic neuropathy. Brain 112: 1359–1376. Mackel R, Brink E (2003). Conduction of neural impulses in diabetic neuropathy. Clin Neurophysiol 114: 248–255. Mackel R, Brink EE, Wittkowsky G (1985). Properties of cutaneous mechanosensitive afferents during the early stages of regeneration in man. Brain Res 329: 49–69. Mackel R, Brink E, Jørum E, Aisen M (1994). Properties of cutaneous afferents during recovery from Guillain–Barré syndrome. Brain 117: 169–183. McGlone F, Kelly E, Trulsson M, Francis S, Westling G, Bowtell R (2002). Functional neuroimaging studies of human somatosensory cortex. Behav Brain Res 135: 147. McMahon SB (1991). Mechanisms of sympathetic pain. Br Med Bull 47: 584–600. Meyer RA, Campbell JN (1981). Evidence for two distinct classes of unmyelinated nociceptive afferents in monkey. Brain Res 224: 149–152. Mogyoros I, Bostock H, Burke D (2000). Mechanisms of paresthesias arising from healthy axons. Muscle Nerve 23: 310–320. Moore CE, Schady W (2000). Investigation of the functional correlates of reorganization within the human somatosensory cortex. Brain 123: 1883–1895. Mørk C, Asker CL, Salerud EG, Kvernebo K (2000). Microvascular arteriovenous shunting is a probable pathogenetic mechanism in erythromelalgia. J Invest Dermatol 114: 643–646. Nordin M (1990). Low-threshold mechanoreceptive and nociceptive units with unmyelinated (C) fibers in the human supraorbital nerve. [Published erratum appears in J Physiol (Lond) 1991, 444: 777.] J Physiol 426: 229–240. Nyström B, Hagbarth KE (1981). Microelectrode recordings from transected nerves in amputees with phantom pain. Neurosci Lett 27: 211–216. Ochoa J, Torebjörk HE (1980). Paresthesia from ectopic impulse generation in human sensory nerves. Brain 103: 835–853. Ochoa J, Torebjörk HE (1983). Sensations evoked by intraneural microstimulation of single mechanoreceptor units innervating the human hand. J Physiol 342: 633–654. Ochoa JL, Torebjörk HE (1989). Sensations evoked by intraneural microstimulation of C nociceptor fibers in human skin nerves. J Physiol 415: 583–599. Olausson H, Lamarre Y, Backlund H, Morin C, Wallin BG, Starck G, Ekholm S, Strigo I, Worsley K, Vallbo AB, Bushnell MC (2002). Unmyelinated tactile afferents signal touch and project to insular cortex. Nat Neurosci 5: 900–904. Ørstavik K, Weidner C, Schmidt R, Schmelz M, Hilliges M, Jørum E, Handwerker H, Torebjörk E (2003). Pathological C-fibers in patients with a chronic painful condition. Brain 2003: 126: 567–578. Ørstavik K, Mørk C, Kvernebo K, Jørum E (2004). Pain in primary erythromelagia – a neuropathic component? Pain 110: 531–538. Peng YB, Ringkamp M, Campbell JN, Meyer RA (1999). Electrophysiological assessment of the cutaneous arborization of Adelta-fiber nociceptors. J Neurophysiol 82: 1164–1177.
437
Raja SN (1995). Role of the sympathetic nervous system in acute pain and inflammation. Ann Med 27: 241–246. Ringkamp M, Peng YB, Campbell JN, Meyer RA (1997). Intradermal capsaicin produces a vigorous discharge in mechanically-insensitive A-fiber nociceptors of the monkey. Soc Neurosci Abstr 23 (part 2): 1258. Rosen L, Ostergren J, Fagrell B, Stranden E (1988). Skin microvascular circulation in the sympathetic dystrophies evaluated by videophotometric capillaroscopy and laser doppler fluxmetry. Eur J Clin Invest 18: 305–308. Rowe MJ (2002). Synaptic transmission between single tactile and kinaesthetic sensory nerve fibers and their central target neurones. Behav Brain Res 135: 197–212. Sandroni P, Davis MDP, Harper M (1999). Neurophysiologic and vascular studies in erythromelalgia: a retrospective study. J Clin Neuromusc Dis 1: 57–63. Schady WJ, Torebjörk HE (1983). Projected and receptive fields: a comparison of projected areas of sensations evoked by intraneural stimulation of mechanoreceptive units, and their innervation territories. Acta Physiol Scand 119: 267–275. Schady W, Ochoa JL, Torebjörk HE, Chen LS (1983a). Peripheral projections of fascicles in the human median nerve. Brain 106: 745–760. Schady WJ, Torebjörk HE, Ochoa JL (1983b). Cerebral localisation function from the input of single mechanoreceptive units in man. Acta Physiol Scand 119: 277–285. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE (1997). Specific C-receptors for itch in human skin. J Neurosci 17: 8003–8008. Schmelz M, Schmidt R, Handwerker HO, Torebjörk HE (2000a). Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibers. Brain 123: 560–571. Schmelz M, Michael K, Weidner C, Schmidt R, Torebjörk HE, Handwerker HO (2000b). Which nerve fibers mediate the axon reflex flare in human skin? Neuroreport 11: 645–648. Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjörk HE, Handwerker HO (2003a). Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 89: 2441–2448. Schmelz M, Hilliges M, Schmidt R, Ørstavik K, Vahlquist C, Weidner C, Handwerker HO, Torebjörk HE (2003b). Active “itch fibers” in chronic pruritus. Neurology 61: 564–566. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjörk E, Handwerker HO (1995). Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 15: 331–341. Schmidt R, Schmelz M, Ringkamp M, Handwerker H, Torebjörk HE (1997). Innervation territories of mechanically activated C nociceptor units in human skin. J Neurophysiol 78: 2641–2648. Schmidt R, Schmelz M, Torebjörk HE, Handwerker HO (2000). Mechano-insensitive nociceptors encode pain by tonic pressure to human skin. Neuroscience 98: 793–800. Schmidt R, Schmelz M, Weidner C, Handwerker H, Torebjörk HE (2002). Innervation territories of mechanoinsensitive C nociceptors in human skin. J Neurophysiol 88: 1859–1866.
438
E. JØRUM AND M. SCHMELZ
Serra J, Campero M, Ochoa J, Bostock H (1999). Activitydependent slowing of conduction differentiates functional subtypes of C fibers innervating human skin. J Physiol 515: 799–811. Serra J, Campero M, Bostock H, Ochoa J (2004). Two types of C-nociceptors and their behavior in areas of capsaicininduced secondary hyperalgesia. J Neurophysiol 91: 2770–2781. Susser E, Sprecher E, Yarnitsky D (1999). Paradoxical heat sensation in healthy subjects: peripherally conducted by A delta or C fibers? Brain 122: 239–246. Thomas CK, Westling G (1995). Tactile unit properties after human cervical spinal cord injury. Brain 118: 1547–1556. Thunberg T (1896). Förnimmelserne vid till samma ställe lokaliserad samtidigt pägäende köld och värmeretning. Uppsala Läkfören Förh 1: 489–495. Torebjörk HE (1974). Afferent C units responding to mechanical, thermal and chemical stimuli in non-glabrous skin. Acta Physiol Scand 92: 374–390. Torebjörk HE, Hallin RG (1976). Skin receptors supplied by unmyelinated (C) fibers in man. In: Zotterman Y (Ed.) Sensory Functions of the Skin in Primates. Pergamon Press, Oxford, UK, pp. 475–485. Torebjörk HE, LaMotte RH, Robinson CJ (1984). Peripheral neural correlates of magnitude of cutaneous pain and hyperalgesia: simultaneous recordings in humans of sensory judgements of pain and evoked responses in nociceptors with C-fibers. J Neurophysiol 51: 325–339. Torebjörk HE, Vallbo AB, Ochoa JL (1987). Intraneural microstimulation in man. Its relation to specificity of tactile sensations. Brain 110: 1509–1529. Torebjörk HE, Wahren L, Wallin G, Hallin R, Koltzenburg M (1995). Noradrenaline-evoked pain in neuralgia. Pain 63: 11–20. Trulsson M, Francis ST, Kelly EF, Westling G, Bowtell R, McGlone F (2001). Cortical responses to single mechanoreceptive afferent microstimulation revealed with fMRI. Neuroimage 13: 613–622.
