Abstract
Background Clinical research suggests that a novel spinal cord stimulation (SCS) waveform, known as Burst-SCS, specifically targets cognitive-motivational aspects of pain. The objective of the present study was to assess the cognitive-motivational aspects of Tonic- and Burst SCS-induced pain relief, by means of exit latency in the mechanical conflict-avoidance system (MCAS), in a rat model of chronic neuropathic pain. Methods Exit latency on the MCAS operant testing setup was evaluated at various probe heights for rats (n = 26) with chronic neuropathic pain induced by a partial sciatic nerve ligation (PSNL). Von Frey paw withdrawal analysis was performed to assess mechanical hypersensitivity. In a second experiment (n = 12), the behavioral effect of Tonic SCS or biphasic Burst SCS on both Von Frey analysis and MCAS exit latency was assessed. Results Burst SCS exit latencies differed significantly from Tonic SCS exit latencies at 4 mm probe height (3.8 vs. 5.8 sec, respectively;p<0.01) and 5 mm probe height (3.2 vs. 5.4 sec respectively;p<0.05). This difference was not detected with reflex-based Von Frey testing (Tonic-SCS vs. Burst-SCS at 30 min stimulation:p= 0.73, and at 60 min stimulation;p= 0.42). Conclusions Testing of MCAS exit latency allows for detection of cognitive-motivational pain relieving aspects induced by either Tonic- or Burst-SCS in treatment of chronic neuropathic rats. Our behavioral findings strongly suggest that Burst-SCS specifically affects, much more than Tonic-SCS, the processing of cognitive-motivational aspects of pain.
| Original language | English |
|---|---|
| Pages (from-to) | 605-612 |
| Number of pages | 8 |
| Journal | Neuromodulation |
| Volume | 23 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Jul 2020 |
Keywords
- Chronic neuropathic pain
- mechanical conflict-avoidance test
- mechanical hypersensitivity
- peripheral nerve injury
- spinal cord stimulation
- ATTENUATES OPERANT ESCAPE
- NEUROPATHIC PAIN
- SCIATIC-NERVE
- ANIMAL-MODEL
- CHRONIC BACK
- RESPONSES
- HYPERSENSITIVITY
- HYPERALGESIA
- REFLEX
- RATS
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In: Neuromodulation, Vol. 23, No. 5, 07.2020, p. 605-612.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Burst and Tonic Spinal Cord Stimulation in the Mechanical Conflict-Avoidance System
T2 - Cognitive-Motivational Aspects
AU - Meuwissen, Koen P.
AU - van Beek, Maarten
AU - Joosten, Elbert A. J.
N1 - Funding Information: The implantation of the SCS device was performed according to the standard protocol. In short, the spinal cord was exposed by a midline, lumbar incision, followed by laminectomy at level T13. During the full procedure, the dura was kept intact. A custom-made cylindrical 4-contact lead (0.72 mm diameter; Boston Scientific Neuromodulation, Valencia, CA, USA) was introduced into the epidural space as previously was performed in Meuwissen et al. The electrode was located caudally below the adjacent one or two lamina. Electrode configuration was set at alternating cathode and anode settings (rostral to caudal: + − + −). After implantation of the electrodes, the rats were given 2 days for recovery prior to the initiation of SCS. All experiments were performed in accordance with the European directive for the protection of vertebrate animals used for experimental and other scientific purposes (86/609/EU). The protocol was approved by the Animal Research Committee of the Maastricht University Medical Centre (DEC-protocol 2014-086). All experiments were performed using male Sprague Dawley rats (n = 38), which were young-adult (5 weeks of age) at the start of the experiment (150-200 g). Animals were housed in groups of 2, in filter-top polycarbonate cages in a climate-controlled vivarium maintained under controlled temperature (21°C ± 1°C), relative humidity (55% ± 15%) and artificial lighting (12:12 hour light/dark cycle) with distilled water and rodent chow available ad libitum. The vivarium was equipped with a mobile radio, continuously producing background music at 45 decibels, in order to desensitize the animals for translocation and experimenter-related noise. All procedures were conducted between 09:00 and 16:00 hours. A unilateral ligation of the left sciatic nerve was performed as described by Seltzer et al. 1990, and previously applied in our laboratory. In short, animals were anesthetized with 3%-5% isoflurane (Abbott Laboratories Ltd., Kent, UK). The left sciatic nerve was