Exploration of the Supraspinal Hypotheses about Spinal Cord Stimulation and Dorsal Root Ganglion Stimulation: A Systematic Review.

Despite the established efficacy and effectiveness of Spinal Cord Stimulation (SCS), there is still no consensus on the supraspinal mechanisms of action of this therapy. The purpose of this study was to systematically review previously raised hypotheses concerning supraspinal mechanisms of action of SCS based on human, animal and computational studies. Searches were conducted using four electronic databases (PubMed, EMBASE, SCOPUS and Web of Science), backward reference searching and consultation with experts. The study protocol was registered prior to initiation of the review process (PROSPERO CRD42020161531). A total of 54 publications were included, 21 of which were animal studies, and 33 were human studies. The supraspinal hypotheses (n = 69) identified from the included studies could be categorized into six groups concerning the proposed supraspinal hypothesis, namely descending pathways (n = 24); ascending medial pathway (n = 13); ascending lateral pathway (n = 10); affective/motivational influences (n = 8); spinal-cerebral (thalamic)-loop (n = 3) and miscellaneous (n = 11). Scientific support is provided for the hypotheses identified. Modulation of the descending nociceptive inhibitory pathways, medial and lateral pathways were the most frequently reported hypotheses about the supraspinal mechanisms of action of SCS. These hypotheses were mainly supported by studies with a high or moderate confidence in the body of evidence.

Effects of spinal cord stimulation on voxel-based brain morphometry in patients with failed back surgery syndrome.

OBJECTIVE: Despite the clinical effectiveness of Spinal Cord Stimulation (SCS), potential structural brain modifications have not been explored. Our aim was to identify structural volumetric changes during subsensory SCS, in patients with Failed Back Surgery Syndrome (FBSS). METHODS: In this cohort study, twenty-two FBSS patients underwent a magnetic resonance imaging protocol before SCS and 3 months after SCS. Clinical parameters were correlated with volumetric changes, calculated with voxel-based morphometry. RESULTS: After 3 months, a significant volume decrease was found in the inferior frontal gyrus, precuneus, cerebellar posterior lobe and middle temporal gyrus. Significant increases were found in the inferior temporal gyrus, precentral gyrus and the middle frontal gyrus after SCS. Additionally, significant increases in volume of superior frontal and parietal white matter and a significant decrease in volume of white matter underlying the premotor/middle frontal gyrus were revealed after SCS. A significant correlation was highlighted between white matter volume underlying premotor/middle frontal gyrus and leg pain relief. CONCLUSIONS: This study revealed for the first time that SCS is able to induce volumetric changes in gray and white matter, suggesting the reversibility of brain alterations after chronic pain treatment. SIGNIFICANCE: Volumetric brain alterations are observable after 3 months of subsensory SCS in FBSS patients.

A Regions of Interest Voxel-Based Morphometry Study of the Human Brain During High-Frequency Spinal Cord Stimulation in Patients With Failed Back Surgery Syndrome.

INTRODUCTION: The effectiveness of spinal cord stimulation (SCS) as pain-relieving treatment for failed back surgery syndrome (FBSS) has already been demonstrated. However, potential structural and functional brain alterations resulting from subsensory SCS are less clear. The aim of this study was to test structural volumetric changes in a priori chosen regions of interest related to chronic pain after 1 month and 3 months of high-frequency SCS in patients with FBSS. METHODS: Eleven patients with FBSS who were scheduled for SCS device implantation were included in this study. All patients underwent a magnetic resonance imaging protocol before SCS device implantation 1 and 3 months after high-frequency SCS. Pain intensity, pain catastrophizing, and sleep quality were also measured. Regions-of-interest voxel-based morphometry was used to explore grey matter volumetric changes over time. Additionally, volumetric changes were correlated with changes in pain intensity, catastrophizing, and sleep quality. RESULTS: Significant decreases were found in volume in the left and right hippocampus over time. More specifically, a significant difference was revealed between volumes before SCS implantation and after 3 months of SCS. Repeated-measures correlations revealed a significant positive correlation between volumetric changes in the left hippocampus and changes in back pain score over time and between volumetric changes in the right hippocampus and changes in back pain score over time. CONCLUSION: In patients with FBSS, high-frequency SCS influences structural brain regions over time. The volume of the hippocampus was decreased bilaterally after 3 months of high-frequency SCS with a positive correlation with back pain intensity.

Magnetic Resonance Imaging Exploration of the Human Brain During 10 kHz Spinal Cord Stimulation for Failed Back Surgery Syndrome: A Resting State Functional Magnetic Resonance Imaging Study.

INTRODUCTION: Apart from the clinical efficacy of high frequency spinal cord stimulation at 10 kHz, the underlying mechanism of action remains unclear. In parallel with spinal or segmental theories, supraspinal hypotheses have been recently proposed. In order to unveil hidden altered brain connectome patterns, a resting state functional magnetic resonance imaging (rsfMRI) protocol was performed in subjects routinely treated for back and/or leg pain with high-frequency spinal cord stimulation (HF-SCS) HF-SCS at 10 kHz. METHODS: RsfMRI imaging was obtained from ten patients with failed back surgery syndrome who were eligible for HF-SCS at 10 kHz. Specifically-chosen regions of interest with different connectivity networks have been investigated over time. Baseline measurements were compared with measurements after 1 month and 3 months of HF-SCS at 10 kHz. Additionally, clinical parameters on pain intensity, central sensitization, pain catastrophizing, and sleep quality were correlated with the functional connectivity strengths. RESULTS: The study results demonstrate an increased connectivity over time between the anterior insula (affective salience network) and regions of the frontoparietal network and the central executive network. After 3 months of HF-SCS, the increased strength in functional connectivity between the left dorsolateral prefrontal cortex and the right anterior insula was significantly correlated with the minimum clinically important difference (MCID) value of the Pittsburgh sleep quality index. CONCLUSION: These findings support the hypothesis that HF-SCS at 10 kHz might influence the salience network and therefore also the emotional awareness of pain.