Vallbo ÅB, Hagbarth KE (1968). Activity from skin mechanoreceptors recorded percutaneously in awake human subjects. Exp Neurol 21: 270–289. Vallbo AB, Hagbarth KE, Torebjörk HE, Wallin BG (1979). Somatosensory, proprioceptive and sympathetic activity in human peripheral nerves. Physiol Rev 59: 919–957. Vallbo AB, Olausson H, Wessberg J, Norrsell U (1993). A system of unmyelinated afferents for innocuous mechanoreception in the human skin. Brain Res 628: 301–304. Vallbo AB, Olausson H, Wessberg J, Kakuda N (1995). Receptive field characteristics of tactile units with myelinated afferents in hairy skin of human subjects. J Physiol 483: 783–795. Vallbo AB, Olausson H, Wessberg J (1999). Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin. J Neurophysiol 81: 2753–2763. Wall PD, McMahon SB (1985). Microneuronography and its relation to perceived sensation. A critical review. Pain 21: 209–229. Wallin BG, Torebjörk HE, Hallin R (1976). Preliminary observations on the pathophysiology of hyperalgesia in the causalgic pain syndrome. In: Zotterman Y (Ed.) Sensory Functions of the Skin in Primates, with Special Reference to Man. Pergamon Press, Oxford, UK, pp. 489–502. Weidner C, Schmelz M, Schmidt R, Hansson B, Handwerker HO, Torebjörk HE (1999). Functional attributes discriminating mechano-insensitive and mechano-responsive C nociceptors in human skin. J Neurosci 19: 10184–10190. Wu G, Ekedahl R, Stark B, Carlstedt T, Nilsson B, Hallin RG (1999). Clustering of Pacinian corpuscle afferent fibers in the human median nerve. Exp Brain Res 126: 399–409. Yarnitsky D, Ochoa JL (1991). Warm and cold specific somatosensory systems. Psychophysical thresholds, reaction times and peripheral conduction velocities. Brain 114: 1819–1826.
Neurophysiology examinations in neuropathic pain Chapter 29
Microneurography in the assessment of neuropathic pain ELLEN JØRUM AND MARTIN SCHMELZ The Laboratory of Clinical Neurophysiology, The Department of Neurology, Rikshospitalet University Hospital, Oslo, Norway and Department of Anesthesiology and Operative Intensive Care, University of Heidelberg, Mannheim, Germany
29.1. Introduction
29.2. Intraneural stimulation
Microneurography is a neurophysiological method allowing microelectrode recordings of impulses in single nerve fibers in awake human subjects. The method which was developed by Swedish neurophysiologists over 35 years ago (Vallbo and Hagbarth, 1968) has been employed for recordings from afferent sensory nerve fibers, efferent sympathetic nerve fibers and proprioceptive nerve fibers (Vallbo et al., 1979). The first paper showing recordings from single afferent unmyelinated C-nociceptors in humans was published by Hallin and Torebjörk in 1970. A large number of papers have been published on the physiological properties of the human nociceptive system. Microneurography experiments in human experimental models of pain/neuropathic pain has shed important light on pathophysiological mechanisms involved in primary and secondary hyperalgesia (Torebjörk et al., 1984; Schmelz et al., 2000a; Serra et al., 2004). Over the last years, a few papers related to pathophysiological mechanisms of thick myelinated nerve fibers as well as nociceptive fibers in neuropathic pain have been published. Before considering results of studies on patients, the chapter will review the principal findings in nociceptive systems of relevance for pathology.
With the microelectrode placed in close relation to bypassing axons, they can also be used to apply low-intensity currents for intraneural microstimulation (Ochoa and Torebjörk, 1983; Schady et al., 1983a,b; Schady and Torebjörk, 1983; Torebjörk et al., 1987). For liminal stimulation of myelinated fibers, different sensory perceptions are generated (tapping, vibration, pressure) which can be correlated with the type of afferent units recorded before. Recently, the successful combination of microneurography, intraneural microstimulation and functional magnetic resonance imaging provided information about unexpectedly strong cortical activation of the primary and secondary somatosensory cortex upon stimulation of single identified myelinated afferents (Trulsson et al., 2001; McGlone et al., 2002). Cortical activations were even observed at stimulus frequencies, which did not induce any sensation. This new observation corroborates the high transmission security from primary afferents to spinal projection neurons (Rowe, 2002). As intraneural microstimulation skips activation of the receptive ending and the distal axon it can also be employed in amputees to activate afferent fibers and assess the induced sensations. Unexpectedly, intraneural microstimulation of nerves innervating amputated limbs elicited perceptions which did not differ in quality
Correspondence to: Ellen Jørum, The Laboratory of Clinical Neurophysiology, The Department of Neurology, Rikshospitalet University Hospital, Sognsvannsveien 20, 0027 Oslo, Norway. E-mail: [email protected], Tel: +47-23-07-08-34, Fax: +47-23-07-35-78.
428
E. JØRUM AND M. SCHMELZ
or location from controls, suggesting a low degree of cortical plasticity (Moore and Schady, 2000). Intraneural microstimulation has also been used to elicit unitary sensation in response to C-fiber activation. However, due to the close relation of several axons in a remak bundle it cannot be expected that a single C-afferent can be excited electrically (Wall and McMahon, 1985; Ochoa and Torebjörk, 1989). Functional clustering of axons in the peripheral nerve may explain that unitary sensations may be elicited despite activation of several axons. Anatomical segregation of axons of similar sensory characteristics and innervation territories has already been shown in myelinated fibers (Jørum et al., 1989; Hallin, 1990; Hallin et al., 1991; Wu et al., 1999; Hallin and Wu, 2001, 2002). However, the significance of functional and topographic segregation in peripheral nerves is yet unclear. 29.3. Thermoreceptors Thermoreceptors can be separated into receptors for warmth and cold detection. According to results of differential nerve blocks and response latencies, the warmth sensation has been attributed to C-fibers, whereas cold detection is a function of A-δ fibers (Erickson and Poulos, 1973; Yarnitsky and Ochoa, 1991). Microneurographic recordings from A-δ fibers are sparse and so far only few examples of human A-δ cold units have been published (Hensel, 1973, 1976; Järvilehto and Hämälainen, 1979). Data on human warm fibers have been described in several papers (Konietzny and Hensel, 1975; Hensel, 1976; Torebjörk and Hallin, 1976; Konietzny, 1984). They are mechano-insensitive and have small innervation territories. They are activated by moderate warming, but may also encode increasing temperature into the noxious range. Their low number and small receptive fields result in a sparse innervation for warmth. This may explain early impairment of warmth detection in peripheral neuropathy as compared to heat pain thresholds which may increase at a later stage of the disease. The phenomenon of paradoxical hot sensation upon mild cooling under a differential A-fiber block has provided evidence for cold specific C-fibers (Susser et al., 1999). Also, for the explanation of a heat pain illusion by a simultaneous stimulation with non-noxious warm and cold (thermal grill illusion) (Craig and Bushnell, 1994; Craig et al., 1996), the Thunberg effect (Thunberg, 1896), the existence of cold sensitive C-fibers has been suggested. Recently, recordings of C-fibers responsive to mild cooling have been identified in humans (Campero et al., 2001). Their activation thresholds were about 29°C, which is compatible with a role of this class of C-fibers in the paradoxical hot sensation.