exposed by blunt dissection and carefully freed from surrounding connective tissue. For sham-PSNL animals, the sciatic nerve was left unaffected and the wound was closed with a 4/0 silk suture. For PSNL animals, distal to the posterior biceps semitendinosus, but proximal to the little fat pad that lies a few millimeters distal to this site, the sciatic nerve was partially ligated. An 8/0 non-absorbable silk suture was used to ligate approximately 1/3 of the diameter of the left sciatic nerve. After ligation, the wound was closed with a 4/0 silk suture. The presence of mechanical hypersensitivity was considered successful if at 13 days post-surgery, paw withdrawal thresholds (PWTs) to Von Frey stimuli (10log [50%]) were decreased by 0.2 units compared with baseline (day 0). Assessment of PWTs was performed according to the standard protocol. Mechanical hypersensitivity based on PWT was assessed according to the “up-down method”. The 50% PWT was calculated after completion of a sequence of six consecutive responses. A cut-off value of 28.84 g was defined. For statistical analysis, 50% PWTs were logarithmically transformed to obtain a linear scale. Familiarization and Training was conducted as described in detail by Harte et al. 2016. Rats underwent room acclimation for 30 min prior to the start of behavioral testing each day. Rats were placed individually, in random order, into the start-compartment with the light turned off and the exit door closed. Animals were acclimatized to the dark for 15 sec, before the compartment light was turned on for the duration of the test. Twenty seconds after the light was turned on the exit door was opened. The latency to exit the light compartment was recorded by means of a stopwatch, starting from the time the exit door was opened until all four paws were placed upon the nociceptive probes. If the animal reached the dark compartment, the door was closed, and the rat was returned gently to its home cage after being rewarded with 20 sec of darkness. Failure to exit the light compartment within 20 sec after opening of the exit door was marked as “failed exit,” which resulted in the exit door being closed and the rat being returned to its home cage. Rats that successfully escaped the light compartment but failed to enter the dark compartment after 120 sec, were marked as failed cross, and were returned to their home cage until the next trial. The test procedure was repeated three times (trials) per test session (a minimum of 20 min between trials), with one test session per probe height, per day. It was decided to introduce the different probe heights in a non-randomized ascending order over the six test days (starting with 0.5 mm on test day 1, followed by 1 mm on test day 2, 2 mm on test day 3, 3 mm on test day 4, 4 mm on test day 5, and 5 mm on day 6). All test sessions were video-recorded with an ultra-wide angle glass lens camera. Recordings were started immediately after the animal was placed inside the start-compartment (with the light turned off), and were continued until the animal was returned to its home cage. After finalization of the entire experiment all recordings of exit latency were re-timed with a stopwatch and compared with the manually collected data acquired during the experiment. The implantation of the SCS device was performed according to the standard protocol. In short, the spinal cord was exposed by a midline, lumbar incision, followed by laminectomy at level T13. During the full procedure, the dura was kept intact. A custom-made cylindrical 4-contact lead (0.72 mm diameter; Boston Scientific Neuromodulation, Valencia, CA, USA) was introduced into the epidural space as previously was performed in Meuwissen et al. The electrode was located caudally below the adjacent one or two lamina. Electrode configuration was set at alternating cathode and anode settings (rostral to caudal: + − + −). After implantation of the electrodes, the rats were given 2 days for recovery prior to the initiation of SCS. Tonic-SCS was performed according to the protocol described in Meuwissen et al. The stimulator was set to deliver constant current biphasic stimulation, with a frequency of 50 Hz and a pulse width of 200 μS at 66% of the Motor Threshold for Tonic SCS (n = 5). For biphasic Burst SCS (n = 5) the stimulator was set to an interburst-frequency 40 Hz, a pulse width 1000 μS, and five active biphasic spikes at 449 Hz intraburst frequency at 50% of the Motor Threshold. Animals