1 Academic GI Science Unit, University of Manchester, Hope Hospital, Salford, M6 8HD; 2 Clinical Neurophysiology Unit, Aston University, Birmingham B4 7ET; and 3 Neuroimaging Research Group, Institute of Psychiatry, London SE5 8AF, United Kingdom
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ABSTRACT |
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The aim of this study was to compare the
characteristics of esophageal cortical evoked potentials (CEP)
following electrical and mechanical stimulation in healthy subjects to
evaluate the afferents involved in mediating esophageal sensation.
Similarities in morphology and interpeak latencies of the CEP to
electrical and mechanical stimulation suggest that they are mediated
via similar pathways. Conduction velocity of CEP to either electrical or mechanical stimulation was 7.9-8.6 m/s, suggesting mediation via thinly myelinated A-fibers. Amplitudes of CEP components to
mechanical stimulation were significantly smaller than to electrical stimulation at the same levels of perception, implying that electrical stimulation activates a larger number of afferents. The latency delay
of ~50 ms for each mechanical CEP component compared with the
corresponding electrical CEP component is consistent with the time
delay for the mechanical stimulus to distend the esophageal wall
sufficiently to trigger the afferent volley. In conclusion, because the
mechanical and electrical stimulation intensities needed to obtain
esophageal CEP are similar and clearly perceived, it is likely that
both spinal and vagal pathways mediate esophageal CEP. Esophageal CEP
to both modalities of stimulation are mediated by myelinated
A
-fibers and produce equally robust CEP responses. Both techniques
may have important roles in the assessment of esophageal sensory
processing in health and disease.
esophagus; spinal afferents; vagal afferents; electrical stimulation; mechanical stimulation
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INTRODUCTION |
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FUNCTIONAL GASTROINTESTINAL disorders such as irritable bowel syndrome and noncardiac chest pain affect between 10 and 20% of the general population (37). Despite their high prevalence, the pathophysiology of these conditions is unknown. One of the most common clinical findings in these patients is hypersensitivity to visceral stimulation (30). The mechanisms responsible for this visceral hypersensitivity remain unclear; however, it has been postulated that symptoms are due to either hypersensitive gut afferent nerves or abnormal cortical processing of visceral sensation (30). Until recently, the lack of suitable noninvasive neurophysiological techniques to assess brain-gut interactions has prevented investigation of either possibility.
Cortical evoked potentials (CEP) are the electrical manifestation of the brain's response to an external stimulus. They are recorded via electrodes placed on the scalp and represent the sequence of negative and positive voltage changes generated in the brain following the arrival of a sensory stimulus (29). Initial CEP components reflect the characteristics of afferent pathways, whereas subsequent components relate to specific steps in cortical sensory processing. The technique is used routinely in clinical practice to assess the integrity of auditory, visual, and somatosensory systems (10, 12, 18). CEP may also be recorded following stimulation of the gastrointestinal tract (3, 4, 8, 15), which allows objective assessment of the mechanisms of human visceral sensation in health and disease.
CEP have been successfully recorded in response to both electrical and mechanical stimulation of the esophagus (3, 8, 15, 16, 21, 23). However, exactly by what route the afferents that mediate esophageal CEP pass to the brain remains controversial. This is because the esophagus receives dual sensory innervation from both vagal and spinal afferents (34, 35). Some investigators have speculated that the vagus is the sole mediator of esophageal CEP (24, 25) because CEP acquired in response to direct vagal stimulation have a similar morphology to esophageal CEP (38). Furthermore, CEP acquired in patients with a spinal cord injury are similar to those acquired in normal subjects, suggesting that intact spinal pathways are not necessary to elicit esophageal CEP (13).
We have provided evidence for the involvement of spinal afferents in the mediation of esophageal CEP because topographic mapping studies indicated that the cortical source of the early CEP component was in the primary somatosensory cortex (3), which only receives spinal and not vagal afferents. These findings have now been supported further by both magnetoencephalography (17) and positron emission tomography studies (2).