Interestingly, these fibers not only differed in their receptive properties, but also their axonal characteristics clearly distinguished them from C-nociceptors. Activity-dependent hyperpolarization of axons which leads to slower conduction velocities was much less pronounced in C-cold fibers as compared to the nociceptors.
29.4. Nociceptors 29.4.1. A-δ Nociceptors Thinly myelinated nociceptors with a conduction velocity of about 20 m/s have been recorded in human radial nerve (Adriaensen et al., 1983). According to their receptive properties they can be separated into a highthreshold mechanoreceptive class and a mechano-heat sensitive class. Activation of A-δ nociceptors underlies the sharp pricking pain inflicted in noxious mechanical and heat stimulation. In monkeys also mechano-insensitive A-δ chemonociceptors have been found which have a chemical response pattern similar (Ringkamp et al., 1997) to that of mechano-insensitive C-fibers (Schmelz et al., 2000a). Moreover, differentiation between A-δ and C-fibers in the periphery can be complicated by the fact that A-δ fibers can have surprisingly long unmyelinated distal branches in the skin of up to 5 cm (Peng et al., 1999). 29.4.2. C-nociceptors 29.4.2.1. Polymodal C-nociceptive afferent fibers Microneurographic recordings have shown that the human skin has a rich supply of polymodal nociceptors which respond to mechanical, thermal and chemical painful stimuli (Torebjörk, 1974). Properties of polymodal C-nociceptive fibers have been well described. In recordings from a total of 118 C-afferent units responding to mechanical stimuli (Schmidt et al., 1995), C-units which were activated by both mechanical stimuli and heat (CMH) were in the majority (66%) (45% of all afferent C-fibers) compared to those only responding to mechanical stimuli (CM). Thresholds of activating CM were from 14 to 360 mN and 3.4 to 750 mN for CMH (Fig. 29.1, example of a CMH unit). Six of the units responded to heating with thresholds from 45° to 48°C. A subpopulation of C-polymodal nociceptors may also be activated by low temperatures between 19° and 0°C, which is in the noxious range and which may contribute to the determination of cold pain (Campero et al., 1996). It has been suggested that the same group of C-nociceptor fibers may play a role in cold hyperalgesia in patients with peripheral nerve lesions (Campero et al., 1996).
C-fiber
C-fiber
Mechanoinsensitive C-fiber
Mechano- and heatLarge and insensitive C-nociceptors irregular (CMiHi )
Large
Small and large C-fiber (variation)
Itch fibers
Low threshold C-fibers
C-fiber
Small
Small
Cold Nociceptors
A-δ fiber
Polymodal C-nociceptors (CM and CMH)
Small
Cold Receptors
C-fiber
A-δ fiber
Small
Warm Receptors
Nerve Fiber
A-δ nociceptors
Receptive Field
Receptor Type
Properties of A-δ and C-fiber receptors
Table 29.1
Accurate stimulus localization of pain
Sharp pricking pain
Cold pain
Cold
Warm
Sensation
Light stroking
Histamine
Pleasant touch?
Itch
Not activated by Plays a role in heat- or mechanical pathophysiology? stimuli
CM: 14–360 mN CMH: 3.4–750 mN Heat 45°–48°C
1. High-threshold mechanical 2. Mechanical and heat
Mechanical Heating Cooling 19°–0°C
Cooling 28°–30°C
Moderate heating
Stimulus
Mean 0.87 m/s
Mean 1.01 m/s
Conduction Velocity
Role in Flare
Yes
Present, but less No pronounced than for CMiHi
ActivityDependent Slowing of Conduction
High: average 60 mA Pronounced
Low: 2.0–5.5 mA (lower and upper quartile)
Transcutaneous Electrical Threshold
E. JØRUM AND M. SCHMELZ
430
These units, which also have been referred to as “silent nociceptors”, have been studied in detail and are suggested to play a particular role in the pathophysiology of pain. For this reason and as a prerequisite for an understanding of alterations observed in patients with chronic pain, the properties of these fibers will be presented.
CMH u. t.
Mech. Stim.
i. t.
Mustard Oil
Heating
29.5. Properties of mechano-insensitive C-units
60 s
420
440
460 Latency ms
Fig. 29.1. CMH unit (top panel) responding to mechanical stimuli (second panel) and to heating (third panel). Notice the irregular increases in latency of this unit during topical application of mustard oil (bottom panel), implying chemosensitivity. (From Schmidt et al., 1995.)
29.4.2.2. Mechano-insensitive Before their identification in humans, animal experiments revealed the existence of mechano-insensitive nociceptors in addition to the mechanoresponsive (Meyer and Campbell, 1981; Garell et al., 1996). Within the last few years, mechano-insensitive C-fibers were discovered in human skin (Schmidt et al., 1995). They were identified following a change in the experimental protocol from the traditional mechanical search stimuli to a search procedure employing electrical stimuli to recruit units independently of their sensitivity to natural stimulation. A computerized version of a method utilizing interactions between naturally and electrically evoked discharges (Hallin and Torebjörk, 1974; Torebjörk, 1974; Torebjörk and Hallin, 1976) allowed reliable testing of responsiveness of individual C-units in multiunit recordings frequently encountered in microneurography. The basis for this technique is the characteristic slowing of impulse conduction in thin fibers that is observed after repetitive firing induced either by electrical or natural skin stimulation, or by sympathetic reflex activation. The method is sensitive enough to allow detection of one or a few extra impulses elicited by any maneuver, which is the basis of the marking technique, and which will be referred to in recordings from patients.