were stimulated for 30 min. in the MCAS-set-up, with the light turned off and the door closed. Subsequently, stimulation was continued during the MCAS-testing session, which was performed according to the standard MCAS-testing protocol. The animals were randomized across experimental groups, and the investigator was blinded to the experimental condition during behavioral testing. SCS in the MCAS-system was performed with use of a custom-made experimental apparatus. The cables from the stimulator were guided to a swivel, which allowed 360° free movement. The cable was then further guided to the SCS connectors in the neck of the animal by means of a fender-tension spring system, which generated the appropriate amount of tension in order to prevent any slacking of the cables. The upper cover of the MCAS crossing area was removed to create access for the SCS-system. Removal of the upper cover was performed at the start of the experiment, before the training phase, to prevent distraction of the animal due to removal. Furthermore, animals underwent an additional training period of 3 days with the complete experimental apparatus before start of the SCS experiment, for the animals to become familiarized with the experimental apparatus before testing. To control for the effects of SCS in the MCAS-system, a sham-SCS group was included (n = 2). After acclimatization to the vivarium, a 2-day familiarization period was initiated, followed by a 5-day training period. This was followed by a 2-day rest period, after which the baseline (pre-PSNL) test period was initiated, which consisted of six subsequent days of testing as described above. Subsequently, animals received either PSNL (n = 18) or sham-PSNL surgery (n = 8). Following a 14-day observation period, during which animals underwent von Frey behavioral analysis in order to assess whether mechanical hypersensitivity was successfully induced, animals were subjected to a two-day “refresher” training period (PSNL [n = 17] and sham-PSNL [n = 8]). During these 2 days it was noted whether animals still displayed stable exit behavior. Finally, a 6-day, post-PSNL, testing period was initiated, identical to the baseline test period (PSNL [n = 17] and sham-PSNL [n = 8]) (Fig.). In a second experiment (Fig.), 12 animals received PSNL surgery and were subjected to the training- and testing period as described above. This period was followed by the implantation of the SCS-electrode, and a post-implantation (Pre-SCS) test week to assess possible implantation-related effects on the MCAS-outcome. Subsequently, two animals received Sham SCS, and the other animals (n = 10) were placed in the MCAS-system after which simultaneous MCAS-SCS testing was performed as described in section 2.7. Five animals received Burst SCS (n = 5), while the other five animals received Tonic SCS (n = 5). The PWTs to von Frey filaments are presented as mean ± standard error of the mean (SEM). For statistical analysis, von Frey data were logarithmically transformed to obtain a linear scale to account for Weber's Law. For the analysis of differences in the withdrawal thresholds between groups, ipsilateral and contralateral PWTs were compared using paired-sampled t-tests. To account for skewness of data at higher probe heights MCAS exit latencies were logarithmically transformed. Effects of probe height on exit latencies were analyzed using repeated-measures analysis of variance (ANOVA). Probe height (six levels: 0, 1, 2, 3, 4, and 5 mm) was assigned as within-subjects factor and the experimental group (Sham-PSNL vs. PSNL or Pre-SCS vs. SCS) was assigned as between-subjects factor. If the assumption of sphericity was violated, the Greenhouse–Geisser correction was used to correct the degrees of freedom in subsequent univariate analyses. Multivariate analyses were used to test for differences between groups at specific probe heights. To assess within-group differences for the Sham-PSNL versus PSNL group, pre- versus post-surgery, and the Pre-SCS versus SCS group, paired-samples t-tests were performed. Furthermore, bivariate correlation between bodyweights, von Frey data, and MCAS exit- latencies were performed to identify possible causalities between the different outcome measures. All statistical analyses were performed with α = 0.05 using IBM SPSS statistics 23. Publisher Copyright: © 2019 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals, Inc. on behalf of International Neuromodulation Society.