Further debate surrounds the fiber types that mediate esophageal CEP to
different stimulation modalities. Several authors have suggested that
CEP to electrical stimulation are mediated by thinly myelinated
A-fibers (15, 26), whereas CEP to balloon distension are mediated via slower conducting, unmyelinated C-fibers (23, 36). This has been based on estimations
of the conduction velocity of the response and by the fact that the
latency of CEP components following electrical stimulation is
significantly shorter than following mechanical stimulation. However,
the methodologies used by different groups to acquire esophageal CEP
differ considerably, and this may very well have contributed to the
variability in the reported CEP data between different groups.
We have recently established the optimal stimulation and recording parameters for recording esophageal CEP to both electrical and mechanical stimulation and have shown that it is possible to record highly reproducible CEP to both stimulation modalities (21, 22). To date, however, a direct comparison of CEP using these optimal parameters with both techniques in the same subjects has not been performed. It was therefore the aim of this study to compare the characteristics of the cortical responses elicited by electrical and mechanical stimulation of the healthy human esophagus in the same subjects and to use this information to evaluate the afferents that mediate esophageal sensation.
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METHODS |
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Subjects
We recruited healthy volunteers free of any gastrointestinal, cardiac, or neurological disorders, none of whom was taking any medication at the time of the study. Informed written consent was obtained from all volunteers, and The Salford Area Health Authority Ethics Committee approved the experimental protocols. Standard esophageal manometry was performed on each volunteer to exclude any esophageal motor disorder and to identify the distance between the lower esophageal sphincter (LES) and the incisors.Esophageal Mechanical Stimulation
Mechanical stimulation of the esophagus was performed using a 2-cm-long silicone balloon (Medasil Surgical, Leeds, UK) sited 10 cm from the tip of a polyvinyl catheter (4-mm diameter; Cook UK, Letchworth, UK). The balloon was connected to a specially constructed pump (Medical Physics Department, Hope Hospital, Salford, UK) that was capable of rapidly distending the balloon. The maximum flow rate produced by the pump was 200 ml/s, and the rise time to maximum balloon inflation remained constant (165 ms) for any given volume. The balloon volume was controlled using a dial on the front of the pump that allowed the pressure in the system to be regulated (pressure range = 0-25 psi). Increasing the pressure in the system increased the flow rate in the air lines, and therefore a greater volume was delivered during the inflation cycle. The balloon was allowed to deflate immediately after maximum inflation. In vitro, the pump was capable of delivering a maximum balloon volume of 30 ml. To mask the noise of the pump, the subjects wore headphones connected to a white-noise generator (65-db output; Medical Physics Department, Hope Hospital) The pump was triggered using a laboratory interface (CED 1401plus, Cambridge Electronic Design, Cambridge, UK).Esophageal Electrical Stimulation
Electrical stimulation of the esophagus was performed using a pair of platinum bipolar ring electrodes (2-mm electrodes with an interelectrode distance of 1 cm) sited 5 cm from the tip of an intraluminal catheter (external diameter = 3 mm). The catheter was constructed from nylon tubing covered with stainless steel braid and sheathed in silicone rubber (Gaeltec, Dunvegan, UK) The electrodes were connected to a constant-current, high-voltage stimulator (Model DS7; Digitimer, Welwyn Garden City, UK). The stimulator was triggered using a laboratory interface (CED 1401plus). The interelectrode impedance was monitored throughout, and a value of <10 kCEP Recording
CEP were recorded using two Ag-AgCl surface electrodes, which were applied to the scalp with electrode paste (Elefix, Nihon Kohden, Japan). With the use of the international 10-20 system of electroencephalograph electrode placement (27), the active electrode was positioned at Cz (vertex) and the reference electrode was positioned on the left ear lobe. An additional ground electrode was positioned on the neck. Recordings were performed in a quiet room with the subject semirecumbent, awake with eyes open, and asked to minimize eye movements and swallowing.The data were acquired using a CED 1902 programmable signal conditioner
(Cambridge Electronics Design). Display and analysis utilized the
SIGAVG program v. 6.04 and Signal for Windows v. 1.72 (Cambridge
Electronic Design). The amplifier gain was set at 100,000, and the
recording sensitivity was 25 µV. The bandpass filter settings were
1-100 Hz, and a 50-Hz notch filter was utilized, if needed, to
reduce interference from the main electrical supply. The sampling rate
was 2,000 Hz, and the recording epoch was 1 s in duration. The
first 200 ms of the epoch was prestimulation time. Each individual
epoch was saved, and the average of the run could be viewed during
acquisition. An automatic artifact rejection facility was employed to
prevent contamination from eye blinks and swallows. Before each
recording, scalp electrode impedance was reduced to <3 k by
applying a preparation paste (Omniprep, Weaver & Aurora).