The mechano-insensitive units are not excited by von Frey hairs of 750 mN. The units (24 % of the afferent C-units), as described in detail in Schmidt et al. (1995), did not respond to mechanical stimulation with von Frey filaments up to 1.6 N (far beyond the threshold of CMH) nor to heating with temperatures of 48°C and above. Because of their unresponsiveness to both mechanical and heat stimuli, these units were termed CMiHi (C-mechano-insensitive and heat-insensitive units). Four of the 15 CMiHi units in this material were sensitized to physical stimuli after treatment with mustard oil. Two CMiHi units became sensitized to mechanical and heat stimuli following topical application of capsaicin (Schmidt et al., 1995). One-third of the units responded to mustard oil and were regarded as chemonociceptors (Fig. 29.1). The “marking technique” as explained in the above section has made it possible to classify C-units in relation to responsiveness, threshold determinations and extensions of innervation territories and to compare differences between CMH and CMi units. There are large differences between the two classes of C-units, which have significance for their function both in a normal state and in a pathophysiological setting. 29.5.1. Conduction velocities, transcutaneous electrical threshold and slowing activity Electrical properties of the two classes of C-fibers are different (Weidner et al., 1999). In this study, it was demonstrated that both conduction velocities and transcutaneous thresholds differed between the two groups. Conduction velocities of CMiHi were lower (mean of 0.87 m/sec) than those of the CMH (mean of 1.01 m/s), while the transcutaneous electrical threshold was higher for the mechano-insensitive nerve fibers (average of 60 mA) than for the CMH fibers (2.0 and 5.5, lower and upper quartile, respectively). The two classes of afferent C-units have a different activity-dependent slowing of conduction which was much more pronounced in mechano-insensitive than in mechano-sensitive nerve fibers. Repetitive electrical stimulation at 0.125, 0.25 and 0.5 Hz gradually increased the response latencies in C-fibers. The slowing of mechano-insensitive units exceeded by far the slowing of mechanoresponsive
MICRONEUROGRAPHY IN THE ASSESSMENT OF NEUROPATHIC PAIN b
c
d
that mechano-insensitive C-units in human skin are equipped with tetrodotoxin TTX-R sodium channels with an elevated activation threshold, which would explain their high activation thresholds for transcutaneous electrical stimuli (Weidner et al., 1999). The finding that mechano-insensitive C-nociceptors have distinct membrane characteristics opens up possibilities for selective pharmacological interventions tailored for these C-fibers, which may be of particular importance for the treatment of inflammatory pain and hyperalgesia (Weidner et al., 1999).
e
1/4 Hz
Traces 1/8 Hz
a
431
1/2 Hz
29.5.2. Role in sensitization following tonic pressure
1/4 Hz
With reference to the above-mentioned results, functional differences in relation to pathophysiological mechanisms have been studied. It has been shown that tonic pressure induced increased pain responses (sensitization), matching the discharges of the mechano-insensitive nerve fibers, and that this class of C-afferent units thereby play an important role in static mechanical hyperalgesia, whereas the polymodal C-nociceptors only displayed a strong initial excitation followed by adaptation (Schmidt et al., 2000).
c
b
d
e
750 mN
a
450
470
490
Response Latency, ms
29.5.3. Role of mechano-insensitive C-fibers in flare response
Fig. 29.2. Slowing of conduction velocity during repetitive stimulation. Specimen obtained during the electrode stimulation protocol applied to a group of five C-units recorded simultaneously. After a 2-min recovery period, the nerve terminals were stimulated by intracutaneous impulses at 0.125, 0.25 and 0.5 Hz and then again at 0.25 Hz. Subsequent traces are shown from top to bottom. The top trace provides an amplified and unfiltered view of the recording also shown in the first trace of the following sequence. For the standard protocol, 20 stimuli were applied at 0.125 and 0.25 Hz and 30 stimuli at 0.5 Hz. In this specimen record, only 20 stimuli at 0.5 Hz are shown. In the bottom, responses of the five units to mechanical stimuli with a stiff von Frey bristle are shown (750 mN; arrow). Unit (b) was mechano-insensitive. Units (a, c–e) showed pronounced marking responses to mechanical stimulation. (From Weidner et al., 1999.)
There is evidence for the mechano-insensitive C-nociceptors and not the polymodal C-units being responsible for the mediation of the axon reflex flare in human skin (Schmelz et al., 2000b). Electrical stimulation of the skin with an intensity of 10 mA, selectively recruiting the mechanoresponsive C-units, produced only a weak and small flare reaction. Following stimulation with an intensity of 25 mA (an intensity known to recruit mechano-insensitive C-units), a persistent and large flare response was produced exceeding the mean receptive field size of 15 mm of the mechanoresponsive units (Schmidt et al., 1997). The findings support the idea that the mechano-insensitive nerve fibers play an important role in both the physiology and especially in the pathophysiology of human skin, by supporting neurogenic vasodilatation.
units at each stimulus frequency and as shown in Fig. 29.2. Differences in activation-dependent slowing between mechanoresponsive C-nociceptors and non-nociceptive C-cold units have also been shown (Serra et al., 1999). Altogether the findings strongly suggest differences in basic membrane properties of different classes of C-units. The details are far from yet known, but one possibility which has been suggested has been
29.5.4. Innervation territories of mechanosensitive and mechano-insensitive C-fibers Innervation territories of CMi units are larger and more irregular compared to those of CMH units and exceeding the latter by a factor of approximately 3 (Schmidt et al., 2002) (see Fig. 29.3). This finding suggests that the CMH are the C-units responsible for an accurate stimulus localization,
432
E. JØRUM AND M. SCHMELZ
A
extensive arborization of the nerve terminals) which again would suggest these units being responsible for large areas of axon reflex flare induced by capsaicin injection, highintensity electrical stimulation or histamine. 29.5.5. Sensitization of mechano-insensitive C-fibers induced by capsaicin
B
C
Fig. 29.3. The “marking method” used for mapping the electroreceptive field (eRF). A: Intracutaneous needles were inserted for regular 0.25-Hz electrical stimulation. Conditioning transcutaneous electrical pulses (pen) delivered in the vicinity of the needles were interposed between regular pulses for mapping the eRF. B: Regular pulses through intracutaneous needles within the receptive field every 4 s (stimulus artifacts under straight arrow) evoked responses of the unit at a stable latency. When additional electrical pulses through a surface probe were applied within the eRF, additional action potentials (left curved arrow) were generated, causing delayed responses to the regular pulses and a slow recovery (right curved arrow). C: Schematic drawing of an electroreceptive field; 50-mA square-wave pulses were applied to the skin (shown by arrows). Points where the unit was activated are marked with filled circles, and points where A was tested but not activated are marked with open circles. (From Schmidt et al., 2002.)
