Neuromodulation: Technology at the Neural Interface Received: August 8, 2013
Revised: September 11, 2013
Accepted: October 3, 2013
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12133
Innocuous Peripheral Nerve Stimulation Shifts Stimulus–Response Function of Painful Laser Stimulation in Man Dejan Ristić, PhD*†; Jens Ellrich, MD, PhD*†‡ Objectives: Electrical peripheral nerve stimulation (PNS) is discussed as an effective neuromodulatory treatment in chronic pain. This human experimental study hypothesized a rightward shift of stimulus–response function as a marker of antinociceptive and analgesic PNS effects. Materials and Methods: Innocuous electrical PNS of the left superficial radial nerve trunk evoked paresthesia on the left hand dorsum in 29 healthy volunteers. In this innervation area, laser stimulation was performed before, during, and after PNS. Ten different laser intensities ranging between perception and tolerance thresholds were applied. Cortical laser-evoked potentials (LEP) were recorded, and perceptual ratings were documented. Data were analyzed in low, medium, and high laser intensity categories. Stimulus–response functions were calculated. Laser detection and pain thresholds were interpolated. Results: Interpolated laser thresholds after logarithmic regression were not different from measured thresholds. Laser pain threshold increased during and after PNS. LEP amplitude decreased at medium and high intensities under PNS. Ratings transiently decreased during PNS at medium and high laser intensities. Conclusions: Modulation of laser pain threshold, perceptual ratings, and LEP indicates a rightward shift of stimulus–response function under PNS. These data emphasize antinociceptive and analgesic effects of PNS in an experimental human model and support its clinical neuromodulative relevance. Keywords: Electrophysiology, evoked potentials, laser, pain, psychophysics Conflicts of Interest: The authors reported no conflicts of interest.
INTRODUCTION
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Nociceptive processing can be inhibited by simultaneous excitation of tactile afferents at the same body site (1). This concept is known as “touch inhibits pain” and led to analgesic treatment of chronic pain by electrical stimulation of Aβ fibers via implanted electrodes (2–5). Peripheral nerve stimulation (PNS) is applied in patients with chronic pain syndromes mainly affecting the extremities (6,7) and the craniofacial region (8). Published PNS parameters like stimulation frequency and pulse duration ranged from 10 to 130 Hz and from 90 to 3000 μsec (9–12). The vast majority of clinical studies applied PNS with a frequency of approximately 100 Hz and pulse duration of about 200 μsec according to analgesic efficacy in patients (13). High-frequency stimulation (up to 10 kHz) for chronic pain treatment is a paresthesia-free method that probably bases upon a mode of action different from conventional PNS and, therefore, was not considered in the present study (14). Neuromodulative PNS has been applied for decades. However, with documented analgesic potency, its antinociceptive effects are still debated (15,16). Whereas analgesic effects were demonstrated in chronic pain patients by pain questionnaires (5,17), a clear proof of antinociception by objective parameters such as electrophysiological assessment in man is still missing. Modulation of nociceptive processing by simultaneous Aβ fiber stimulation in man was demonstrated in electrophysiological and psychophysical studies (13,18–20). Most studies focused on mechanisms of transcutaneous electrical nerve stimulation (TENS) but not www.neuromodulationjournal.com
on PNS. With PNS, a certain nerve trunk is specifically targeted. With TENS, cutaneous nerves of a certain area are stimulated. Preceding studies assessed effects of therapeutic PNS on vertex laser-evoked potentials (LEPs) and pain perception in healthy men (13,18). Electrical, innocuous conditioning stimulation of the superficial radial nerve mimicked therapeutic PNS and significantly reduced LEPs and pain perception. However, both studies focused on laser stimulation with only one fixed, clearly painful stimulus intensity. Possible effects of PNS on the complete pain stimulus–response function (SRF) are hypothesized but not shown yet.
Address correspondence to: Jens Ellrich, MD, PhD, Department of Health Science and Technology, Medical Faculty, Aalborg University, Fredrik Bajers Vej 7D2, Aalborg DK-9220, Denmark. Email: [email protected] * Experimental Neurosurgery Section, Department of Neurosurgery, RWTH Aachen University, Aachen, Germany; † Department of Health Science and Technology, Aalborg University, Aalborg, Denmark; and ‡ Institute of Physiology and Pathophysiology, University of ErlangenNuremberg, Erlangen, Germany For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1 Financial support: The study was funded by grants from the Interdisciplinary Center for Clinical Research of RWTH Aachen University (520507; Pain Research Group) and a PhD grant from Aalborg University.
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PNS SHIFTS PAIN STIMULUS–RESPONSE FUNCTION The present study addressed the neuromodulatory impact of electrical PNS on the perceptive spectrum covering a wide range of both nonpainful and painful sensations. It was hypothesized that conditioning electrical PNS of the superficial radial nerve provoked a rightward shift of SRF of nociception and pain elicited by laser stimulation in the corresponding cutaneous innervation area in man. The hypothesis was tested by psychophysical and electrophysiological means. Preliminary results of the study were presented as abstract (21).
MATERIALS AND METHODS Subjects Twenty-nine healthy volunteers (19 women, 10 men, 24.9 ± 0.7 years; mean ± standard error) participated in the study. Participants gave their informed consent prior to their inclusion in the study according to the 1964 Declaration of Helsinki (as amended by the 52nd General Assembly, Edinburgh, Scotland, 2000; http:// www.wma.net). The local ethics committee of RWTH Aachen University approved the protocol before the study began. Each experiment lasted approximately three hours. Volunteers were awake, relaxed with eyes closed, and sitting comfortably on a reclined chair. Exclusion criteria were presence of neurological disorders and drug usage. Adequate knowledge of the German language was essential for appropriate understanding of the instructions. The design of the present experimental model targets the clinical situation of standard PNS with implanted devices. The target nerve model had to meet the following requirements: 1) easy noninvasive access to the nerve trunk in order to apply transcutaneous, electrical, conditioning stimulation (quasi-PNS); 2) easy access to the corresponding cutaneous receptive field in order to apply painful, laser, test stimulation. The superficial radial nerve trunk was selected because of its accessibility by transcutaneous electrical stimulation and the cutaneous receptive field for noxious stimulation. In general, innocuous, electrical, conditioning stimulation of the left superficial radial nerve trunk at the forearm in healthy volunteers simulated neuromodulatory PNS treatment in pain patients. Ten distinct laser stimulus intensities were applied to the innervation area of the superficial radial nerve on the left hand dorsum from nonpainful to painful range. Volunteers rated perceived sensation after each laser stimulus on a verbal rating scale covering nonpainful and painful range. Laser stimulation was applied before, during, and after condition PNS.
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Laser Stimulation and Electroencephalogram Recording Painful heat test stimulation of the left hand by a laser (ThuliumYAG laser, Carl Baasel Lasertechnik, Starnberg, Germany) provided for selective excitation of Aδ and C fiber nociceptors in hairy skin inducing warm, heat, pricking, or burning painful sensations. The laser emitted infrared light of 2 μm wavelength for 1 msec duration. In order to avoid adaptation of nociceptors and skin reddening, the stimulation spot (5 mm diameter) varied from stimulus to stimulus within the innervation area of the superficial radial nerve on the left hand dorsum. Selective excitation of cutaneous nociceptors via laser stimulation generates a typical pattern of LEP recorded by electroencephalography. Late-latency LEP were recorded from positions Fz, Cz (vertex), and Pz vs. a left earlobe (A1) reference and middle-latency LEP at positions T3 and T4 vs. an Fz reference according to the international 10–20 system (band pass 0.08–30 Hz). In order to monitor artifacts derived from eye and lid movement, an electrooculogram of the right eye was recorded (band pass 0.01– 100 Hz). Laser detection threshold (LDT), laser pain threshold (LPT), and laser pain tolerance threshold (LTT) were determined with four series of descending and ascending intensities (23). LTT was defined as the maximal stimulus energy the subjects were willing to experience not exceeding a stimulus intensity of 800 mJ. Lowest applicable intensity was 110 mJ. Ten individual, equidistant intensities were chosen from the range between LDT and LTT according to following equation:
In1−10 = LDT + (n1−10 − 1) × (LT T − LDT ) ÷ 9 Laser stimuli were applied before (T0), during (T1), and after (T2) PNS (Fig. 1). Each stimulation series consisted of 50 stimuli. In each series, ten distinct laser intensities were applied five times in a pseudorandomized manner. In order to reduce habituation of LEP, laser stimuli occurred with variable interstimulus intervals between 8 and 12 sec. One and a half seconds after each laser stimulus, an audible signal prompted the volunteer to rate the laser-evoked sensation intensity (rating) according to a common ordinal scale (0: no perception, 1–39: nonpainful perception, 40–100: pricking painful). An interval of 15 min between laser stimulation series (T0, T1, T2) avoided intrinsic inhibition on LEP by habituation (Fig. 1). In two preceding studies, LEP amplitudes and latencies remained
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PNS Superficial local anesthesia of the skin above the left superficial radial nerve at the distal forearm was administered via plaster ® (EMLA -plaster, AstraZeneca GmbH, Wedel, Germany). Each plaster contained 25 mg lidocaine and 25 mg prilocaine with a skin contact area of about 27 cm2 and remained on the skin for one hour. This application time was shown to be sufficient to establish significant local anesthesia and short enough to avoid any affection of the adjacent superficial radial nerve trunk (22). Effectiveness of local anesthesia was monitored with von Frey hairs (mechanical detection) and pinprick stimulators (mechanical pain threshold) after one hour of plaster treatment. This procedure was demonstrated to minimize local excitation of cutaneous afferents by PNS and to provide for preferential activation of the nerve trunk without affecting radial nerve trunk function (13).
