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

Abstract

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.

Spinal cord stimulation in chronic neuropathic pain: mechanisms of action, new locations, new paradigms

“…With the MCAS, Burst SCS exit latencies differed significantly from Tonic SCS exit latencies, and from this, it was concluded that Burst SCS specifically affects, much more than Tonic SCS, supraspinal areas responsible for the processing of cognitive-motivational aspects of pain. These findings were further substantiated with fMRI imaging 66 : fMRI analysis of Burst SCS in chronic neuropathic animals showed specific involvement and activation of limbic brain areas including the ACC as well as the amygdala and insula, areas known to be involved in cognitive and emotional aspects of pain. The behavioral and imaging studies on Burst SCS and Tonic SCS in pain relief in a neuropathic animal model strongly suggest that the mechanism underlying Burst SCS significantly differs from that of Tonic, although some overlap in underlying mechanism (eg, GABA release in dorsal spinal horn) does exist.…”

“…That Tonic SCS can also modulate activation patterns in brain areas at subcortical and cortical levels has been shown in a rodent model of chronic neuropathic pain. 66 , 70 How Tonic SCS alters cortical processing has also been shown by clinical studies using imaging approaches such as functional magnetic resonance imaging (fMRI), positron-emission tomography, single-photon emission computed tomography, and 133-Xe inhalation (reviewed in Bentley et al 11 ). These cortical changes during Tonic SCS may represent direct effects from dorsal column stimulation or inhibition of nociceptive signals arising from the periphery, or they may reflect complex modulatory effects on somatosensory and affective processing.…”

“… 70 This indicates that Tonic SCS, in addition to local spinal modulation, also recruits supraspinal brain areas, a finding further substantiated by fMRI analysis of brain areas including the anterior cingulate cortex (ACC). 66 These findings make clear that operant behavioral testing should be considered when analyzing the analgesic effects of SCS in chronic neuropathic pain because this is not only likely to increase the translation of experimental findings to the clinic but will also help to better understand the underlying mechanisms of action.…”

Brain fMRI during orientation selective epidural spinal cord stimulation

“…In such earlier studies, negative activations of the thalamus, cingulate cortex and insula were seen in failed back surgery patients 28 , but also negative and positive activations have been reported in the somatosensory cortex while having negative activation in the primary motor cortex 5 . ESCS and brain fMRI studies have been conducted also in rats 30,31 . Upon stimulation of the dorsal root ganglion of a rat, nearly no brain fMRI response was observed with a therapeutic level stimulus, although at higher stimulus positive activation of the thalamus and negative activation of the caudate and putamen were www.nature.com/scientificreports/ seen, corresponding to noxious stimuli 31 .…”

“…Upon stimulation of the dorsal root ganglion of a rat, nearly no brain fMRI response was observed with a therapeutic level stimulus, although at higher stimulus positive activation of the thalamus and negative activation of the caudate and putamen were www.nature.com/scientificreports/ seen, corresponding to noxious stimuli 31 . In chronic neuropathic rats, activation of cortical and subcortical brain areas like the thalamus, the anterior cingulate cortex as well as the motor and sensorimotor cortices was observed during conventional and burst SCS 30 . Such areas resemble the outcomes presented in the current study, therefore in the sense of elicited activation patterns, our results are in line with existing literature.…”