supporting previous findings that localization of noxious events from pure C-fiber stimulation is fairly precise from the foot and the hand (Jørum et al., 1989; Koltzenburg et al., 1993). The innervation territories of the CMi displayed a considerable expansion (several square centimeters) which could only be explained by an
Mechano-insensitive nerve fibers have been shown to be sensitized following application of capsaicin (Schmelz et al., 2000a). Capsaicin-induced primary and secondary hyperalgesia has been regarded as a model of chronic pain. Microneurographic recordings were obtained from a total of 12 mechanoresponsive and 20 mechanoinsensitive C-fibers before and after intracutaneous injection of capsaicin in the innervation territory of the cutaneous branch of the peroneal nerve. All mechanoresponsive and 17 of the 20 mechano-insensitive C-units were activated by the capsaicin, but the duration of the responses in the mechano-insensitive units was much longer than for the mechanosensitive units (median 170 s versus 8 s), matching the duration of the capsaicininduced pain responses. Eight of the total 17 mechanoinsensitive units became sensitized to mechanical stimulation of the receptive field, evidence of a sensitization of the units. The differential capsaicin sensitivity adds to the accumulating evidence for the existence of two categories of functionally different nociceptors in human skin and with a special role for mechanoinsensitive fibers in sensitization and hyperalgesia (Schmelz et al., 2000a). 29.6. Itch fibers About 10% of the mechano-insensitive nociceptors show lasting activation by histamine which parallels the itch sensation in humans (Schmelz et al., 1997). Supporting the view of “itch selective” neurons only the histaminepositive fibers were also excited by intracutaneous injection of the weak pruritogen prostaglandin E2, whereas histamine-negative mechano-insensitive nociceptors and polymodal nociceptors were not activated (Schmelz et al., 2003a). “Itch selective” spinal neurons have been identified in the cat (Andrew and Craig, 2001), which strengthens the concept of a labeled line also for the central processing of itch. Recently, spontaneous activity of “itch selective” neurons in a patient with chronic itch have been published (Schmelz et al., 2003b), supporting a clinical relevance for this fiber class. 29.7. Low-threshold C-fibers Traditionally afferent C-fiber function has been restricted to nociception and warmth detection. Therefore, the
MICRONEUROGRAPHY IN THE ASSESSMENT OF NEUROPATHIC PAIN
finding of C-fibers which can be activated by slightly stroking the skin and discharge at high frequencies was surprising (Nordin, 1990; Vallbo et al., 1993, 1995, 1999), as no obvious sensory correlate for this activity was known. This class of afferent C-fibers has been hypothesized to have a role in grooming behavior. Recently, touch-evoked activation of the insular cortex, but not primary and secondary somatosensory cortex, combined with a faint sensation of pleasant touch, has been described in a patient without myelinated fibers (Olausson et al., 2002). This result strengthens the view that these fibers have a role in emotional or limbic touch as suggested before (Bolanowski et al., 1999; Essick et al., 1999). Although impaired function of these fiber classes is problematic to quantify in neuropathy patients, it might well considerably affect their social life.
29.8. Studies with microneurography in patients 29.8.1. Paresthesias and spontaneous activity in myelinated fibers In healthy nerves spontaneous activity can be generated by hyperventilation, and ischemia, but it is also observed upon reperfusion and following long impulse trains (Mogyoros et al., 2002). Microneurographic recordings have verified irregular bursting discharges in A-fibers under these conditions (Ochoa and Torebjörk, 1980). As underlying mechanism for the generation of spontaneous activity observed in hyperventilation, high-pHinduced activation of persistent axonal Na channels have been proposed, which might be of more significance as compared to lowering of free Ca concentration (Mogyoros et al., 2000). Under ischemic conditions the impaired electrogenic Na–K pump and accumulation of extracellular K facilitate spontaneous activity (Mogyoros et al., 2000). It is yet unclear as to whether the same mechanisms leading to paresthesias in healthy subjects also play a critical role under pathophysiological conditions. Spontaneous and abnormal evoked activity in myelinated afferents corresponding to paresthesia has been recorded by microneurography in neuropathy patients (Campero et al., 1998), in patients recovering from Guillain–Barré syndrome (Mackel et al., 1994) and also in amputees (Nyström and Hagbarth, 1981). In some patients the generating site of the spontaneous activity was investigated by proximal and distal local anesthesia. As anesthesia of the nerve proximal to the recording site stopped on-going activity in one patient (Campero et al., 1998) the origin was either along the central path of the axon or the dorsal root ganglion cell. Similarly local anesthesia of the neuroma in an amputee did not abolish spontaneous activity (Nyström and Hagbarth, 1981),
433
suggesting a central origin. However, microneurography results will not provide more specific information about the ional mechanism leading to spontaneous activity. In diabetic patients low-threshold mechanoreceptors showed pronounced fatigue slowly adapting units (SA I), and lower discharge rates (SA), which may correspond to impaired tactile function in the patients (Mackel, 1989). More specifically, diabetes patients had shorter refractory periods despite unchanged conduction velocity and action potential duration (Mackel and Brink, 2003). Pronounced fatigue in low-threshold mechanoreceptors was also described in regenerating fibers following nerve transection (Mackel, 1985; Mackel et al., 1985), whereas spinal injury did not substantially change sensory characteristics of the primary afferents (Thomas and Westling, 1995). 29.8.2. Pathological C-fibers in patients with a chronic painful condition If mechano-insensitive afferent C-units might be sensitized in the capsaicin model, a natural question was whether sensitization of afferent C-units could be demonstrated in patients with chronic pain. One previous study has demonstrated sensitization of C-nociceptive afferents in a patient with chronic, possibly nociceptive pain (Cline et al., 1989). To further address this question, microneurographic recordings were performed in patients with the painful condition of erythromelalgia. Erythromelalgia is a rare condition characterized by painful, red, hot extremities. Characteristically the symptoms are aggravated by heat and patients find relief from their symptoms by cooling the affected limbs (Mørk et al., 2000). Most patients report pain only during attacks provoked by increased environmental temperature, physical activity, alcohol or sleeping. According to the definition of neuropathic pain, erythromelalgia is not a neuropathic pain syndrome. However, recent studies have unmasked alterations in function of both the efferent sympathetic nervous fibers (Sandroni et al., 1999) as well as afferent myelinated and unmyelinated nerve fibers (Ørstavik et al., 2004), raising the question of a neuropathic component. Microneurographic recordings were made from a total of 103 C-units from eight patients (Ørstavik et al., 2003). The mean conduction velocity was reduced (0.81 m/s) compared with 96 units from a study on healthy subjects (Weidner et al., 1999). A total of 24 units not responding to mechanical stimulation and not characterized as sympathetic units were classified as mechano-insensitive C-nociceptive fibers (Ørstavik et al., 2003). These mechano-insensitive afferents had substantially reduced conduction velocity (mean of 0.67 m/s) compared to mechano-insensitive C-afferent units in
E. JØRUM AND M. SCHMELZ
434 70 m/s
Total Slowing
60 EM Patients
50
Control
40 30 20 10 0 1.1
in healthy subjects. Their transcutaneous electrical thresholds were within the range normally restricted to mechano-insensitive units and two of the units exhibited a long-lasting response to histamine iontophoresis, a finding which previously only has been seen exclusively in mechano-insensitive itch fibers in healthy subjects (Schmelz et al., 1997). A pathological mechanoresponsiveness in several C-nociceptors is demonstrated here for the first time, which by previously established criteria would be classified as mechano-insensitive units (Fig. 29.5). This finding, in addition to the demonstration of spontaneous activity of one afferent mechano-insensitive
m/s 1.0 Conduction Velocity
Control
EM Patient
0.9 0.8 0.125 Hz 0.7
0.25 Hz
0.6 0.5 Hz 0.5 Mechanoinsensitive
Mechanoresponsive
Sympathetic 0.25 Hz
Unit Class
Fig. 29.4. Altered conductive properties only in afferent fibers of erythromelalgia patients. Conduction velocity (lower panel) and total slowing (upper panel), obtained with a standardized protocol, differed significantly ( P < 0.05) between healthy subjects and erythromelalgia patients. (From Ørstavik et al., 2003.)