Conditioning nonpainful PNS was performed in healthy volunteers by electrical stimulation of the left superficial radial nerve trunk via two surface electrodes (5 mm diameter) with stimulus intensities sufficient for excitation of tactile Aβ fibers inducing tingling but no painful sensations in the dorsum of the left hand (rectangular pulse, 200 μsec, 100 Hz). PNS parameters were adjusted to values that resembled clinical PNS in chronic pain patients. Optimal stimulation site was found by using minimal electrical currents that caused maximal, nonpainful tingling paresthesia in the innervation area of the superficial radial nerve, which was determined via verbal report from each participant. This electrically evoked paresthetic area at the same time indicated the laser stimulation site (see below). The cathode position was proximal to the anode distal. Electrical stimuli were applied with a constant current stimulator (Model DS7A, Digitimer Limited, Hertfordshire, UK). The electrical detection threshold was determined under local skin anesthesia in four series of descending and ascending intensities (23). PNS intensity was adjusted to about twofold the individual detection threshold. Conditioning PNS lasted for 23 min (Fig. 1).
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Figure 1. Stimulation protocol. Laser stimuli were applied to the innervation area of left superficial radial nerve on the hand dorsum at time windows T0, T1, and T2. Conditioning innocuous electrical peripheral nerve stimulation (PNS) of the left superficial radial nerve lasted for 23 min and was applied in T1 section. Mechanical detection thresholds were determined before and after each laser stimulation series at laser stimulation site at time windows T0, T1, T2, and T3.
unchanged in three successive laser stimulation series within control groups with an identical laser stimulus protocol (13,18). In these former studies, inhibition of LEP was present exclusively within the PNS group. Whereas the former studies only investigated PNS effects on one fixed, painful laser intensity, the present study focused on the effect of neuromodulatory PNS on an extensive dose–response function under ipsilateral conditioning stimulation. Electrophysiological signals were recorded with the electroencephalogram (EEG) bioamplifier (VD32, Schwarzer, Munich, Germany), a converter (Power1401 A/D-converter, Cambridge Electronic Design Limited, Cambridge, UK; sampling rate 2000 Hz), and the Signal software (http://www.ced.co.uk). Within one laser stimulation series, five LEP sweeps per laser stimulus intensity were digitally filtered (low pass 20 Hz) and averaged. Averaged EEG data were processed with the matching pursuit algorithm (24–27) in order to eliminate further contamination of the LEP, for example, auditoryevoked potentials. Upward deflection of recorded LEP waveform was referred to as negativity (N), downward deflection as positivity (P). Latencies and amplitudes of ipsilateral N1 (T3: N1il), contralateral N1 (T4: N1cl), N2, and P2 LEP components as well as peak-topeak amplitude between N2 and P2 (N2P2 amplitude) were determined between 100 and 500 msec after laser stimulation. Within this experimental setup, previous studies reproducibly demonstrated constant ratings over time in control conditions (without PNS and with contralateral PNS) (13,18). As a direct continuation with an identical experimental setup besides the number of stimulus intensities, no additional control experiments were performed in this study.
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Mechanical Detection Threshold Mechanical detection threshold (MDT) was measured in the innervation area of the superficial radial nerve at the hand dorsum www.neuromodulationjournal.com
before and after each laser stimulation series (Fig. 1). MDT measurements were performed with von Frey filaments (OptiHair2, MARSTOCKnervtest, Marburg, Germany). Filaments of forces 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256, and 512 mN had rounded tips with a diameter of about 0.4 mm. MDT was determined by the method of limits starting with a clearly noticeable filament of 16 mN. MDT was defined as the geometric mean of five series of descending and ascending stimulus intensities. Afferent tactile processing evoked by mechanical stimulation with von Frey filaments interfered with electrical antidromic excitation of tactile fibers in the superficial radial nerve trunk by PNS. This peripheral collision caused increased MDT lasting for the time of electrical conditioning. Thus, the PNS effect could be validated by transiently increased MDT. Laser Threshold Interpolation and Statistical Analysis Mathematical regression was used to compare measured with calculated laser perception and pain thresholds. Stimulus intensities and the corresponding subjects’ ratings were used as the basis for logarithmic and linear regression. For the logarithmic interpolation of laser thresholds, the following equation was used with X as stimulus intensity, Y as corresponding rating, a as steepness, and Y0 as Y-axis intercept:
Y = Y0 + a × ln (X ) For linear interpolation of laser thresholds, the following equation was used:
Y = Y0 + a × X Interpolations were performed for ratings from all time windows for each subject. Ratings ≤30 and corresponding laser intensities
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PNS SHIFTS PAIN STIMULUS–RESPONSE FUNCTION were used for LDT interpolation and ratings >30 and corresponding laser intensities for LPT interpolation. From the derived individual functions, stimulus intensities producing a rating of 1 and 40 equaling laser perception and pain thresholds were interpolated and then compared with the initially measured laser thresholds. Initially, sigmoidal functions were applied, but the differences between measured and interpolated values were too large to be considered acceptable in contrast to logarithmic and linear regression. Data were described by arithmetic mean and standard error, by median, 5th, 25th, 75th, and 95th percentiles (box plot). Two-way repeated measures analysis of variance (ANOVA) with time window and laser stimulus intensity as factors served as main statistical analysis (EEG, ratings). Depending on data distribution, the statistical comparison within and between groups (including MDT, LDT, LPT) was performed via one-way repeated measures ANOVA (F and p value) or by Friedman repeated measures ANOVA (χ2 and p values). For post-hoc comparison, the Student-Newman-Keuls test (p value) was used. The Kolmogorov–Smirnov test was used to determine data distribution. The level of significance was set to p < ® 0.05. Only results with appropriate power (0.8) given by SigmaStat software 10.0 (SPSS Inc., Chicago, IL, USA) were considered.
RESULTS In all 29 trials, LEP and sensory thresholds were recorded. Two subjects were excluded from further analysis because N2 and P2 LEP components were not detectable under baseline conditions at T0. With absent cortical potentials under and after PNS, the values for the statistical analysis were set to 0 μV for LEP amplitudes and to 256 msec (N2), 395 msec (P2), 206 msec (N1cl), and 222 msec (N1il) as upper limits for LEP latencies. These upper limit values were derived from the sum of mean latency plus 2.5-fold the standard deviation collected in own laboratory. Latencies and amplitudes in the present study corresponded to values from other laboratories applying an infrared laser (28–30). Average LDT was 202 ± 11 mJ (mean ± standard error mean), average LPT 385 ± 12 mJ, and LTT 655 ± 12 mJ. These test stimulus intensities elicited single or mixed sensations of warmth, touch, heat, and pricking pain to burning pain in all participants. Conditioning PNS of the superficial radial nerve was conducted with a stimulus intensity of 2.5 ± 0.1 mA corresponding to 168 ± 5% of electrical detection threshold. The electrical stimulus intensity evoked nonpainful tingling sensations in the innervation area of the superficial radial nerve on the hand dorsum in all subjects. MDT underwent significant changes (Fig. 2). MDT increased under PNS (T1, 146.4 ± 31.2 mN) compared with all other time windows T0 (3.1 ± 0.9 mN, p < 0.05), T2 (7.3 ± 4.7 mN, p < 0.05), and T3 (2.9 ± 0.7 mN, p < 0.05).
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from measured thresholds. In consequence, logarithmic regression was systematically used for interpolation of LDT and LPT at all time windows. Logarithmic LDT remained unchanged before, during, and after PNS (Fig. 4a). Logarithmic LPTs differed from each other (Fig. 4b). Post hoc comparison revealed elevated LPT during and after PNS.
LEP Late vertex potentials (N2, P2) and middle-latency LEP components in temporal leads (N1il, N1cl) were recorded at time windows T0, T1, and T2 (Fig. 1). Because of low signal-to-noise ratio, data were pooled according to low (I1–4), medium (I5–7), and high intensities (I8–10). LEP latencies and amplitude corresponded to values from other laboratories using a laser (28–30).
N2P2 Amplitude and Late LEP Latencies (Fig. 5) Late vertex potentials were reproducibly elicited in all but two out of 29 volunteers before PNS (Fig. 5). In consequence, LEP, perceptual ratings, MDT, and interpolated laser thresholds from the remaining 27 subjects were analyzed. In one out of those 27 subjects, the N2 component was absent. Consequently, the N2P2 consisted of only the P2 amplitude in this case. The comparison of vertex potentials between laser stimulus intensity groups within the same time window showed increasing amplitudes with increased intensity at T0 (χ2 = 70.1, p < 0.001), T1 (χ2 = 38.0, p < 0.001), and T2 (F = 62.2, p < 0.001). Before (high intensity vs. all: p < 0.001; low vs. medium intensity: p < 0.01) and after PNS (high intensity vs. all: p < 0.001; low vs. medium intensity: p < 0.01), N2P2 differed from each other. During PNS, high intensity N2P2 differed from both other groups (each p < 0.05). Comparison between laser intensity groups at different time windows demonstrated significant differences for N2P2 amplitudes within medium and high intensities (Fig. 5). N2P2 amplitude was reduced under PNS and partially recovered after electrical conditioning.
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Interpolation of Laser Thresholds (Figs 3 and 4) ANOVA revealed significant differences in measured and interpolated LDT (Fig. 3a). Post-hoc comparison documented variation between linearly interpolated LDT from both measured LDT and logarithmically interpolated LDT. ANOVA revealed significant differences in measured and interpolated LPT (Fig. 3b). Post-hoc comparison of linearly interpolated LPT resulted in statistical difference of linearly interpolated LPT to both measured LPT and logarithmically interpolated LPT. Logarithmic regression produced interpolated LDT and LPT that were not significantly different
Figure 2. Mechanical detection threshold transiently increased under peripheral nerve stimulation (PNS). Mechanical detection threshold was measured before (T0) and after each laser stimulation series (T1, T2, T3) (N = 27). Data are shown as box plots (dotted line: arithmetic mean). χ2 and p values correspond to Friedman one-way repeated measures analysis of variance (ANOVA). Asterisks mark threshold differences as analyzed by Student-Newman-Keuls post hoc tests (*p < 0.05).