PY - 2020/7
Y1 - 2020/7
N2 - Background Clinical research suggests that a novel spinal cord stimulation (SCS) waveform, known as Burst-SCS, specifically targets cognitive-motivational aspects of pain. The objective of the present study was to assess the cognitive-motivational aspects of Tonic- and Burst SCS-induced pain relief, by means of exit latency in the mechanical conflict-avoidance system (MCAS), in a rat model of chronic neuropathic pain. Methods Exit latency on the MCAS operant testing setup was evaluated at various probe heights for rats (n = 26) with chronic neuropathic pain induced by a partial sciatic nerve ligation (PSNL). Von Frey paw withdrawal analysis was performed to assess mechanical hypersensitivity. In a second experiment (n = 12), the behavioral effect of Tonic SCS or biphasic Burst SCS on both Von Frey analysis and MCAS exit latency was assessed. Results Burst SCS exit latencies differed significantly from Tonic SCS exit latencies at 4 mm probe height (3.8 vs. 5.8 sec, respectively;p<0.01) and 5 mm probe height (3.2 vs. 5.4 sec respectively;p<0.05). This difference was not detected with reflex-based Von Frey testing (Tonic-SCS vs. Burst-SCS at 30 min stimulation:p= 0.73, and at 60 min stimulation;p= 0.42). Conclusions Testing of MCAS exit latency allows for detection of cognitive-motivational pain relieving aspects induced by either Tonic- or Burst-SCS in treatment of chronic neuropathic rats. Our behavioral findings strongly suggest that Burst-SCS specifically affects, much more than Tonic-SCS, the processing of cognitive-motivational aspects of pain.
AB - Background Clinical research suggests that a novel spinal cord stimulation (SCS) waveform, known as Burst-SCS, specifically targets cognitive-motivational aspects of pain. The objective of the present study was to assess the cognitive-motivational aspects of Tonic- and Burst SCS-induced pain relief, by means of exit latency in the mechanical conflict-avoidance system (MCAS), in a rat model of chronic neuropathic pain. Methods Exit latency on the MCAS operant testing setup was evaluated at various probe heights for rats (n = 26) with chronic neuropathic pain induced by a partial sciatic nerve ligation (PSNL). Von Frey paw withdrawal analysis was performed to assess mechanical hypersensitivity. In a second experiment (n = 12), the behavioral effect of Tonic SCS or biphasic Burst SCS on both Von Frey analysis and MCAS exit latency was assessed. Results Burst SCS exit latencies differed significantly from Tonic SCS exit latencies at 4 mm probe height (3.8 vs. 5.8 sec, respectively;p<0.01) and 5 mm probe height (3.2 vs. 5.4 sec respectively;p<0.05). This difference was not detected with reflex-based Von Frey testing (Tonic-SCS vs. Burst-SCS at 30 min stimulation:p= 0.73, and at 60 min stimulation;p= 0.42). Conclusions Testing of MCAS exit latency allows for detection of cognitive-motivational pain relieving aspects induced by either Tonic- or Burst-SCS in treatment of chronic neuropathic rats. Our behavioral findings strongly suggest that Burst-SCS specifically affects, much more than Tonic-SCS, the processing of cognitive-motivational aspects of pain.
KW - Chronic neuropathic pain
KW - mechanical conflict-avoidance test
KW - mechanical hypersensitivity
KW - peripheral nerve injury
KW - spinal cord stimulation
KW - ATTENUATES OPERANT ESCAPE
KW - NEUROPATHIC PAIN
KW - SCIATIC-NERVE
KW - ANIMAL-MODEL
KW - CHRONIC BACK
KW - RESPONSES
KW - HYPERSENSITIVITY
KW - HYPERALGESIA
KW - REFLEX
KW - RATS
U2 - 10.1111/ner.12955
DO - 10.1111/ner.12955
M3 - Article
C2 - 30974021
SN - 1094-7159
VL - 23
SP - 605
EP - 612
JO - Neuromodulation
JF - Neuromodulation
IS - 5
ER -