healthy subjects (mean of 0.86 m/s). They also displayed a higher degree of activity-dependent slowing (Fig. 29.4). Decreased conduction velocity and increased activitydependent slowing are possible features of a small-fiber neuropathy. One of the mechano-insensitive units showed spontaneous activity, with two bursts of action potentials in a patient with only a slightly elevated temperature of 31.5°C on the dorsum of the foot. The unit was classified in detail and had a high degree of total slowing, low conduction velocity, an electrical threshold of 60 mA and a heat threshold of > 46.7°C. It did not respond to sympathetic arousal provocations. Seven other C-units showed on-going activity, but reliable classification of their properties was not obtained. Three mechanoresponsive units were identified and they were all activated by mechanical stimulation with von Frey < 750 mN. Three mechanoresponsive fibers in the patients showed a total slowing that previously has never been observed
530
560
590 500
530
560
Response Latency, ms
Fig. 29.5. Left panel: sensitization of a mechano-insensitive nociceptor. Simultaneous recording of three afferent C-fibers in a healthy subject. The first trace is shown as the original nerve signal; for all successive traces, action potentials are symbolized by rhombi at their appropriate latencies. Two fibers (filled symbols) developed pronounced activity-dependent slowing of conduction velocity on increasing stimulus frequency; slowing was much less for the third fiber (open symbols). The marking response induced by stimulation with a 750 mN von Frey hair (arrow) proved this fiber to be mechanoresponsive. The two fibers with pronounced activity-dependent slowing were not activated (mechano-insensitive fibers). Right panel: a fiber recorded from a patient, showing a slowing of conduction velocity similar to that observed in mechano-insensitive fibers of healthy subjects. However, the mechanical stimulation induced a clear and reproducible marking response. (From Ørstavik et al., 2003.)
MICRONEUROGRAPHY IN THE ASSESSMENT OF NEUROPATHIC PAIN
fiber, shows some principal alterations which may occur in patients with chronic pain. 29.8.3. On the relation between efferent sympathetic nerve fibers and afferent C-nociceptive nerve fibers in neuropathic pain For many years, there have been controversies regarding the role of the sympathetic nervous system in the generation of pain. Sympathetically maintained pain has been the term used for pain which is relieved by sympathetic blocks. In spite of the many questions related to the effect of sympathetic blockades, the fact that some patients obtain pain reduction indicates that the sympathetic nervous system is involved in the generation of pain. This is supported by the fact that application of norepinephrine (NE) in the painful skin area may aggravate pain (Torebjörk et al., 1995; Wallin et al., 1976; Ali et al., 2000). Sympathetic arousal may increase the pain in patients with complex regional pain syndrome (CRPS) (Drummond and Finch, 2004) but the question still remains how the activity in the sympathetic nervous system may affect activity in afferent nociceptive neurons. The role of the sympathetic nervous system in neuropathic pain has also been studied with the use of microneurography in humans. Microneurographic recordings from a patient with reflex sympathetic dystrophy (CRPS type 1) and with pain, sensory abnormalities and signs of sympathetic hyperactivity as evidenced by low skin temperature, showed no increase in sympathetic neural discharge (Casale and Elam, 1992). This finding coincides with previous results from microneurography (Wallin et al., 1976). Since there is no evidence for increased sympathetic outflow in patients with CRPS, no increase in venous concentration of NE in the affected limb (Drummond et al., 1991) and no increase in reflex vasoconstrictor response in the sympathetic extremity (Christensen and Henriksen, 1983; Rosen et al., 1988), α-adrenergic receptor supersensitivity to cathecholamines has been postulated as a likely mechanism for both the hyperalgesia and autonomic disturbances associated with sympathetically maintained pain (SMP) (Raja, 1995). Another hypothesis has been a coupling of afferent and efferent axons via ephaptic interactions (McMahon, 1991; Jänig et al., 1996). Attempts have been made to study possible coupling between efferent sympathetic nerve fibers and afferent C-units in an experimental hyperalgesia model in healthy volunteers (Elam et al., 1999). Microneurographic recordings on C-mechano- and heat-sensitive nerve fibers were performed before and after chemical sensitization of receptive fields by topical application of
435
mustard oil. The aim of the study was to see whether intense excitation of the sympathetic nervous system could affect the firing properties of the afferent C-units. As a consequence of sympatho-excitation of the patient, sympathetic nerve traffic increased considerably, but there was no alteration in the firing of the afferent units and there were similar results before and after sensitization of cutaneous receptive fields. The authors could not show any abnormal coupling between efferent sympathetic activity and the activity in the polymodal C-fibers. One may argue that the question of whether the firing of mechano-insensitive nerve fibers would be altered following sympatho-excitation in this experimental model still remains to be answered. Microneurographic recordings from low-threshold cutaneous mechanoreceptors were performed on healthy subjects (Elam and Macefield, 2004). Recordings from 17 rapidly adapting and 20 slowly adapting units revealed no increase in the firing rates of these afferents as a consequence of sympathetic arousal. However, a modest reduced afferent firing was observed, which could be argued to have consequences for sympathetically elicited vascular changes, but which could not explain any worsening of pain following sympathetic activation. 29.9. Future perspectives of microneurography Although microneurography has provided unique information about neural encoding in humans, functional electrophysiological data provided by this technique were basically isolated from developments in cellular biology on a molecular level. As microneurography does not allow recording directly from the sensory endings or of the membrane potential, molecular mechanisms of transduction cannot be investigated directly. However, axonal mechanisms of membrane potential modulation, such as post-excitatory hyperpolarization, are also currently being identified on a molecular level (Cordoba-Rodriguez et al., 1999). The time course of post-excitatory hyperpolarization can be assessed by microneurography and, thus, there is an exciting perspective to finally bridge the gap between the cellular and systemic approach. Moreover, the unexpected segregation of axonal and sensory properties in C-fibers might also help to link the electrophysiological data to analysis using immunohistochemistry, as has been successfully shown in cold-sensitive units (Koltzenburg and Koerber, 2002). Despite many limitations the microneurographic approach provides unique data from healthy human subjects and patients and has a mediative position between clinical science and basic research.
436
E. JØRUM AND M. SCHMELZ
References Adriaensen H, Gybels J, Handwerker HO, Van HJ (1983). Response properties of thin myelinated (A-delta) fibers in human skin nerves. J Neurophysiol 49: 111–122. Ali Z, Raja SN, Wesselmann U, Fuchs PN, Meyer RA, Campbell JN (2000). Intradermal injection of norepinephrine evokes pain in patients with sympathetically maintained pain. Pain 88: 161–168. Andrew D, Craig AD (2001). Spinothalamic lamina 1 neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 4: 72–77. Bolanowski SJ, Verrillo RT, McGlone F (1999). Passive, active and intra-active (self) touch. Somatosens Mot Res 16: 304–311. Campero M, Serra J, Ochoa JL (1996). C-polymodal nociceptors activated by noxious low temperature in human skin. J Physiol 497: 565–572. Campero M, Serra J, Marchettini P, Ochoa JL (1998). Ectopic impulse generation and autoexcitation in single myelinated afferent fibers in patients with neuropathy and positive sensory symptoms. Muscle Nerve 21: 1661–1667. Campero M, Serra J, Bostock H, Ochoa JL (2001). Slowly conducting afferents activated by innocuous low temperature in human skin. J Physiol 535: 855–865. Casale R, Elam M (1992). Normal sympathetic nerve activity in a reflex sympathetic dystrophy with marked skin vasoconstriction. J Auton Nerv Syst 41: 215–220. Christensen K, Henriksen O (1983). The reflex sympathetic dystrophy syndrome. An experimental study of sympathetic reflex control of subcutaneous blood flow in the hand. Scand J Rheumatol 12: 263–267. Cline M, Ochoa J, Torebjörk HE (1989). Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain 112: 621–647. Cordoba-Rodriguez R, Moore KA, Kao JP, Weinreich D (1999). Calcium regulation of a slow post-spike hyperpolarization in vagal afferent neurons. Proc Natl Acad Sci USA 96: 7650–7657. Craig AD, Bushnell MC (1994). The thermal grill illusion: unmasking the burn of cold pain. Science 265: 252–255. Craig AD, Reiman EM, Evans A, Bushnell MC (1996). Functional imaging of an illusion of pain [see comments]. Nature 384: 258–260. Drummond PD, Finch PM (2004). Persistence of pain induced by startle and forehead cooling after sympathetic blockade in patients with complex regional pain syndrome. J Neurol Neurosurg Psychiatry 75: 98–102. Drummond PD, Finch PM, Smythe GA (1991). Reflex sympathetic dystrophy: the significance of differing plasma catecholamine concentrations in affected and unaffected limbs. Brain 114: 2025–2036. Elam M, Macefield V (2004). Does sympathetic nerve discharge affect the firing of myelinated cutaneous afferents in humans? Auton Neurosci 111: 116–126. Elam M, Olaussen B, Skarphedinsson JO, Wallin BG (1999). Does sympathetic nerve discharge affect the firing of polymodal C-fiber afferents in humans? 122: 2237–2244.