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Figure 3. Logarithmic interpolation resembled measured laser detection threshold (LDT) and laser pain threshold (LPT). Box plots (dotted line: arithmetic mean) show measured and interpolated laser thresholds. a. Comparison of measured laser detection thresholds with interpolated values from logarithmic and linear regression of ratings (≤30) and corresponding stimulus intensities at T0 (N = 29). b. Comparison of measured LPTs with interpolated values from logarithmic and linear regression of ratings (>30) and corresponding stimulus intensities at T0 (N = 29). χ2 and p values correspond to Friedman one-way repeated measures analysis of variance (ANOVA). Asterisks mark threshold differences as analyzed by Student-Newman-Keuls post hoc tests (*p < 0.05).
Values for N2 and P2 latencies are summarized in Table 1. Differences in N2 latency between time windows occurred at both medium and high intensities (Table 2). With medium intensities, N2 latency was transiently prolonged, whereas at high intensities N2 latencies only partially recovered after PNS accordingly to vertex potential. P2 latencies varied at high intensities between time windows (Table 2). Latencies were transiently prolonged during conditioning PNS.
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Ipsilateral and Contralateral N1 Latencies and amplitudes for N1il and N1cl are summarized in Table 1. All statistically significant effects occurred at medium and high laser intensities (Table 2). N1cl latency increased during and after PNS at medium intensities. At high intensities, N1cl latency prolonged transiently with PNS. At medium intensities, N1il latency increased during and after PNS as well. At high intensities, N1il latency increased during conditioning and partly recovered at T2. Middle-latency LEP amplitudes showed similar behavior (Table 2). N1cl amplitude decreased under PNS at medium intensiwww.neuromodulationjournal.com
Figure 4. Increased laser pain thresholds under peripheral nerve stimulation (PNS). Box plots (dotted line: arithmetic mean) show interpolated laser detection threshold (LDT) and laser pain thresholds (LTP). a. Interpolated LDT after logarithmic regression at T0, T1, and T2 (N = 27). b. Interpolated LPT after logarithmic regression at T0, T1, and T2 (N = 27). χ2 and p values correspond to Friedman one-way repeated measures analysis of variance (ANOVA). F value corresponds to one-way repeated measures ANOVA. Asterisks mark threshold differences as analyzed by Student-Newman-Keuls post hoc tests (*p < 0.05). NS, not significant.
ties. This component transiently decreased at high intensities. N1il amplitude transiently decreased at medium laser intensities. At high intensities, this component showed a sustained decrease under PNS. Ratings Analysis of perceptual ratings showed significant effects of time window, intensity, and interaction (Fig. 6a). At low intensities, there were no differences between ratings at T0, T1, and T2. At medium intensities, ratings under PNS differed from each other at all time windows. With high laser intensities, rating under PNS varied from both T0 and T2 values. Ratings from all laser intensities varied between each other at each time window. There were significant effects for the factors time window, intensity, and interaction with single intensity ratings (Fig. 6b). Ratings under PNS were lower than T0 values at intensities I4–10. T1 ratings also were lower than T2 ratings at intensities I5–9. Differences in ratings before and after PNS occurred at intensity I5, I7, and I10.
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PNS SHIFTS PAIN STIMULUS–RESPONSE FUNCTION radial nerve was established. This procedure was shown to increase PNS selectivity without impairing radial nerve function (13). PNS intensity of twice the electrical detection threshold sufficed for predominant Aβ fiber excitation in animals and men (13,18,36–39). Mean stimulus intensity of 2.4 mA equated to 1.7-fold the perception threshold and provided for predominant excitation of tactile radial nerve fibers. Correspondingly, subjects reported nonpainful, tingling sensations during PNS.
Figure 5. Reduced late laser-evoked potential (LEP) at medium and high intensities during peripheral nerve stimulation (PNS). Grand averages of cortical potentials (left column) and box plots of N2P2 amplitudes (right column; dotted line: arithmetic mean) recorded in laser stimulation series at time windows T0, T1, and T2. Grand averages and N2P2 amplitudes were elicited by low (a), medium (b), and high laser stimulus intensities (c) (N = 27). χ2 and p values correspond to Friedman one-way repeated measures analysis of variance ANOVA). Asterisks mark significant differences within experimental groups as analyzed by Student-Newman-Keuls post hoc tests (*p < 0.05).
Logarithmic regression was performed on the basis of each stimulus intensity that elicited a rating >30 for each time window (Fig. 6c). Steepness and Y-axis intercept of these logarithmic functions before, during, and after PNS are summarized in Table 3.
DISCUSSION
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SRF Logarithmic and linear regressions were applied to interpolate LDT and LPT during a stimulus series covering a broad range of laser stimulus intensities. Present results suggest the feasibility of logarithmic regression when interpolating concrete threshold values for detection and pain. Consequently, a rightward shift of SRF during PNS can be implied. In accordance with a PNS effect on vertex LEP, perception of laser stimuli is reduced at moderate to strong painful stimulus intensities. Logarithmic regression curves show modified SRF during PNS. Correlations between stimulus intensity and perception intensity have been studied extensively. Admittedly, a sigmoidal function seems best suited for depicturing the actual SRF. However, this function did not reproduce reliably laser detection and LPTs. Applying nonpainful and painful cutaneous CO2 laser and contact heat stimuli, SRF was described as linear (50). Accordingly, SRF between stimulus intensity and both reflex magnitude and perceived pain intensity was determined via linear regression while
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PNS Efficacy Transient increase of MDT under active PNS acted as an indicator for sufficient excitation of radial nerve afferents. As antidromic and orthodromic action potentials collide, peripheral tactile processing is diminished (31–34). Collision occurred between signals derived from electrically stimulated radial nerve Aβ fibers and tactile processing elicited via mechanical von Frey hair stimulation at the corresponding skin site. Accordingly, MDT changes were limited to the duration of active PNS. Vibrotactile threshold increase during TENS is explained by collision phenomenon as well (35). Whereas TENS addresses small afferents in a specific skin area, PNS targets on a well-defined nerve trunk. In order to clearly provide for PNS and to avoid any TENS, local anesthesia of the skin above the superficial
LEP Laser heat stimulation selectively excites Aδ and C fiber nociceptors and evokes typical cortical potentials recorded by EEG (13). Main LEP components are N1, N2, and P2. With maximum amplitude at temporal leads, the bilateral N1 component is mainly generated by operculoinsular cortex (40,41). N2 generation is suggested to occur in bilateral operculoinsular cortices and contralateral primary somatosensory cortex. The probable source of P2 is the anterior cingulate cortex (41,42). PNS at 30 Hz and 100 Hz frequencies suppressed late components of nociceptive LEP with one constant, painful laser stimulus intensity in two former trials (13,18). The present study provides evidence that PNS modulation occurs in a broad range of nociceptive processing with ten laser intensities instead of only one. Furthermore, the present study additionally addressed modulatory PNS effects on middle-latency LEP component N1. Temporary reduction of late vertex LEP at medium intensities (moderate painful) and prolonged reduction at high intensities (strongly painful) point to antinociceptive potential of PNS. Natural vibratory and tactile stimulation can delay and decrease LEP (43– 45). TENS of cutaneous afferents reduced pain perception and N2P2 amplitude (20,46). Latency reduction can also occur under distraction and drowsiness (47–49). Distraction and drowsiness are factors unlikely to have occurred in the present study because random interstimulus intervals and pseudorandomized laser stimulus intensities elicited steady LEP and steady ratings under control conditions without any conditioning stimulation in corresponding former trials (13,18). With contralateral PNS control, ratings were unaffected as well (13). This demonstrates an overall reproducible and unaffected pain rating within the designed experimental setup. As a direct continuation, the present study utilized the same experimental setup that was shown to be resistant to influencing factors such as habituation or distraction.
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Table 1. Latencies and Amplitudes of LEP Components Elicited with Low, Medium, and High Laser Intensities. Parameter N2 (N = 26) Latency (msec) P2 (N = 27) Latency (msec) N1cl (N = 21) Latency (msec) N1il (N = 20) Latency (msec) N1cl (N = 21) Amplitude (μV) N1il (N = 20) Amplitude (μV)
Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM
T0 Low
Med
High
257 2.0 389 5.9 199 4.2 218 2.8 −1.5 0.7 −0.4 0.3
240 5.4 368 9.0 180 6.0 194 7.0 −5.1 0.9 −4.7 1.0
202 5.3 321 8.6 168 5.8 167 5.6 −8.0 1.2 −7.5 0.9
T1 Low 256 0.0 395 0.0 206 0.0 222 0.0 0.0 0.0 0.0 0.0
Med
High
T2 Low
Med
High
251 2.8 385 5.8 201 2.6 215 3.8 −2.4 0.9 −0.9 0.5
230 6.8 351 9.3 190 4.2 201 5.3 −4.6 1.2 −4.2 1.1
256 0.0 394 1.2 204 1.3 220 1.6 −0.8 0.5 −0.1 0.1
240 5.3 370 8.1 193 4.6 207 5.6 −3.3 1.0 −3.6 1.1
217 6.1 323 12.1 176 5.5 179 7.2 −8.8 1.1 −5.9 1.2
LEP, laser-evoked potential; SEM, standard error mean.