Experimental Protocols
Experiment 1: CEP characteristics. To compare the characteristics of CEP obtained to mechanical and electrical stimulation, we studied six healthy volunteers (5 male, 1 female; mean age = 31.6 yr, age range = 21-47 yr). At the beginning of the study, the catheter was passed perorally into the esophagus and positioned so that the electrodes or the midballoon level was 5 cm above the LES.
CEP MORPHOLOGY. CEP to electrical and mechanical stimulation were recorded from each of the six subjects on separate days, within the same week, using the average of 200 stimuli acquired in 4 runs of 50 stimuli. A 10-min rest period was left between each run. Stimulation was performed at a frequency of 0.2 Hz and at an intensity that was 75% of the subjects' maximum tolerated value. The parameters used were selected on the basis of our previous work to provide optimal CEP responses (21, 22). EFFECT OF STIMULATION INTENSITY. To demonstrate the effect of stimulation intensity on the characteristics of the CEP response to electrical and mechanical stimulation, the average of 200 stimuli were acquired at 5 stimulation intensities ranging from sensory threshold to pain threshold in 3 subjects (2 male, 1 female; mean age = 37 yr, age range = 39-47 yr) and the data were compared. Sensory threshold was labeled as 0% and maximum tolerated intensity as 100%. Stimulation intensities that were 25, 50, and 75% of the difference between sensory threshold and maximum tolerated intensity were then identified. For example, if sensory threshold was reported at 30 mA and maximum tolerated intensity at 70 mA, then 25, 50, and 75% were calculated as 40 mA, 50 mA, and 60 mA, respectively. This method has been validated in our previous work (21, 22). REPRODUCIBILITY. The robustness of each CEP component for electrical and mechanical stimulation was assessed by comparing data in three subjects (2 male, 1 female; mean age = 37 yr, age range = 39-47 yr). CEP were acquired using the optimal stimulation parameters described above on three separate occasions, at least two days apart, at the same time of the day, for each modality.Experiment 2: CEP conduction velocity. To estimate the conduction velocity of the pathways involved in the mediation of electrical and mechanical CEP, we studied 6 healthy volunteers (5 male, 1 female; mean age = 31.6 yr, age range = 21-47 yr). CEP to electrical and mechanical stimulation were recorded on separate days, within the same week, at 5 cm and 15 cm above the LES. The same recording and stimulation parameters were used as described in experiment 1A. Stimulation intensity was first determined at the distal site, and the same intensity was then used for the proximal site.
Definition of Terms
Latency is the interval between the onset of the stimulus and the peak of each potential. Values are expressed in milliseconds.Amplitude is the potential difference between the maximal positive and the maximal negative deflection. Values are expressed in microvolts.
Interpeak latency is the interval between consecutive peaks. Values are expressed in milliseconds.
Sensory threshold is the intensity at which a stimulus was first perceived. Maximum tolerated intensity is the lowest stimulation intensity at which the subject described pain.
Data Analysis
All recordings are displayed using common neurophysiological convention, i.e., a negative potential is displayed as an upward deflection. For each experimental protocol, the average CEP to 200 stimuli were analyzed.Experiment 1A. Group mean values for amplitude and latency were calculated for both modalities and compared. The difference between the latency of each CEP component for each stimulation modality was calculated by subtracting the latency of the mechanical component from that of the corresponding electrical component. Electrical and mechanical CEP acquired in the same subject were superimposed to compare morphology.