Erickson RP, Poulos DA (1973). On the qualitative aspect of the temperature sense. Brain Res 61: 107–112. Essick GK, James A, McGlone FP (1999). Psychophysical assessment of the affective components of non-painful touch. Neuroreport 10: 2083–2087. Garell PC, McGillis SL, Greenspan JD (1996). Mechanical response properties of nociceptors innervating feline hairy skin. J Neurophysiol 75: 1177–1189. Hallin RG, Torebjörk HE (1970). Afferent and efferent C units recorded from human skin nerves in situ. A preliminary report. Acta Soc Med Uppsala 75: 277–281. Hallin RG (1990). Microneurography in relation to intraneural topography: somatotopic organisation of median nerve fascicles in humans. J Neurol Neurosurg Psychiatry 53: 736–744. Hallin RG, Torebjörk HE (1974). Methods to differentiate electrically induced afferent and sympathetic C unit responses in human cutaneous nerves. Acta Physiol Scand 92: 318–331. Hallin RG, Wu G (2001). Fitting pieces in the peripheral nerve puzzle. Exp Neurol 172: 482–492. Hallin RG, Wu G (2002). Novel information on peripheral tactile mechanisms in man acquired with concentric needle electrode microneurography. Behav Brain Res 135: 11–18. Hallin RG, Ekedahl R, Frank O (1991). Segregation by modality of myelinated and unmyelinated fibers in human sensory nerve fascicles. Muscle Nerve 14: 157–165. Hensel H (1973). Cutaneous thermoreceptors. In: Iggo A (Ed.) Handbook of Sensory Physiology. Springer Verlag, Berlin, p. 79. Hensel H (1976). Correlations of neural activity and thermal sensation in man. In: Zotterman Y (Ed.) Sensory Functions of the Skin in Primates. Pergamon Press, Oxford, pp. 331–352. Jänig W, Levine JD, Michaelis M (1996). Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma. Prog Brain Res 113: 161–184. Järvilehto T, Hämälainen H (1979). Touch and thermal sensations: psychophysical observations and unit activity in human skin nerves. In: Kenshalo DR (Ed.) Sensory Functions of the Skin in Humans. Plenum Publishing, New York, p. 279. Jørum E, Lundberg LER, Torebjörk HE (1989). Peripheral projections of nociceptive unmyelinated axons in the peroneal nerve. J Physiol 416: 291–301. Koltzenburg M, Koerber RH (2002). Diversity of nociceptors – which are important for the generation of clinically relevant persistent pains? In: Proceedings of 10th World Congress on Pain. IASP, Seattle, WA, p. 710. Koltzenburg M, Handwerker HO, Torebjörk HE (1993). The ability of humans to localise noxious stimuli. Neurosci Lett 150: 219–222. Konietzny F (1984). Peripheral neural correlates of temperature sensations in man. Hum Neurobiol 3: 21–32. Konietzny F, Hensel H (1975). Letters and notes: warm fiber activity in human skin nerves. Pflugers Arch 359: 265–267. Mackel R (1985). Human cutaneous mechanoreceptors during regeneration: physiology and interpretation. Ann Neurol 18: 165–172.
MICRONEUROGRAPHY IN THE ASSESSMENT OF NEUROPATHIC PAIN Mackel R (1989). Properties of cutaneous afferents in diabetic neuropathy. Brain 112: 1359–1376. Mackel R, Brink E (2003). Conduction of neural impulses in diabetic neuropathy. Clin Neurophysiol 114: 248–255. Mackel R, Brink EE, Wittkowsky G (1985). Properties of cutaneous mechanosensitive afferents during the early stages of regeneration in man. Brain Res 329: 49–69. Mackel R, Brink E, Jørum E, Aisen M (1994). Properties of cutaneous afferents during recovery from Guillain–Barré syndrome. Brain 117: 169–183. McGlone F, Kelly E, Trulsson M, Francis S, Westling G, Bowtell R (2002). Functional neuroimaging studies of human somatosensory cortex. Behav Brain Res 135: 147. McMahon SB (1991). Mechanisms of sympathetic pain. Br Med Bull 47: 584–600. Meyer RA, Campbell JN (1981). Evidence for two distinct classes of unmyelinated nociceptive afferents in monkey. Brain Res 224: 149–152. Mogyoros I, Bostock H, Burke D (2000). Mechanisms of paresthesias arising from healthy axons. Muscle Nerve 23: 310–320. Moore CE, Schady W (2000). Investigation of the functional correlates of reorganization within the human somatosensory cortex. Brain 123: 1883–1895. Mørk C, Asker CL, Salerud EG, Kvernebo K (2000). Microvascular arteriovenous shunting is a probable pathogenetic mechanism in erythromelalgia. J Invest Dermatol 114: 643–646. Nordin M (1990). Low-threshold mechanoreceptive and nociceptive units with unmyelinated (C) fibers in the human supraorbital nerve. [Published erratum appears in J Physiol (Lond) 1991, 444: 777.] J Physiol 426: 229–240. Nyström B, Hagbarth KE (1981). Microelectrode recordings from transected nerves in amputees with phantom pain. Neurosci Lett 27: 211–216. Ochoa J, Torebjörk HE (1980). Paresthesia from ectopic impulse generation in human sensory nerves. Brain 103: 835–853. Ochoa J, Torebjörk HE (1983). Sensations evoked by intraneural microstimulation of single mechanoreceptor units innervating the human hand. J Physiol 342: 633–654. Ochoa JL, Torebjörk HE (1989). Sensations evoked by intraneural microstimulation of C nociceptor fibers in human skin nerves. J Physiol 415: 583–599. Olausson H, Lamarre Y, Backlund H, Morin C, Wallin BG, Starck G, Ekholm S, Strigo I, Worsley K, Vallbo AB, Bushnell MC (2002). Unmyelinated tactile afferents signal touch and project to insular cortex. Nat Neurosci 5: 900–904. Ørstavik K, Weidner C, Schmidt R, Schmelz M, Hilliges M, Jørum E, Handwerker H, Torebjörk E (2003). Pathological C-fibers in patients with a chronic painful condition. Brain 2003: 126: 567–578. Ørstavik K, Mørk C, Kvernebo K, Jørum E (2004). Pain in primary erythromelagia – a neuropathic component? Pain 110: 531–538. Peng YB, Ringkamp M, Campbell JN, Meyer RA (1999). Electrophysiological assessment of the cutaneous arborization of Adelta-fiber nociceptors. J Neurophysiol 82: 1164–1177.