Table 2. Statistics of LEP Components Elicited with Low, Medium, and High Laser Intensities. Parameter
ANOVA
Post hoc
N2 Latency
Time: F = 18.7, *** Intensity: F = 36.0, *** Interaction: F = 5.7, *** Time: F = 6.7, ** Intensity: F = 23.7, *** Interaction: F = 2.9, * Time: F = 11.8, *** Intensity: F = 25.0, *** Interaction: F = 2.8, * Time: F = 14.5, *** Intensity: F = 41.7, *** Interaction: F = 4.3, ** Time: F = 7.9, ** Intensity: F = 31.0 *** Interaction: F = 2.6, * T0: F = 24.8, *** T1: χ2 = 16.2, *** T2: F = 13.8, *** low: χ2 = 2.0, NS med: F = 7.0, ** high: F = 3.9, *
Low: NS Med: T0 vs. T1*, T1 vs. T2** High: T0 vs. T1***, T0 vs. T2***, T1 vs. T2** Low: NS Med: NS High: T0 vs. T1***, T1 vs. T2*** Low: NS Med: T0 vs. T1***, T0 vs. T2** High: T0 vs. T1***, T1 vs. T2** Low: NS Med: T0 vs. T1***, T0 vs. T2* High: T0 vs. T1***, T0 vs. T2*, T1 vs. T2*** Low: NS Med: T0 vs. T1* High: T0 vs. T1**, T1 vs. T2*** Low vs. med***, low vs. high***, med vs. high** Low vs. high*, med vs. high* Low vs. med**, low vs. high***, med vs. high* — T0 vs. T1**, T1 vs. T2* T0 vs. T1*
P2 Latency ¥ N1cl Latency N1il Latency N1cl Amplitude N1il Amplitude
Time window Stimulus intensity group
*p < 0.05; **p < 0.01; ***p < 0.001; ¥, after reciprocal transformation. ANOVA, analysis of variance; LEP, laser-evoked potential; NS, not significant.
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examining nociceptive withdrawal reflexes after painful CO2 stimulation (51). Temperature-dependent correlation of pain ratings and amplitudes of N1 and N2P2 with contact heat stimuli was demonstrated (52). Another study focused on the encoding of thermal stimulus intensity at the secondary somatosensory cortex and the insula. Whereas secondary somatosensory cortex responses gradually increased between sensory and pain thresholds, insular activations encoded painful intensities (53). According to Weber–Fechner law, a sensory detection threshold can be described as the number of just noticeable difference values against the logarithm of the stimulus intensity. Consequently, this could account for a better interpolation fit for LDT with logarithmic than with linear regression. A sigmoidal function depicts the transition of an exponential into a logarithmic function within two horizontal asymptotes. Hence, www.neuromodulationjournal.com
interpolation of LPT via logarithmic regression is probably more suited than linear regression, both for interpolation of concrete LPT value and depicting the SRF. In summary, logarithmic regression offers a suitable method to interpolate LDT and LPT for a distinct data range despite a probably better fitting overall sigmoid shape for the entire data range. Thus, changes in ratings, LEP, and LPT depending on stimulus intensity point to a shift of SRF to the right. The design of the present experimental model targets the clinical situation of standard PNS with implanted devices. The superficial radial nerve trunk was selected because of its accessibility by transcutaneous electrical stimulation and the cutaneous receptive field for noxious stimulation. The application of various painful intensities in contrast to only one fixed painful stimulus clearly upgrades possible implications for treatment of fluctuating clinical pain.
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Figure 6. Decrease of ratings at medium and high laser intensities during peripheral nerve stimulation (PNS). Ratings for stimulus intensity groups (a), single intensities (b), and logarithmic regression (c) at T0, T1, and T2 (N = 27). a. Data are presented as box plots (dotted line: arithmetic mean) of ratings at low, medium, and high laser stimulus intensities at T0, T1, and T2. F and p values correspond to two-way repeated measures analysis of variance (ANOVA). Asterisks indicate significance derived from Student-Newman-Keuls post hoc testing (*p < 0.05, **p < 0.01, ***p < 0.001). b. Ratings with corresponding single laser stimulus intensities are presented as mean ± SEM for T0, T1, and T2. F and p values correspond to two-way repeated measures ANOVA. Asterisks indicate significance derived from Student-NewmanKeuls post hoc testing (*p < 0.05, **p < 0.01, ***p < 0.001). c. Logarithmic regression over stimulus intensities and corresponding ratings (>30) at T0, T1, and T2. Dotted line represents minimal pain perception. SEM, standard error mean.
Table 3. Parameters of Logarithmic Regression. Time window
Steepness (a)
Y-axis intercept (Y0)
T0 T1 T2
11.5,*** 9.1,*** 12.3,***
−27.4,*** −14.9,** −32.9,***
in healthy volunteers in a broad stimulus intensity spectrum. Data provide further objective evidence for clinical application that needs to be validated in chronic pain patients. The underlying sensory mechanism can be described as a right shift in nociceptive SRF and, thus, could result in pain relief.
**p < 0.01; ***p < 0.001. Significances derived from logarithmic regression.
However, some limitations of the experimental trial have to be considered. Clinical pain mainly arises from musculoskeletal tissues. In the experimental study, laser pain stimuli were applied to the skin of hand dorsum. Deep pain partly involves other nociceptors and pathways as compared with superficial pain. This might affect translatability of the present results to clinical pain. Furthermore, laser pain stimuli are acute and phasic nociceptive events in contrast to frequently ongoing pain in patients. However, the experimental model seems to be an appropriate, significant step on the way to clinical models.
Authorship Statement The manuscript has been read and agreed upon by all authors. All authors contributed to the design of the trial, the practical execution of experiments, the data analysis, and the writing of the manuscript.
How to Cite this Article: Ristić D., Ellrich J. 2014. Innocuous Peripheral Nerve Stimulation Shifts Stimulus–Response Function of Painful Laser Stimulation in Man. Neuromodulation 2014; 17: 686–695
CONCLUSION
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COMMENTS For many decades peripheral nerve stimulation (PNS) has been used for the treatment of all kinds of pathological conditions – from muscle weakness, sleep apnea and urinary incontinence to epilepsy and depression—and various types of chronic pain have been successfully managed with PNS through different external, short-term and longterm implanted devices. Despite the long track record of PNS in clinical practice of pain management, exact mechanisms of its pain-relieving effect remain unknown. This study of PNS mechanisms provides additional insight into the way repetitive nerve stimulation affects perception and transmission of pain information. The authors’ methods are sound and the results are convincing—and the only remaining questions would be (a) whether findings of stimulus response shift due to transcutaneous PNS may be translated into PNS with implanted devices, and (b) whether peripheral nerves involved in chronic pain syndromes respond to PNS similar to the normal ones. The authors have been studying this subject for a long time—and, hopefully, will continue their investigations in order to better understand the mechanism of PNS and explain the basis of our clinical work.
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Konstantin Slavin, MD Chicago, IL, USA Neuromodulation 2014; 17: 686–695
PNS SHIFTS PAIN STIMULUS–RESPONSE FUNCTION *** This contribution to Neuromodulation offers a glimpse in the toolbox containing a mechanism of action for peripheral nerve stimulation (PNS). Building on earlier work, the authors have shown that PNS elicits antinociception and analgesia in healthy human subjects—clearly putting to rest the many criticisms with which this modality has labored in the absence of definitive experimental studies. Just as van den Honert and Mortimer (1), 30 years ago demonstrated that collision in A beta fibers between otho- and antidromic impulses impaired tactile processing thereby raising the mechanical detection threshold (MTD), these authors have clearly documented that using a broad stimulus spectrum, PNS provides both antinociception and analgesia. Using laser evoked potentials (LEP) and laser pain thresholds (LPT) with logarithmic regression the stimulus-response function (SRF) were moved to the right—raising the mechanical detection threshold (MTD). This work complements contemporary activity exploring the physical modalities of waveform, frequency and amplitude used to achieve neurostimulation. As the authors rightly state, similar experimental protocols are now needed to validate these results in chronic pain patients. Studies of this nature move the science of Neuromodulation forward. I look forward to further papers from this research group.
*** As one of the first described and exercised methods of neuromodulation therapy, peripheral nerve stimulation (PNS) has undergone a refreshing revitalization in the last 5–10 years. For example in some pain entities, spinal cord stimulation (SCS) was transferred successfully to (indirect) nerve field stimulation [1]; in other neuropathic conditions revised lead developments in dorsal root ganglion stimulation seems to be promising [2]. Beneath the limitation of direct PNS to peripheral nerve surgeons the lack of a well defined mode of action led to the rest period of PNS between 1980 and 2000. As assumed in my own clinical practice, PNS seems to act more antinociceptive (peripherally) than in a central inhibitory manner. The present investigation seems to direct us this way, whereas related studies for central neuromodulatory effects of PNS are not available thus far. I think this paper could help us in better understanding of PNS effects, but further studies are necessary. For instance this paper refers specifically to healthy volunteers and it remains to be seen if in chronic neuropathic pain patients these conclusions can be confirmed. Daniel Klase, MD Hamburg, Germany
Michael Stanton-Hicks, MD Cleveland, OH, USA REFERENCES REFERENCE 1. van den Honert, Mortimer JT. Generation of unidirectionally propogated action potentials in a peripheral-nerve by brief stimuli. Science 1979;206:1311–1312.
1. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 1999 Jul;2:217–212. 2. Van Buyten JP, Smet I, Liem L, Russo M, Huygen F. Stimulation of Dorsal Root Ganglia for the Management of Complex Regional Pain Syndrome: A Prospective Case Series. Pain Pract. 2014 Jan 23. doi: 10.1111/papr.12170. [Epub ahead of print].
Comments not included in the Early View version of this paper.