Experiment 1B. For each stimulation modality, group mean values were calculated for amplitude and latency of each component at each of the five intensities. Data are displayed as group means ± SD.
Experiment 1C. Intrasubject variability was assessed by comparing values for amplitude and latency in each individual on three separate occasions for each modality. Intersubject variability was assessed by comparing values for amplitude and latency across all three individuals for each occasion for both modalities.
Experiment 2. The latency of the first positive (P1) component was compared for CEP elicited via both modalities at 5 cm and 15 cm above the LES. The latency difference between the two sites allowed the conduction velocity of the response to be calculated. Values are displayed as group means ± SD and expressed in meters per second.
Statistical Analysis
Descriptive statistical analysis was performed using Arcus Quickstat (Biomedical version 1.0; Addison Wesley Longman, Research Solutions). In experiment 1 we used a Shapiro-Wilk test for normality and a paired two-tailed Student's t-test. We calculated the coefficient of variance of the values for amplitude and latency in experiment 1C to demonstrate intra- and intersubject variability of CEP components. ![]() |
RESULTS |
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Perception of Stimuli by Subjects
Electrical stimulation was described as a sharp, nonpainful pulse felt retrosternally. Mechanical stimulation was felt as a strong, nonpainful pulse retrosternally, duller in nature and more long lasting. Triphasic CEP were recorded in response to both stimulation modalities in all subjects. An illustrative example of these responses in one subject is shown in Fig. 1. The three components seen consistently were labeled P1 (first positive), N1 (first negative), and P2 (second negative).
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Experiment 1
Experiment 1A: CEP characteristics.
All values for peak latency, amplitude, and interpeak latency are
shown in Table 1. The morphology of the
CEP response was similar in all subjects, with the P1-N1-P2 complex
being present in each subject for both modalities (Fig.
2).
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Experiment 1B: stimulation intensity.
The latency of CEP components decreased and their amplitude
increased as stimulation intensity increased both for electrical and
mechanical stimulation (Figs. 3,
4, and
5).
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Experiment 1C: reproducibility.
The intra- and intersubject variability of the latency of CEP
components was similar for both modalities (Table
2). For electrical stimulation, the
intersubject coefficient of variance was <0.1 for all three
components. For mechanical stimulation, the intersubject coefficient of
variance was <0.1 for the P1 and N1 components, but the P2 component
showed a variability of 0.2. Intra- and intersubject amplitude
variability was more pronounced (40-60%) but similar for each
modality.
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Experiment 2: CEP Conduction Velocity
The conduction velocity of the CEP response was 7.9 ± 1.9 m/s for mechanical stimulation and 8.6 ± 2.3 m/s for electrical stimulation. ![]() |
DISCUSSION |
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The results of our study show that the morphology, interpeak latencies, and conduction velocity of CEP responses to both electrical and mechanical stimulation are similar. This implies that similar neural pathways and cortical processing are likely to be involved in the mediation of both mechanical and electrical CEP. There were, however, significant differences in the peak latencies and amplitudes of CEP components elicited by the two modalities.
There is currently a debate in the literature about the nature of the afferents that mediate esophageal CEP. Some authors (23, 38) have suggested that CEP to both electrical and mechanical stimulation are mainly mediated via vagal afferents, because CEP elicited by electrical stimulation of the esophagus and direct vagal stimulation in humans have a similar morphology. However, there are several reasons to question this assertion. First, it has been shown that, due to the close proximity of the vagal electrodes to the surrounding somatic tissue, stimulation of somatic afferents also occurs because the desired signal can often be contaminated by myogenic potentials (20). It is therefore likely that somatic spinal afferents also contribute to the CEP responses described. Second, CEP with similar morphology can be obtained following electrical stimulation of the esophagus and the skin over the anterior chest wall (16). Because stimulation of the skin will activate spinal afferents, it could therefore be similarly argued that spinal afferents are involved in the mediation of esophageal CEP.
