The descending pain modulatory system (DPMS) comprises a network of cortical and subcortical brain and brainstem regions that can inhibit nociceptive afferent brain input (Ossipov et al., 2010; Tracey, 2010; Zhuo and Gebhart, 1997). These pathways seem to be altered in several chronic pain syndromes such as knee osteoarthritis, fibromyalgia, painful diabetic neuropathy and low back pain (Brietzke et al., 2019; da Graca-Tarrago et al., 2019; Kong et al., 2018; Segerdahl et al., 2018). The DPMS network comprises the bilateral anterior insulae (AI), the anterior cingulate cortex (ACC), bilateral middle frontal gyri (mFG), both amygdalae (AMY), the rostral ventromedial medulla (RVM) and the periaqueductal gray (PAG) (Goksan et al., 2018; Schweinhardt and Bushnell, 2010). In the past, it has been suggested that traditional, paresthesia-generating Spinal Cord Stimulation (SCS) induces several changes in modulation circuits located in the cerebrum and brainstem. An inhibitory effect of traditional SCS on somatosensory evoked potentials, and potential mediators like the thalamus and the anterior cingulate cortex (ACC), could play a role in the mechanism of action (MOA) of SCS as well (Bentley et al., 2016; De Ridder and Vanneste, 2016; Moens et al., 2013, 2012). Several studies have provided evidence of the impact of SCS on the DPMS resulting in this inhibitory supraspinal effect (Sankarasubramanian et al., 2018; Schuh-Hofer et al., 2018). More recently, researchers have hypothesized similar influences on the DPMS by other paradigms of SCS such as high frequency SCS at 10 kHz and Burst SCS, as well as by other forms of neurostimulation e.g. occipital nerve field stimulation (Ahmed et al., 2018a, 2018c). Tonic SCS at sub-sensory threshold and at 500 Hz and pulse width 500μsec, so called high density or high dose SCS (HD-SCS), is a SCS form based on the impact of electrical charge delivery to the spinal cord (Chen et al., 2018; Linderoth and Foreman, 2017; Miller et al., 2016; Sweet et al., 2016; Wille et al., 2017). After some initial case series studies, researchers are still exploring the clinical effect and impact on chronic pain of HD-SCS (De Jaeger et al., 2017; Provenzano et al., 2017; Wille et al., 2017). In the past, several researchers have investigated the supraspinal effects of SCS by examining human cerebral circuits via different neuroimaging techniques (e.g. MR Spectroscopy (MRS), single photon emission computerized tomography (SPECT), positron emission tomography (PET), electroencephalography (EEG) and, functional magnetic resonance imaging (fMRI)) to capture alterations in modulation circuits (De Ridder and Vanneste, 2016; Kishima et al., 2010; Moens et al., 2013, 2012; Nagamachi et al., 2006). fMRI is especially interesting due to the robustness and test-retest reliability of the functional connectivity (FC) method in clinical applications (Apkarian, 2015; Shehzad et al., 2009). Additionally, the introduction of MRI-conditioned SCS devices enables further exploration of MOA of SCS, not only during trial period but also on long-term implanted devices. Based on this knowledge, we hypothesized, in this study, that HD-SCS may alter the DPMS and indirectly, might generate an inhibitory supraspinal effect. This hypothesis-driven pilot study aimed to investigate the influence of HD-SCS on FC within the DPMS, measured by resting state fMRI.
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