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Revised: September 11, 2013
Accepted: October 3, 2013
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12133
Innocuous Peripheral Nerve Stimulation Shifts Stimulus–Response Function of Painful Laser Stimulation in Man Dejan Ristić, PhD*†; Jens Ellrich, MD, PhD*†‡ Objectives: Electrical peripheral nerve stimulation (PNS) is discussed as an effective neuromodulatory treatment in chronic pain. This human experimental study hypothesized a rightward shift of stimulus–response function as a marker of antinociceptive and analgesic PNS effects. Materials and Methods: Innocuous electrical PNS of the left superficial radial nerve trunk evoked paresthesia on the left hand dorsum in 29 healthy volunteers. In this innervation area, laser stimulation was performed before, during, and after PNS. Ten different laser intensities ranging between perception and tolerance thresholds were applied. Cortical laser-evoked potentials (LEP) were recorded, and perceptual ratings were documented. Data were analyzed in low, medium, and high laser intensity categories. Stimulus–response functions were calculated. Laser detection and pain thresholds were interpolated. Results: Interpolated laser thresholds after logarithmic regression were not different from measured thresholds. Laser pain threshold increased during and after PNS. LEP amplitude decreased at medium and high intensities under PNS. Ratings transiently decreased during PNS at medium and high laser intensities. Conclusions: Modulation of laser pain threshold, perceptual ratings, and LEP indicates a rightward shift of stimulus–response function under PNS. These data emphasize antinociceptive and analgesic effects of PNS in an experimental human model and support its clinical neuromodulative relevance. Keywords: Electrophysiology, evoked potentials, laser, pain, psychophysics Conflicts of Interest: The authors reported no conflicts of interest.
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Nociceptive processing can be inhibited by simultaneous excitation of tactile afferents at the same body site (1). This concept is known as “touch inhibits pain” and led to analgesic treatment of chronic pain by electrical stimulation of Aβ fibers via implanted electrodes (2–5). Peripheral nerve stimulation (PNS) is applied in patients with chronic pain syndromes mainly affecting the extremities (6,7) and the craniofacial region (8). Published PNS parameters like stimulation frequency and pulse duration ranged from 10 to 130 Hz and from 90 to 3000 μsec (9–12). The vast majority of clinical studies applied PNS with a frequency of approximately 100 Hz and pulse duration of about 200 μsec according to analgesic efficacy in patients (13). High-frequency stimulation (up to 10 kHz) for chronic pain treatment is a paresthesia-free method that probably bases upon a mode of action different from conventional PNS and, therefore, was not considered in the present study (14). Neuromodulative PNS has been applied for decades. However, with documented analgesic potency, its antinociceptive effects are still debated (15,16). Whereas analgesic effects were demonstrated in chronic pain patients by pain questionnaires (5,17), a clear proof of antinociception by objective parameters such as electrophysiological assessment in man is still missing. Modulation of nociceptive processing by simultaneous Aβ fiber stimulation in man was demonstrated in electrophysiological and psychophysical studies (13,18–20). Most studies focused on mechanisms of transcutaneous electrical nerve stimulation (TENS) but not www.neuromodulationjournal.com
on PNS. With PNS, a certain nerve trunk is specifically targeted. With TENS, cutaneous nerves of a certain area are stimulated. Preceding studies assessed effects of therapeutic PNS on vertex laser-evoked potentials (LEPs) and pain perception in healthy men (13,18). Electrical, innocuous conditioning stimulation of the superficial radial nerve mimicked therapeutic PNS and significantly reduced LEPs and pain perception. However, both studies focused on laser stimulation with only one fixed, clearly painful stimulus intensity. Possible effects of PNS on the complete pain stimulus–response function (SRF) are hypothesized but not shown yet.
Address correspondence to: Jens Ellrich, MD, PhD, Department of Health Science and Technology, Medical Faculty, Aalborg University, Fredrik Bajers Vej 7D2, Aalborg DK-9220, Denmark. Email: [email protected] * Experimental Neurosurgery Section, Department of Neurosurgery, RWTH Aachen University, Aachen, Germany; † Department of Health Science and Technology, Aalborg University, Aalborg, Denmark; and ‡ Institute of Physiology and Pathophysiology, University of ErlangenNuremberg, Erlangen, Germany For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1 Financial support: The study was funded by grants from the Interdisciplinary Center for Clinical Research of RWTH Aachen University (520507; Pain Research Group) and a PhD grant from Aalborg University.
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PNS SHIFTS PAIN STIMULUS–RESPONSE FUNCTION The present study addressed the neuromodulatory impact of electrical PNS on the perceptive spectrum covering a wide range of both nonpainful and painful sensations. It was hypothesized that conditioning electrical PNS of the superficial radial nerve provoked a rightward shift of SRF of nociception and pain elicited by laser stimulation in the corresponding cutaneous innervation area in man. The hypothesis was tested by psychophysical and electrophysiological means. Preliminary results of the study were presented as abstract (21).
MATERIALS AND METHODS Subjects Twenty-nine healthy volunteers (19 women, 10 men, 24.9 ± 0.7 years; mean ± standard error) participated in the study. Participants gave their informed consent prior to their inclusion in the study according to the 1964 Declaration of Helsinki (as amended by the 52nd General Assembly, Edinburgh, Scotland, 2000; http:// www.wma.net). The local ethics committee of RWTH Aachen University approved the protocol before the study began. Each experiment lasted approximately three hours. Volunteers were awake, relaxed with eyes closed, and sitting comfortably on a reclined chair. Exclusion criteria were presence of neurological disorders and drug usage. Adequate knowledge of the German language was essential for appropriate understanding of the instructions. The design of the present experimental model targets the clinical situation of standard PNS with implanted devices. The target nerve model had to meet the following requirements: 1) easy noninvasive access to the nerve trunk in order to apply transcutaneous, electrical, conditioning stimulation (quasi-PNS); 2) easy access to the corresponding cutaneous receptive field in order to apply painful, laser, test stimulation. The superficial radial nerve trunk was selected because of its accessibility by transcutaneous electrical stimulation and the cutaneous receptive field for noxious stimulation. In general, innocuous, electrical, conditioning stimulation of the left superficial radial nerve trunk at the forearm in healthy volunteers simulated neuromodulatory PNS treatment in pain patients. Ten distinct laser stimulus intensities were applied to the innervation area of the superficial radial nerve on the left hand dorsum from nonpainful to painful range. Volunteers rated perceived sensation after each laser stimulus on a verbal rating scale covering nonpainful and painful range. Laser stimulation was applied before, during, and after condition PNS.
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Laser Stimulation and Electroencephalogram Recording Painful heat test stimulation of the left hand by a laser (ThuliumYAG laser, Carl Baasel Lasertechnik, Starnberg, Germany) provided for selective excitation of Aδ and C fiber nociceptors in hairy skin inducing warm, heat, pricking, or burning painful sensations. The laser emitted infrared light of 2 μm wavelength for 1 msec duration. In order to avoid adaptation of nociceptors and skin reddening, the stimulation spot (5 mm diameter) varied from stimulus to stimulus within the innervation area of the superficial radial nerve on the left hand dorsum. Selective excitation of cutaneous nociceptors via laser stimulation generates a typical pattern of LEP recorded by electroencephalography. Late-latency LEP were recorded from positions Fz, Cz (vertex), and Pz vs. a left earlobe (A1) reference and middle-latency LEP at positions T3 and T4 vs. an Fz reference according to the international 10–20 system (band pass 0.08–30 Hz). In order to monitor artifacts derived from eye and lid movement, an electrooculogram of the right eye was recorded (band pass 0.01– 100 Hz). Laser detection threshold (LDT), laser pain threshold (LPT), and laser pain tolerance threshold (LTT) were determined with four series of descending and ascending intensities (23). LTT was defined as the maximal stimulus energy the subjects were willing to experience not exceeding a stimulus intensity of 800 mJ. Lowest applicable intensity was 110 mJ. Ten individual, equidistant intensities were chosen from the range between LDT and LTT according to following equation:
In1−10 = LDT + (n1−10 − 1) × (LT T − LDT ) ÷ 9 Laser stimuli were applied before (T0), during (T1), and after (T2) PNS (Fig. 1). Each stimulation series consisted of 50 stimuli. In each series, ten distinct laser intensities were applied five times in a pseudorandomized manner. In order to reduce habituation of LEP, laser stimuli occurred with variable interstimulus intervals between 8 and 12 sec. One and a half seconds after each laser stimulus, an audible signal prompted the volunteer to rate the laser-evoked sensation intensity (rating) according to a common ordinal scale (0: no perception, 1–39: nonpainful perception, 40–100: pricking painful). An interval of 15 min between laser stimulation series (T0, T1, T2) avoided intrinsic inhibition on LEP by habituation (Fig. 1). In two preceding studies, LEP amplitudes and latencies remained
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PNS Superficial local anesthesia of the skin above the left superficial radial nerve at the distal forearm was administered via plaster ® (EMLA -plaster, AstraZeneca GmbH, Wedel, Germany). Each plaster contained 25 mg lidocaine and 25 mg prilocaine with a skin contact area of about 27 cm2 and remained on the skin for one hour. This application time was shown to be sufficient to establish significant local anesthesia and short enough to avoid any affection of the adjacent superficial radial nerve trunk (22). Effectiveness of local anesthesia was monitored with von Frey hairs (mechanical detection) and pinprick stimulators (mechanical pain threshold) after one hour of plaster treatment. This procedure was demonstrated to minimize local excitation of cutaneous afferents by PNS and to provide for preferential activation of the nerve trunk without affecting radial nerve trunk function (13).