Further evidence used to support the vagal afferent route is the finding that esophageal CEP to mechanical stimulation in patients with a C6/C7 spinal cord injury were similar to those seen in normal subjects (13). However, as the animal data suggest (11, 19) and the authors themselves concluded, this may only mean that a C6/C7 spinal cord lesion does not interrupt all the spinal afferents that mediate esophageal sensation (13).
The arguments in favor of a spinal afferent route for esophageal perception and pain are based mainly on animal data that show that vagal afferents saturate at low intensities, whereas spinal afferents respond to intensities ranging from subthreshold to nociception (32, 34, 35). Furthermore, our previous work has shown that stimulus perception and CEP thresholds are identical to both mechanical and electrical stimulation (21, 22) and that CEP amplitudes increase and latencies decrease with increasing stimulus intensity (21, 22, 24, 36). In this study we have demonstrated that this relationship between stimulation intensity and the amplitude and latency of CEP is consistent for both modalities. Since thresholds for activation of spinal and vagal afferents appear to be similar (32), it seems implausible that the strongly perceived stimulation intensities needed to elicit reproducible CEP would preferentially activate only vagal or spinal pathways.
Studies of the central processing of human esophageal sensation using functional brain imaging techniques such as positron emission tomography (2) and magnetoencephalography (17) have demonstrated that both nonnociceptive and nociceptive esophageal stimulation activate the primary somatosensory cortex, an area that receives projections from spinal but not vagal afferents (9). In addition, however, the studies also show activation of the insula and the limbic cortices, brain areas that receive both spinal and vagal projections. Therefore, it is likely that both vagal and spinal pathways contribute to the esophageal CEP responses to electrical and mechanical stimulation. The fact that the morphology and the interpeak latencies of CEP to both modalities were similar strongly supports the argument that they are mediated by similar pathways.
The longer latencies of CEP components to mechanical compared with
electrical stimulation has led some authors to suggest that the two
responses are mediated via different afferent fiber types
(23, 36). In addition, several groups have
looked at the conduction velocity of CEP by stimulating two esophageal
sites (14, 15, 23). All studies
using electrical stimulation have shown that esophageal CEP are
mediated by afferents with conduction velocities between 7 and 11 m/s,
indicating mediation by thinly myelinated A-fibers (15,
23). However, studies using mechanical stimulation have
shown that afferents with conduction velocities that range from 1.7 to
8 m/s mediate esophageal CEP, implicating either unmyelinated C- or
A
-fibers (14, 23).
There are, however, several other explanations for the apparent differences between conduction velocities for mechanical and electrical CEP. First, the inflation pump used in the studies by Hollerbach et al. (23) and DeVault et al. (14) had a flow rate of 170 ml/s. Because the flow rate was constant, the rise time to maximum inflation for different balloon volumes was variable; a 1-ml difference in the eventual balloon volume would therefore produce a 6-ms difference in rise time. Because balloon volumes required to induce similar sensory endpoints at the two esophageal stimulation sites differed, and because the rise time of balloon inflation was variable, using the peak latencies to estimate conduction velocity will give an inaccurate estimation of the true conduction velocity. Second, the proximal esophageal stimulation site used in these two studies was almost certainly within the striated muscle portion of the esophagus (28). Because there are differences in the innervation and cortical projections of striated and smooth muscle esophagus (3, 17, 28), comparing data from the proximal and distal sites to calculate conduction velocities may not be valid.
We attempted to control for these variables by keeping the rise time to
maximum balloon inflation constant for any given volume and using the
same stimulation intensity at both esophageal sites. In addition, the
two sites we stimulated within the esophagus are both within the smooth
muscle portion of the esophageal body (28). The conduction
velocities obtained using these parameters were 7.9 ± 1.9 m/s for
mechanical stimulation and 8.6 ± 2.3 m/s for electrical
stimulation, indicating that the first CEP component (P1) for both
stimulation modalities is probably mediated via myelinated A-fibers.
This is not to say that unmyelinated C-fibers are not also activated by
mechanical and electrical stimulation. Indeed, animal studies show that
both A- and C-fibers are present in spinal and vagal afferents, and
both have similar thresholds of activation to esophageal distension
(32). However, because A
-fibers have faster conduction
velocities, it would be expected that they would mediate the first CEP potential.
