Active Recharge Burst and Tonic Spinal Cord Stimulation Engage Different Supraspinal Mechanisms: A Functional Magnetic Resonance Imaging Study in Peripherally Injured Chronic Neuropathic Rats.

OBJECTIVES: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS. METHODS: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner. RESULTS: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas. CONCLUSIONS: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst.

Burst and Tonic Spinal Cord Stimulation in the Mechanical Conflict-Avoidance System: Cognitive-Motivational Aspects.

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.

Burst and Tonic Spinal Cord Stimulation Both Activate Spinal GABAergic Mechanisms to Attenuate Pain in a Rat Model of Chronic Neuropathic Pain.

BACKGROUND: Experimental and clinical studies have shown that tonic spinal cord stimulation (SCS) releases gamma-aminobutyric acid (GABA) in the spinal dorsal horn. Recently, it was suggested that burst SCS does not act via spinal GABAergic mechanisms. Therefore, we studied spinal GABA release during burst and tonic SCS, both anatomically and pharmacologically, in a well-established chronic neuropathic pain model. METHODS: Animals underwent partial sciatic nerve ligation (PSNL). Quantitative immunohistochemical (IHC) analysis of intracellular GABA levels in the lumbar L4 to L6 dorsal spinal cord was performed after 60 minutes of burst, tonic, or sham SCS in rats that had undergone PSNL (n = 16). In a second pharmacological experiment, the effects of intrathecal administration of the GABAA antagonist bicuculline (5 µg) and the GABAB antagonist phaclofen (5 µg) were assessed. Paw withdrawal thresholds to von Frey filaments of rats that had undergone PSNL (n = 20) were tested during 60 minutes of burst and tonic SCS 30 minutes after intrathecal administration of the drugs. RESULTS: Quantitative IHC analysis of GABA immunoreactivity in spinal dorsal horn sections of animals that had received burst SCS (n = 5) showed significantly lower intracellular GABA levels when compared to sham SCS sections (n = 4; P = 0.0201) and tonic SCS sections (n = 7; P = 0.0077). Intrathecal application of the GABAA antagonist bicuculline (5 µg; n = 10) or the GABAB antagonist phaclofen (5 µg; n = 10) resulted in ablation of the analgesic effect for both burst SCS and tonic SCS. CONCLUSIONS: In conclusion, our anatomical and pharmacological data demonstrate that, in this well-established chronic neuropathic animal model, the analgesic effects of both burst SCS and tonic SCS are mediated via spinal GABAergic mechanisms.

Burst Spinal Cord Stimulation in Peripherally Injured Chronic Neuropathic Rats: A Delayed Effect.

OBJECTIVE: Two well-known spinal cord stimulation (SCS) paradigms, conventional (Con) and burst SCS, are hypothesized to exert their antinociceptive effects through different stimulation-induced mechanisms. We studied the course of the behavioral antinociceptive effect during 60 minutes of SCS and 30 minutes post-SCS in a rat model of chronic neuropathic pain. METHODS: Animals underwent a unilateral partial sciatic nerve ligation, after which quadripolar electrodes were implanted into the epidural space at vertebral level T13 (n = 43 rats). While receiving either Con SCS or biphasic burst SCS, the pain behavior of the rats was assessed by means of paw withdrawal thresholds (WTs) in response to the application of von Frey monofilaments. RESULTS: After 15 minutes of Con SCS (n = 21), WTs significantly differed from baseline (P = 0.04), whereas WTs of the burst SCS group (n = 22) did not. After 30 minutes of SCS, WTs of the Con SCS and burst SCS groups reached similar levels, both significantly different from baseline, indicating a comparable antinociceptive effect for these SCS paradigms. Yet, the WTs of the burst SCS group were still significantly increased compared with baseline at 30 minutes post-stimulation, whereas the WTs of the Con SCS group were not. CONCLUSIONS: To conclude, biphasic burst SCS results in a delayed antinociceptive effect after onset of the stimulation, as compared with Con SCS, in a chronic neuropathic pain model. Furthermore, biphasic burst SCS seems to exhibit a delayed wash-out of analgesia after stimulation is turned off.

Conventional-SCS vs. Burst-SCS and the Behavioral Effect on Mechanical Hypersensitivity in a Rat Model of Chronic Neuropathic Pain: Effect of Amplitude.

OBJECTIVE: Various spinal cord stimulation (SCS) modes are used in the treatment of chronic neuropathic pain disorders. Conventional (Con) and Burst-SCS are hypothesized to exert analgesic effects through different stimulation-induced mechanisms. Preclinical electrophysiological findings suggest that stimulation intensity is correlated with the effectiveness of Burst-SCS. Therefore, we aimed to investigate the relation between amplitude (charge per second) and behavioral effects in a rat model of chronic neuropathic pain, for both Conventional Spinal Cord Stimulation (Con-SCS) and biphasic Burst-SCS. MATERIALS AND METHODS: Animals (n = 12 rats) received a unilateral partial sciatic nerve ligation, after which they were implanted with quadripolar electrodes in the epidural space at thoracic level 13. Mechanical hypersensitivity was assessed using paw withdrawal thresholds (WTs) to von Frey monofilaments, at various SCS intensities (amplitudes) and multiple time points during 60 minutes of stimulation and 30 minutes post stimulation. RESULTS: Increasing amplitude was shown to improve the efficacy of Con-SCS, whereas the efficacy of Burst-SCS showed a non-monotonic relation with amplitude. Con-SCS at 66% MT (n = 5) and Burst-SCS at 50% MT (n = 6) were found to be equally effective in normalizing mechanical hypersensitivity. However, in the assessed time period Burst-SCS required significantly more mean charge per second to do so (p < 0.01). When applied at comparable mean charge per second, Con-SCS resulted in a superior behavioral outcome (p < 0.01), compared with Burst-SCS. CONCLUSION: Biphasic Burst-SCS requires significantly more mean charge per second in order to achieve similar pain relief, as compared with Con-SCS, in an experimental model of chronic neuropathic pain.

Epigenetic modifications in mouse cerebellar Purkinje cells: effects of aging, caloric restriction, and overexpression of superoxide dismutase 1 on 5-methylcytosine and 5-hydroxymethylcytosine.

The aim of the present study was to assess alterations in DNA methylation and hydroxymethylation during aging in cerebellar Purkinje cells and to determine the effects of putatively preventative measures to such age-related changes. Using immunohistochemical techniques, 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) immunoreactivity in cerebellar Purkinje cells of 12-month- and 24-month-old mice was interrogated. Additionally, the modulatory effects of caloric restriction (CR) and normal human Cu/Zn super oxide dismutase 1 overexpression on these changes were assessed. We show that aging is associated with an increase of 5-mC and 5-hmC immunoreactivity in mouse cerebellar Purkinje cells. These age-related increases were mitigated by CR but not super oxide dismutase 1 overexpression. Additionally, the ratio between 5-mC and 5-hmC decreased with age and CR treatment, suggesting that CR has a stronger effect on DNA methylation than DNA hydroxymethylation. These findings enforce the notion that aging is closely connected to marked epigenetic changes, affecting multiple brain regions, and that CR is an effective means to prevent or counteract deleterious age-related epigenetic alterations.