Conditioning nonpainful PNS was performed in healthy volunteers by electrical stimulation of the left superficial radial nerve trunk via two surface electrodes (5 mm diameter) with stimulus intensities sufficient for excitation of tactile Aβ fibers inducing tingling but no painful sensations in the dorsum of the left hand (rectangular pulse, 200 μsec, 100 Hz). PNS parameters were adjusted to values that resembled clinical PNS in chronic pain patients. Optimal stimulation site was found by using minimal electrical currents that caused maximal, nonpainful tingling paresthesia in the innervation area of the superficial radial nerve, which was determined via verbal report from each participant. This electrically evoked paresthetic area at the same time indicated the laser stimulation site (see below). The cathode position was proximal to the anode distal. Electrical stimuli were applied with a constant current stimulator (Model DS7A, Digitimer Limited, Hertfordshire, UK). The electrical detection threshold was determined under local skin anesthesia in four series of descending and ascending intensities (23). PNS intensity was adjusted to about twofold the individual detection threshold. Conditioning PNS lasted for 23 min (Fig. 1).
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Figure 1. Stimulation protocol. Laser stimuli were applied to the innervation area of left superficial radial nerve on the hand dorsum at time windows T0, T1, and T2. Conditioning innocuous electrical peripheral nerve stimulation (PNS) of the left superficial radial nerve lasted for 23 min and was applied in T1 section. Mechanical detection thresholds were determined before and after each laser stimulation series at laser stimulation site at time windows T0, T1, T2, and T3.
unchanged in three successive laser stimulation series within control groups with an identical laser stimulus protocol (13,18). In these former studies, inhibition of LEP was present exclusively within the PNS group. Whereas the former studies only investigated PNS effects on one fixed, painful laser intensity, the present study focused on the effect of neuromodulatory PNS on an extensive dose–response function under ipsilateral conditioning stimulation. Electrophysiological signals were recorded with the electroencephalogram (EEG) bioamplifier (VD32, Schwarzer, Munich, Germany), a converter (Power1401 A/D-converter, Cambridge Electronic Design Limited, Cambridge, UK; sampling rate 2000 Hz), and the Signal software (http://www.ced.co.uk). Within one laser stimulation series, five LEP sweeps per laser stimulus intensity were digitally filtered (low pass 20 Hz) and averaged. Averaged EEG data were processed with the matching pursuit algorithm (24–27) in order to eliminate further contamination of the LEP, for example, auditoryevoked potentials. Upward deflection of recorded LEP waveform was referred to as negativity (N), downward deflection as positivity (P). Latencies and amplitudes of ipsilateral N1 (T3: N1il), contralateral N1 (T4: N1cl), N2, and P2 LEP components as well as peak-topeak amplitude between N2 and P2 (N2P2 amplitude) were determined between 100 and 500 msec after laser stimulation. Within this experimental setup, previous studies reproducibly demonstrated constant ratings over time in control conditions (without PNS and with contralateral PNS) (13,18). As a direct continuation with an identical experimental setup besides the number of stimulus intensities, no additional control experiments were performed in this study.
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Mechanical Detection Threshold Mechanical detection threshold (MDT) was measured in the innervation area of the superficial radial nerve at the hand dorsum www.neuromodulationjournal.com
before and after each laser stimulation series (Fig. 1). MDT measurements were performed with von Frey filaments (OptiHair2, MARSTOCKnervtest, Marburg, Germany). Filaments of forces 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256, and 512 mN had rounded tips with a diameter of about 0.4 mm. MDT was determined by the method of limits starting with a clearly noticeable filament of 16 mN. MDT was defined as the geometric mean of five series of descending and ascending stimulus intensities. Afferent tactile processing evoked by mechanical stimulation with von Frey filaments interfered with electrical antidromic excitation of tactile fibers in the superficial radial nerve trunk by PNS. This peripheral collision caused increased MDT lasting for the time of electrical conditioning. Thus, the PNS effect could be validated by transiently increased MDT. Laser Threshold Interpolation and Statistical Analysis Mathematical regression was used to compare measured with calculated laser perception and pain thresholds. Stimulus intensities and the corresponding subjects’ ratings were used as the basis for logarithmic and linear regression. For the logarithmic interpolation of laser thresholds, the following equation was used with X as stimulus intensity, Y as corresponding rating, a as steepness, and Y0 as Y-axis intercept:
Y = Y0 + a × ln (X ) For linear interpolation of laser thresholds, the following equation was used:
Y = Y0 + a × X Interpolations were performed for ratings from all time windows for each subject. Ratings ≤30 and corresponding laser intensities
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PNS SHIFTS PAIN STIMULUS–RESPONSE FUNCTION were used for LDT interpolation and ratings >30 and corresponding laser intensities for LPT interpolation. From the derived individual functions, stimulus intensities producing a rating of 1 and 40 equaling laser perception and pain thresholds were interpolated and then compared with the initially measured laser thresholds. Initially, sigmoidal functions were applied, but the differences between measured and interpolated values were too large to be considered acceptable in contrast to logarithmic and linear regression. Data were described by arithmetic mean and standard error, by median, 5th, 25th, 75th, and 95th percentiles (box plot). Two-way repeated measures analysis of variance (ANOVA) with time window and laser stimulus intensity as factors served as main statistical analysis (EEG, ratings). Depending on data distribution, the statistical comparison within and between groups (including MDT, LDT, LPT) was performed via one-way repeated measures ANOVA (F and p value) or by Friedman repeated measures ANOVA (χ2 and p values). For post-hoc comparison, the Student-Newman-Keuls test (p value) was used. The Kolmogorov–Smirnov test was used to determine data distribution. The level of significance was set to p < ® 0.05. Only results with appropriate power (0.8) given by SigmaStat software 10.0 (SPSS Inc., Chicago, IL, USA) were considered.
RESULTS In all 29 trials, LEP and sensory thresholds were recorded. Two subjects were excluded from further analysis because N2 and P2 LEP components were not detectable under baseline conditions at T0. With absent cortical potentials under and after PNS, the values for the statistical analysis were set to 0 μV for LEP amplitudes and to 256 msec (N2), 395 msec (P2), 206 msec (N1cl), and 222 msec (N1il) as upper limits for LEP latencies. These upper limit values were derived from the sum of mean latency plus 2.5-fold the standard deviation collected in own laboratory. Latencies and amplitudes in the present study corresponded to values from other laboratories applying an infrared laser (28–30). Average LDT was 202 ± 11 mJ (mean ± standard error mean), average LPT 385 ± 12 mJ, and LTT 655 ± 12 mJ. These test stimulus intensities elicited single or mixed sensations of warmth, touch, heat, and pricking pain to burning pain in all participants. Conditioning PNS of the superficial radial nerve was conducted with a stimulus intensity of 2.5 ± 0.1 mA corresponding to 168 ± 5% of electrical detection threshold. The electrical stimulus intensity evoked nonpainful tingling sensations in the innervation area of the superficial radial nerve on the hand dorsum in all subjects. MDT underwent significant changes (Fig. 2). MDT increased under PNS (T1, 146.4 ± 31.2 mN) compared with all other time windows T0 (3.1 ± 0.9 mN, p < 0.05), T2 (7.3 ± 4.7 mN, p < 0.05), and T3 (2.9 ± 0.7 mN, p < 0.05).
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from measured thresholds. In consequence, logarithmic regression was systematically used for interpolation of LDT and LPT at all time windows. Logarithmic LDT remained unchanged before, during, and after PNS (Fig. 4a). Logarithmic LPTs differed from each other (Fig. 4b). Post hoc comparison revealed elevated LPT during and after PNS.
LEP Late vertex potentials (N2, P2) and middle-latency LEP components in temporal leads (N1il, N1cl) were recorded at time windows T0, T1, and T2 (Fig. 1). Because of low signal-to-noise ratio, data were pooled according to low (I1–4), medium (I5–7), and high intensities (I8–10). LEP latencies and amplitude corresponded to values from other laboratories using a laser (28–30).
N2P2 Amplitude and Late LEP Latencies (Fig. 5) Late vertex potentials were reproducibly elicited in all but two out of 29 volunteers before PNS (Fig. 5). In consequence, LEP, perceptual ratings, MDT, and interpolated laser thresholds from the remaining 27 subjects were analyzed. In one out of those 27 subjects, the N2 component was absent. Consequently, the N2P2 consisted of only the P2 amplitude in this case. The comparison of vertex potentials between laser stimulus intensity groups within the same time window showed increasing amplitudes with increased intensity at T0 (χ2 = 70.1, p < 0.001), T1 (χ2 = 38.0, p < 0.001), and T2 (F = 62.2, p < 0.001). Before (high intensity vs. all: p < 0.001; low vs. medium intensity: p < 0.01) and after PNS (high intensity vs. all: p < 0.001; low vs. medium intensity: p < 0.01), N2P2 differed from each other. During PNS, high intensity N2P2 differed from both other groups (each p < 0.05). Comparison between laser intensity groups at different time windows demonstrated significant differences for N2P2 amplitudes within medium and high intensities (Fig. 5). N2P2 amplitude was reduced under PNS and partially recovered after electrical conditioning.
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Interpolation of Laser Thresholds (Figs 3 and 4) ANOVA revealed significant differences in measured and interpolated LDT (Fig. 3a). Post-hoc comparison documented variation between linearly interpolated LDT from both measured LDT and logarithmically interpolated LDT. ANOVA revealed significant differences in measured and interpolated LPT (Fig. 3b). Post-hoc comparison of linearly interpolated LPT resulted in statistical difference of linearly interpolated LPT to both measured LPT and logarithmically interpolated LPT. Logarithmic regression produced interpolated LDT and LPT that were not significantly different
Figure 2. Mechanical detection threshold transiently increased under peripheral nerve stimulation (PNS). Mechanical detection threshold was measured before (T0) and after each laser stimulation series (T1, T2, T3) (N = 27). Data are shown as box plots (dotted line: arithmetic mean). χ2 and p values correspond to Friedman one-way repeated measures analysis of variance (ANOVA). Asterisks mark threshold differences as analyzed by Student-Newman-Keuls post hoc tests (*p < 0.05).