Studies of somatosensory CEP elicited by laser stimulation have shown
that it is extremely difficult to record reliable cortical responses to
pure C-fiber stimulation due to the enormous latency jitter of
C-fiber-evoked cortical responses (1,
5-7, 39). The first laser-evoked
cortical potential components are mediated by A-fibers occurring at
a latency of 240-370 ms (6). The C-fiber-mediated
components, known as ultra-late components, that occur between 1,050 and 1,250 ms are not apparent without blockade of A
-fiber
transmission (6). The C-fiber-mediated CEP components have
a standard deviation of 150 ms, which makes conventional signal-averaging techniques ineffective and requires the use of an
iterative latency correction filter (40). This makes it
unlikely that esophageal CEP we recorded without blockade of A
afferents and with conventional signal averaging are primarily mediated by C-fibers in humans.
A further reason why C-fiber transmission of the CEP responses is unlikely is because the latency difference of the P1 components to electrical and mechanical stimulation, which in our study was consistently 50 ms, is much less than would be expected if mechanical stimulation was mediated only via unmyelinated C-fibers. Our data lead us to suggest that the differences in the P1 latencies can be explained simply and adequately by differences in time between triggering of stimulation onset and the development of an adequate esophageal stimulus. In the case of electrical stimulation, this delay will be very short; for mechanical stimulation the delay will be much longer because the mechanical pump has to deliver sufficient air into the intraluminal balloon for esophageal distension to occur and for the esophageal distension to then induce afferent neural activation. The fact that the latency differences between the two modalities were similar for all three CEP components indicates that all of the components are probably responsive to the initial afferent volley arriving at the cortex and that the later components probably represent secondary cortical processing of the initial afferent volley and not activation of different fiber types.
The differences in amplitude of CEP components to electrical and mechanical stimulation in our study are again consistent with the animal data. Although esophageal distension will activate only those afferents that are mechanosensitive, electrical stimulation will activate all afferents regardless of modality (32). Because the amplitude of the CEP components is directly related to the number of afferents contributing to the signal, then it would be expected that CEP to electrical stimulation would be larger than CEP to mechanical stimulation, as was found in our study.
These amplitude differences raise an intriguing potential for the application of CEP in the assessment of clinical disorders. It is known that a large proportion of afferent fibers [both myelinated and unmyelinated fibers (31-33)] are normally mechanoinsensitive in healthy subjects (silent nociceptors) and that some of these fibers become mechanically sensitive in conditions such as inflammation (32). Although electrical stimulation would be expected to activate all of these fibers regardless of modality and pathological condition, CEP components to mechanical stimulation may become enhanced only in injury, due to the recruitment of the additional, previously insensitive, afferent fibers. This may mean that changes in mechanical CEP could be used to monitor abnormalities in inflammatory conditions. Electrical CEP, on the other hand, might be better suited to detecting abnormalities in conditions in which visceral hypersensitivity is thought to occur as a result of central rather than peripheral sensitization.
In conclusion, we have shown evidence to indicate that CEP to
mechanical and electrical stimulation of the esophagus are mediated by
similar afferent pathways, most likely a combination of both vagal and
spinal afferents, and that the early components of the CEP to both
stimulation modalities are mediated via A-fibers. The combined use
of both may have an important role in the assessment of esophageal
sensory processing in disease states.
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ACKNOWLEDGEMENTS |
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We thank the members of Department of Medical Physics at Hope Hospital for their help in designing and constructing the equipment used in this study. Additional thanks go to Helen Navarro for her help in the preparation of this text.
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FOOTNOTES |
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Q. Aziz is a Medical Research Council Clinician Scientist.
Address for reprint requests and other correspondence: Q. Aziz, Academic GI Science Unit, Univ. of Manchester, Hope Hospital, Eccles Old Rd., Salford, M6 8HD, UK.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 14 October 1999; accepted in final form 9 February 2000.
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