437
Raja SN (1995). Role of the sympathetic nervous system in acute pain and inflammation. Ann Med 27: 241–246. Ringkamp M, Peng YB, Campbell JN, Meyer RA (1997). Intradermal capsaicin produces a vigorous discharge in mechanically-insensitive A-fiber nociceptors of the monkey. Soc Neurosci Abstr 23 (part 2): 1258. Rosen L, Ostergren J, Fagrell B, Stranden E (1988). Skin microvascular circulation in the sympathetic dystrophies evaluated by videophotometric capillaroscopy and laser doppler fluxmetry. Eur J Clin Invest 18: 305–308. Rowe MJ (2002). Synaptic transmission between single tactile and kinaesthetic sensory nerve fibers and their central target neurones. Behav Brain Res 135: 197–212. Sandroni P, Davis MDP, Harper M (1999). Neurophysiologic and vascular studies in erythromelalgia: a retrospective study. J Clin Neuromusc Dis 1: 57–63. Schady WJ, Torebjörk HE (1983). Projected and receptive fields: a comparison of projected areas of sensations evoked by intraneural stimulation of mechanoreceptive units, and their innervation territories. Acta Physiol Scand 119: 267–275. Schady W, Ochoa JL, Torebjörk HE, Chen LS (1983a). Peripheral projections of fascicles in the human median nerve. Brain 106: 745–760. Schady WJ, Torebjörk HE, Ochoa JL (1983b). Cerebral localisation function from the input of single mechanoreceptive units in man. Acta Physiol Scand 119: 277–285. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE (1997). Specific C-receptors for itch in human skin. J Neurosci 17: 8003–8008. Schmelz M, Schmidt R, Handwerker HO, Torebjörk HE (2000a). Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibers. Brain 123: 560–571. Schmelz M, Michael K, Weidner C, Schmidt R, Torebjörk HE, Handwerker HO (2000b). Which nerve fibers mediate the axon reflex flare in human skin? Neuroreport 11: 645–648. Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjörk HE, Handwerker HO (2003a). Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 89: 2441–2448. Schmelz M, Hilliges M, Schmidt R, Ørstavik K, Vahlquist C, Weidner C, Handwerker HO, Torebjörk HE (2003b). Active “itch fibers” in chronic pruritus. Neurology 61: 564–566. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjörk E, Handwerker HO (1995). Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 15: 331–341. Schmidt R, Schmelz M, Ringkamp M, Handwerker H, Torebjörk HE (1997). Innervation territories of mechanically activated C nociceptor units in human skin. J Neurophysiol 78: 2641–2648. Schmidt R, Schmelz M, Torebjörk HE, Handwerker HO (2000). Mechano-insensitive nociceptors encode pain by tonic pressure to human skin. Neuroscience 98: 793–800. Schmidt R, Schmelz M, Weidner C, Handwerker H, Torebjörk HE (2002). Innervation territories of mechanoinsensitive C nociceptors in human skin. J Neurophysiol 88: 1859–1866.
438
E. JØRUM AND M. SCHMELZ
Serra J, Campero M, Ochoa J, Bostock H (1999). Activitydependent slowing of conduction differentiates functional subtypes of C fibers innervating human skin. J Physiol 515: 799–811. Serra J, Campero M, Bostock H, Ochoa J (2004). Two types of C-nociceptors and their behavior in areas of capsaicininduced secondary hyperalgesia. J Neurophysiol 91: 2770–2781. Susser E, Sprecher E, Yarnitsky D (1999). Paradoxical heat sensation in healthy subjects: peripherally conducted by A delta or C fibers? Brain 122: 239–246. Thomas CK, Westling G (1995). Tactile unit properties after human cervical spinal cord injury. Brain 118: 1547–1556. Thunberg T (1896). Förnimmelserne vid till samma ställe lokaliserad samtidigt pägäende köld och värmeretning. Uppsala Läkfören Förh 1: 489–495. Torebjörk HE (1974). Afferent C units responding to mechanical, thermal and chemical stimuli in non-glabrous skin. Acta Physiol Scand 92: 374–390. Torebjörk HE, Hallin RG (1976). Skin receptors supplied by unmyelinated (C) fibers in man. In: Zotterman Y (Ed.) Sensory Functions of the Skin in Primates. Pergamon Press, Oxford, UK, pp. 475–485. Torebjörk HE, LaMotte RH, Robinson CJ (1984). Peripheral neural correlates of magnitude of cutaneous pain and hyperalgesia: simultaneous recordings in humans of sensory judgements of pain and evoked responses in nociceptors with C-fibers. J Neurophysiol 51: 325–339. Torebjörk HE, Vallbo AB, Ochoa JL (1987). Intraneural microstimulation in man. Its relation to specificity of tactile sensations. Brain 110: 1509–1529. Torebjörk HE, Wahren L, Wallin G, Hallin R, Koltzenburg M (1995). Noradrenaline-evoked pain in neuralgia. Pain 63: 11–20. Trulsson M, Francis ST, Kelly EF, Westling G, Bowtell R, McGlone F (2001). Cortical responses to single mechanoreceptive afferent microstimulation revealed with fMRI. Neuroimage 13: 613–622.
Vallbo ÅB, Hagbarth KE (1968). Activity from skin mechanoreceptors recorded percutaneously in awake human subjects. Exp Neurol 21: 270–289. Vallbo AB, Hagbarth KE, Torebjörk HE, Wallin BG (1979). Somatosensory, proprioceptive and sympathetic activity in human peripheral nerves. Physiol Rev 59: 919–957. Vallbo AB, Olausson H, Wessberg J, Norrsell U (1993). A system of unmyelinated afferents for innocuous mechanoreception in the human skin. Brain Res 628: 301–304. Vallbo AB, Olausson H, Wessberg J, Kakuda N (1995). Receptive field characteristics of tactile units with myelinated afferents in hairy skin of human subjects. J Physiol 483: 783–795. Vallbo AB, Olausson H, Wessberg J (1999). Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin. J Neurophysiol 81: 2753–2763. Wall PD, McMahon SB (1985). Microneuronography and its relation to perceived sensation. A critical review. Pain 21: 209–229. Wallin BG, Torebjörk HE, Hallin R (1976). Preliminary observations on the pathophysiology of hyperalgesia in the causalgic pain syndrome. In: Zotterman Y (Ed.) Sensory Functions of the Skin in Primates, with Special Reference to Man. Pergamon Press, Oxford, UK, pp. 489–502. Weidner C, Schmelz M, Schmidt R, Hansson B, Handwerker HO, Torebjörk HE (1999). Functional attributes discriminating mechano-insensitive and mechano-responsive C nociceptors in human skin. J Neurosci 19: 10184–10190. Wu G, Ekedahl R, Stark B, Carlstedt T, Nilsson B, Hallin RG (1999). Clustering of Pacinian corpuscle afferent fibers in the human median nerve. Exp Brain Res 126: 399–409. Yarnitsky D, Ochoa JL (1991). Warm and cold specific somatosensory systems. Psychophysical thresholds, reaction times and peripheral conduction velocities. Brain 114: 1819–1826.