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Figure 3. Logarithmic interpolation resembled measured laser detection threshold (LDT) and laser pain threshold (LPT). Box plots (dotted line: arithmetic mean) show measured and interpolated laser thresholds. a. Comparison of measured laser detection thresholds with interpolated values from logarithmic and linear regression of ratings (≤30) and corresponding stimulus intensities at T0 (N = 29). b. Comparison of measured LPTs with interpolated values from logarithmic and linear regression of ratings (>30) and corresponding stimulus intensities at T0 (N = 29). χ2 and p values correspond to Friedman one-way repeated measures analysis of variance (ANOVA). Asterisks mark threshold differences as analyzed by Student-Newman-Keuls post hoc tests (*p < 0.05).
Values for N2 and P2 latencies are summarized in Table 1. Differences in N2 latency between time windows occurred at both medium and high intensities (Table 2). With medium intensities, N2 latency was transiently prolonged, whereas at high intensities N2 latencies only partially recovered after PNS accordingly to vertex potential. P2 latencies varied at high intensities between time windows (Table 2). Latencies were transiently prolonged during conditioning PNS.
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Ipsilateral and Contralateral N1 Latencies and amplitudes for N1il and N1cl are summarized in Table 1. All statistically significant effects occurred at medium and high laser intensities (Table 2). N1cl latency increased during and after PNS at medium intensities. At high intensities, N1cl latency prolonged transiently with PNS. At medium intensities, N1il latency increased during and after PNS as well. At high intensities, N1il latency increased during conditioning and partly recovered at T2. Middle-latency LEP amplitudes showed similar behavior (Table 2). N1cl amplitude decreased under PNS at medium intensiwww.neuromodulationjournal.com
Figure 4. Increased laser pain thresholds under peripheral nerve stimulation (PNS). Box plots (dotted line: arithmetic mean) show interpolated laser detection threshold (LDT) and laser pain thresholds (LTP). a. Interpolated LDT after logarithmic regression at T0, T1, and T2 (N = 27). b. Interpolated LPT after logarithmic regression at T0, T1, and T2 (N = 27). χ2 and p values correspond to Friedman one-way repeated measures analysis of variance (ANOVA). F value corresponds to one-way repeated measures ANOVA. Asterisks mark threshold differences as analyzed by Student-Newman-Keuls post hoc tests (*p < 0.05). NS, not significant.
ties. This component transiently decreased at high intensities. N1il amplitude transiently decreased at medium laser intensities. At high intensities, this component showed a sustained decrease under PNS. Ratings Analysis of perceptual ratings showed significant effects of time window, intensity, and interaction (Fig. 6a). At low intensities, there were no differences between ratings at T0, T1, and T2. At medium intensities, ratings under PNS differed from each other at all time windows. With high laser intensities, rating under PNS varied from both T0 and T2 values. Ratings from all laser intensities varied between each other at each time window. There were significant effects for the factors time window, intensity, and interaction with single intensity ratings (Fig. 6b). Ratings under PNS were lower than T0 values at intensities I4–10. T1 ratings also were lower than T2 ratings at intensities I5–9. Differences in ratings before and after PNS occurred at intensity I5, I7, and I10.
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PNS SHIFTS PAIN STIMULUS–RESPONSE FUNCTION radial nerve was established. This procedure was shown to increase PNS selectivity without impairing radial nerve function (13). PNS intensity of twice the electrical detection threshold sufficed for predominant Aβ fiber excitation in animals and men (13,18,36–39). Mean stimulus intensity of 2.4 mA equated to 1.7-fold the perception threshold and provided for predominant excitation of tactile radial nerve fibers. Correspondingly, subjects reported nonpainful, tingling sensations during PNS.
Figure 5. Reduced late laser-evoked potential (LEP) at medium and high intensities during peripheral nerve stimulation (PNS). Grand averages of cortical potentials (left column) and box plots of N2P2 amplitudes (right column; dotted line: arithmetic mean) recorded in laser stimulation series at time windows T0, T1, and T2. Grand averages and N2P2 amplitudes were elicited by low (a), medium (b), and high laser stimulus intensities (c) (N = 27). χ2 and p values correspond to Friedman one-way repeated measures analysis of variance ANOVA). Asterisks mark significant differences within experimental groups as analyzed by Student-Newman-Keuls post hoc tests (*p < 0.05).
Logarithmic regression was performed on the basis of each stimulus intensity that elicited a rating >30 for each time window (Fig. 6c). Steepness and Y-axis intercept of these logarithmic functions before, during, and after PNS are summarized in Table 3.
DISCUSSION
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SRF Logarithmic and linear regressions were applied to interpolate LDT and LPT during a stimulus series covering a broad range of laser stimulus intensities. Present results suggest the feasibility of logarithmic regression when interpolating concrete threshold values for detection and pain. Consequently, a rightward shift of SRF during PNS can be implied. In accordance with a PNS effect on vertex LEP, perception of laser stimuli is reduced at moderate to strong painful stimulus intensities. Logarithmic regression curves show modified SRF during PNS. Correlations between stimulus intensity and perception intensity have been studied extensively. Admittedly, a sigmoidal function seems best suited for depicturing the actual SRF. However, this function did not reproduce reliably laser detection and LPTs. Applying nonpainful and painful cutaneous CO2 laser and contact heat stimuli, SRF was described as linear (50). Accordingly, SRF between stimulus intensity and both reflex magnitude and perceived pain intensity was determined via linear regression while
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PNS Efficacy Transient increase of MDT under active PNS acted as an indicator for sufficient excitation of radial nerve afferents. As antidromic and orthodromic action potentials collide, peripheral tactile processing is diminished (31–34). Collision occurred between signals derived from electrically stimulated radial nerve Aβ fibers and tactile processing elicited via mechanical von Frey hair stimulation at the corresponding skin site. Accordingly, MDT changes were limited to the duration of active PNS. Vibrotactile threshold increase during TENS is explained by collision phenomenon as well (35). Whereas TENS addresses small afferents in a specific skin area, PNS targets on a well-defined nerve trunk. In order to clearly provide for PNS and to avoid any TENS, local anesthesia of the skin above the superficial
LEP Laser heat stimulation selectively excites Aδ and C fiber nociceptors and evokes typical cortical potentials recorded by EEG (13). Main LEP components are N1, N2, and P2. With maximum amplitude at temporal leads, the bilateral N1 component is mainly generated by operculoinsular cortex (40,41). N2 generation is suggested to occur in bilateral operculoinsular cortices and contralateral primary somatosensory cortex. The probable source of P2 is the anterior cingulate cortex (41,42). PNS at 30 Hz and 100 Hz frequencies suppressed late components of nociceptive LEP with one constant, painful laser stimulus intensity in two former trials (13,18). The present study provides evidence that PNS modulation occurs in a broad range of nociceptive processing with ten laser intensities instead of only one. Furthermore, the present study additionally addressed modulatory PNS effects on middle-latency LEP component N1. Temporary reduction of late vertex LEP at medium intensities (moderate painful) and prolonged reduction at high intensities (strongly painful) point to antinociceptive potential of PNS. Natural vibratory and tactile stimulation can delay and decrease LEP (43– 45). TENS of cutaneous afferents reduced pain perception and N2P2 amplitude (20,46). Latency reduction can also occur under distraction and drowsiness (47–49). Distraction and drowsiness are factors unlikely to have occurred in the present study because random interstimulus intervals and pseudorandomized laser stimulus intensities elicited steady LEP and steady ratings under control conditions without any conditioning stimulation in corresponding former trials (13,18). With contralateral PNS control, ratings were unaffected as well (13). This demonstrates an overall reproducible and unaffected pain rating within the designed experimental setup. As a direct continuation, the present study utilized the same experimental setup that was shown to be resistant to influencing factors such as habituation or distraction.
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Table 1. Latencies and Amplitudes of LEP Components Elicited with Low, Medium, and High Laser Intensities. Parameter N2 (N = 26) Latency (msec) P2 (N = 27) Latency (msec) N1cl (N = 21) Latency (msec) N1il (N = 20) Latency (msec) N1cl (N = 21) Amplitude (μV) N1il (N = 20) Amplitude (μV)
Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM Mean SEM
T0 Low
Med
High
257 2.0 389 5.9 199 4.2 218 2.8 −1.5 0.7 −0.4 0.3
240 5.4 368 9.0 180 6.0 194 7.0 −5.1 0.9 −4.7 1.0
202 5.3 321 8.6 168 5.8 167 5.6 −8.0 1.2 −7.5 0.9
T1 Low 256 0.0 395 0.0 206 0.0 222 0.0 0.0 0.0 0.0 0.0
Med
High
T2 Low
Med
High
251 2.8 385 5.8 201 2.6 215 3.8 −2.4 0.9 −0.9 0.5
230 6.8 351 9.3 190 4.2 201 5.3 −4.6 1.2 −4.2 1.1
256 0.0 394 1.2 204 1.3 220 1.6 −0.8 0.5 −0.1 0.1
240 5.3 370 8.1 193 4.6 207 5.6 −3.3 1.0 −3.6 1.1
217 6.1 323 12.1 176 5.5 179 7.2 −8.8 1.1 −5.9 1.2
LEP, laser-evoked potential; SEM, standard error mean.
Table 2. Statistics of LEP Components Elicited with Low, Medium, and High Laser Intensities. Parameter
ANOVA
Post hoc
N2 Latency
Time: F = 18.7, *** Intensity: F = 36.0, *** Interaction: F = 5.7, *** Time: F = 6.7, ** Intensity: F = 23.7, *** Interaction: F = 2.9, * Time: F = 11.8, *** Intensity: F = 25.0, *** Interaction: F = 2.8, * Time: F = 14.5, *** Intensity: F = 41.7, *** Interaction: F = 4.3, ** Time: F = 7.9, ** Intensity: F = 31.0 *** Interaction: F = 2.6, * T0: F = 24.8, *** T1: χ2 = 16.2, *** T2: F = 13.8, *** low: χ2 = 2.0, NS med: F = 7.0, ** high: F = 3.9, *
Low: NS Med: T0 vs. T1*, T1 vs. T2** High: T0 vs. T1***, T0 vs. T2***, T1 vs. T2** Low: NS Med: NS High: T0 vs. T1***, T1 vs. T2*** Low: NS Med: T0 vs. T1***, T0 vs. T2** High: T0 vs. T1***, T1 vs. T2** Low: NS Med: T0 vs. T1***, T0 vs. T2* High: T0 vs. T1***, T0 vs. T2*, T1 vs. T2*** Low: NS Med: T0 vs. T1* High: T0 vs. T1**, T1 vs. T2*** Low vs. med***, low vs. high***, med vs. high** Low vs. high*, med vs. high* Low vs. med**, low vs. high***, med vs. high* — T0 vs. T1**, T1 vs. T2* T0 vs. T1*
P2 Latency ¥ N1cl Latency N1il Latency N1cl Amplitude N1il Amplitude
Time window Stimulus intensity group
*p < 0.05; **p < 0.01; ***p < 0.001; ¥, after reciprocal transformation. ANOVA, analysis of variance; LEP, laser-evoked potential; NS, not significant.
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examining nociceptive withdrawal reflexes after painful CO2 stimulation (51). Temperature-dependent correlation of pain ratings and amplitudes of N1 and N2P2 with contact heat stimuli was demonstrated (52). Another study focused on the encoding of thermal stimulus intensity at the secondary somatosensory cortex and the insula. Whereas secondary somatosensory cortex responses gradually increased between sensory and pain thresholds, insular activations encoded painful intensities (53). According to Weber–Fechner law, a sensory detection threshold can be described as the number of just noticeable difference values against the logarithm of the stimulus intensity. Consequently, this could account for a better interpolation fit for LDT with logarithmic than with linear regression. A sigmoidal function depicts the transition of an exponential into a logarithmic function within two horizontal asymptotes. Hence, www.neuromodulationjournal.com
interpolation of LPT via logarithmic regression is probably more suited than linear regression, both for interpolation of concrete LPT value and depicting the SRF. In summary, logarithmic regression offers a suitable method to interpolate LDT and LPT for a distinct data range despite a probably better fitting overall sigmoid shape for the entire data range. Thus, changes in ratings, LEP, and LPT depending on stimulus intensity point to a shift of SRF to the right. The design of the present experimental model targets the clinical situation of standard PNS with implanted devices. The superficial radial nerve trunk was selected because of its accessibility by transcutaneous electrical stimulation and the cutaneous receptive field for noxious stimulation. The application of various painful intensities in contrast to only one fixed painful stimulus clearly upgrades possible implications for treatment of fluctuating clinical pain.
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PNS SHIFTS PAIN STIMULUS–RESPONSE FUNCTION
Figure 6. Decrease of ratings at medium and high laser intensities during peripheral nerve stimulation (PNS). Ratings for stimulus intensity groups (a), single intensities (b), and logarithmic regression (c) at T0, T1, and T2 (N = 27). a. Data are presented as box plots (dotted line: arithmetic mean) of ratings at low, medium, and high laser stimulus intensities at T0, T1, and T2. F and p values correspond to two-way repeated measures analysis of variance (ANOVA). Asterisks indicate significance derived from Student-Newman-Keuls post hoc testing (*p < 0.05, **p < 0.01, ***p < 0.001). b. Ratings with corresponding single laser stimulus intensities are presented as mean ± SEM for T0, T1, and T2. F and p values correspond to two-way repeated measures ANOVA. Asterisks indicate significance derived from Student-NewmanKeuls post hoc testing (*p < 0.05, **p < 0.01, ***p < 0.001). c. Logarithmic regression over stimulus intensities and corresponding ratings (>30) at T0, T1, and T2. Dotted line represents minimal pain perception. SEM, standard error mean.
Table 3. Parameters of Logarithmic Regression. Time window
Steepness (a)
Y-axis intercept (Y0)
T0 T1 T2
11.5,*** 9.1,*** 12.3,***
−27.4,*** −14.9,** −32.9,***
in healthy volunteers in a broad stimulus intensity spectrum. Data provide further objective evidence for clinical application that needs to be validated in chronic pain patients. The underlying sensory mechanism can be described as a right shift in nociceptive SRF and, thus, could result in pain relief.
**p < 0.01; ***p < 0.001. Significances derived from logarithmic regression.
However, some limitations of the experimental trial have to be considered. Clinical pain mainly arises from musculoskeletal tissues. In the experimental study, laser pain stimuli were applied to the skin of hand dorsum. Deep pain partly involves other nociceptors and pathways as compared with superficial pain. This might affect translatability of the present results to clinical pain. Furthermore, laser pain stimuli are acute and phasic nociceptive events in contrast to frequently ongoing pain in patients. However, the experimental model seems to be an appropriate, significant step on the way to clinical models.
Authorship Statement The manuscript has been read and agreed upon by all authors. All authors contributed to the design of the trial, the practical execution of experiments, the data analysis, and the writing of the manuscript.
How to Cite this Article: Ristić D., Ellrich J. 2014. Innocuous Peripheral Nerve Stimulation Shifts Stimulus–Response Function of Painful Laser Stimulation in Man. Neuromodulation 2014; 17: 686–695
CONCLUSION
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COMMENTS For many decades peripheral nerve stimulation (PNS) has been used for the treatment of all kinds of pathological conditions – from muscle weakness, sleep apnea and urinary incontinence to epilepsy and depression—and various types of chronic pain have been successfully managed with PNS through different external, short-term and longterm implanted devices. Despite the long track record of PNS in clinical practice of pain management, exact mechanisms of its pain-relieving effect remain unknown. This study of PNS mechanisms provides additional insight into the way repetitive nerve stimulation affects perception and transmission of pain information. The authors’ methods are sound and the results are convincing—and the only remaining questions would be (a) whether findings of stimulus response shift due to transcutaneous PNS may be translated into PNS with implanted devices, and (b) whether peripheral nerves involved in chronic pain syndromes respond to PNS similar to the normal ones. The authors have been studying this subject for a long time—and, hopefully, will continue their investigations in order to better understand the mechanism of PNS and explain the basis of our clinical work.
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Konstantin Slavin, MD Chicago, IL, USA Neuromodulation 2014; 17: 686–695
PNS SHIFTS PAIN STIMULUS–RESPONSE FUNCTION *** This contribution to Neuromodulation offers a glimpse in the toolbox containing a mechanism of action for peripheral nerve stimulation (PNS). Building on earlier work, the authors have shown that PNS elicits antinociception and analgesia in healthy human subjects—clearly putting to rest the many criticisms with which this modality has labored in the absence of definitive experimental studies. Just as van den Honert and Mortimer (1), 30 years ago demonstrated that collision in A beta fibers between otho- and antidromic impulses impaired tactile processing thereby raising the mechanical detection threshold (MTD), these authors have clearly documented that using a broad stimulus spectrum, PNS provides both antinociception and analgesia. Using laser evoked potentials (LEP) and laser pain thresholds (LPT) with logarithmic regression the stimulus-response function (SRF) were moved to the right—raising the mechanical detection threshold (MTD). This work complements contemporary activity exploring the physical modalities of waveform, frequency and amplitude used to achieve neurostimulation. As the authors rightly state, similar experimental protocols are now needed to validate these results in chronic pain patients. Studies of this nature move the science of Neuromodulation forward. I look forward to further papers from this research group.
*** As one of the first described and exercised methods of neuromodulation therapy, peripheral nerve stimulation (PNS) has undergone a refreshing revitalization in the last 5–10 years. For example in some pain entities, spinal cord stimulation (SCS) was transferred successfully to (indirect) nerve field stimulation [1]; in other neuropathic conditions revised lead developments in dorsal root ganglion stimulation seems to be promising [2]. Beneath the limitation of direct PNS to peripheral nerve surgeons the lack of a well defined mode of action led to the rest period of PNS between 1980 and 2000. As assumed in my own clinical practice, PNS seems to act more antinociceptive (peripherally) than in a central inhibitory manner. The present investigation seems to direct us this way, whereas related studies for central neuromodulatory effects of PNS are not available thus far. I think this paper could help us in better understanding of PNS effects, but further studies are necessary. For instance this paper refers specifically to healthy volunteers and it remains to be seen if in chronic neuropathic pain patients these conclusions can be confirmed. Daniel Klase, MD Hamburg, Germany
Michael Stanton-Hicks, MD Cleveland, OH, USA REFERENCES REFERENCE 1. van den Honert, Mortimer JT. Generation of unidirectionally propogated action potentials in a peripheral-nerve by brief stimuli. Science 1979;206:1311–1312.
1. Weiner RL, Reed KL. Peripheral neurostimulation for control of intractable occipital neuralgia. Neuromodulation 1999 Jul;2:217–212. 2. Van Buyten JP, Smet I, Liem L, Russo M, Huygen F. Stimulation of Dorsal Root Ganglia for the Management of Complex Regional Pain Syndrome: A Prospective Case Series. Pain Pract. 2014 Jan 23. doi: 10.1111/papr.12170. [Epub ahead of print].
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© 2013 International Neuromodulation Society
Neuromodulation 2014; 17: 686–695
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