Association Between Spinal Cord Stimulation and Top-Down Nociceptive Inhibition in People With Failed Back Surgery Syndrome: A Cohort Study.

BACKGROUND: Descending nociceptive inhibitory pathways often malfunction in people with chronic pain. Conditioned pain modulation (CPM) is an experimental evaluation tool for assessing the functioning of these pathways. Spinal cord stimulation (SCS), a well-known treatment option for people with failed back surgery syndrome (FBSS), probably exerts its pain-relieving effect through a complex interplay of segmental and higher-order structures. OBJECTIVE: To the best of our knowledge, no clinical studies have thoroughly investigated the associations between SCS and CPM. DESIGN: This was a prospective cohort study in people with FBSS. METHODS: Seventeen people who had FBSS and were scheduled for SCS were enrolled in this study. The CPM model was evaluated at both sural nerves and was induced by electrical stimulation as the test stimulus and the cold pressor test as the conditioning stimulus. RESULTS: Before SCS, less than 30% of the participants with FBSS showed a CPM effect. Significant increases in the electrical detection threshold on the symptomatic side and the nonsymptomatic side were found. On the symptomatic side, no differences in the numbers of CPM responders before and after SCS could be found. On the nonsymptomatic side, more participants showed a CPM effect during SCS. Additionally, there were significant differences for CPM activation and SCS treatment. LIMITATIONS: Limitations were the small sample size and the subjective outcome parameters in the CPM model. CONCLUSIONS: This study revealed a bilateral effect of SCS that suggests the involvement of higher-order structures, such as the periaqueductal gray matter and rostroventromedial medulla (key regions in the descending pathways), as previously suggested by animal research.

Does Spinal Cord Stimulation Really Influence Sleep?

BACKGROUND: To date, clinical pain research has typically used subjective questionnaires to assess effectiveness of treatment. However, in the near future, new technologies may provide us objective outcome measures as an alternative to self-report. The goal of this study is to compare subjective and objective sleep assessments in a population of failed back surgery syndrome (FBSS) patients, treated with spinal cord stimulation (SCS). METHODS: Twenty-two patients diagnosed with FBSS received SCS. Sleep data was collected at three time point: prior to SCS implantation (B), one month after SCS (T1), and two months after SCS (T2). Sleep data measured by actigraphy provided objective sleep data and were compared to Pittsburgh sleep quality index (PSQI) scores. Agreement between sleep parameters, total sleep time (TST), sleep efficiency (SE), and sleep onset latency (SOL), was examined. RESULTS: Nineteen out of 22 patients completed the study. We identified significant differences between objective and subjective measurements for TST and SE at baseline and after two months of SCS, with patients underestimating both parameters on the PSQI in comparison to objective measurements. For SOL no significant differences were found, although patients subjectively overestimated SOL at B. CONCLUSION: The results about sleep measurements shown in this population of chronic pain patients, suggest that the subjective ratings scored worse than the objective measurements. Second, short-term SCS mainly seems to affect subjectively measured sleep parameters, especially SOL. This study shows the discrepancies between objective and subjective assessments in chronic pain research. Objective tools are indispensable for a correct assessment and treatment of sleep parameters. They are also playing a role as a biofeedback tool and are supporting the rehabilitation process.

Functional magnetic resonance imaging: cerebral function alterations in subthreshold and suprathreshold spinal cord stimulation.

BACKGROUND AND PURPOSE: Failed back surgery syndrome (FBSS) is a common and devastating chronic neuropathic pain disorder. Conventional spinal cord stimulation (SCS) applies electrical suprathreshold pulses to the spinal cord at a frequency of 40-60 Hz and relieves pain in FBSS patients. During the last decade, two major changes have emerged in the techniques of stimulating the spinal cord: paresthesia-free or subthreshold stimulation and administration of higher frequency or higher amounts of energy to the spinal cord. Despite the positive clinical results, the mechanism of action remains unclear. A functional MRI (fMRI) study was conducted to investigate the brain alterations during subthreshold and suprathreshold stimulation at different frequencies. METHODS: Ten subjects with FBSS, treated with externalized SCS, received randomly four different stimulation frequencies (4 Hz, 60 Hz, 500 Hz, and 1 kHz) during four consecutive days. At every frequency, the patient underwent sub- and suprathreshold stimulation. Cerebral activity was monitored and assessed using fMRI. RESULTS: Suprathreshold stimulation is generally accompanied with more activity than sub-threshold SCS. Suprathreshold SCS resulted in increased bilateral activation of the frontal cortex, thalamus, pre- and postcentral gyri, basal ganglia, cingulate gyrus, insula, thalamus, and claustrum. We observed deactivation of the bilateral parahippocampus, amygdala, precuneus, posterior cingulate gyrus, postcentral gyrus, and unilateral superior temporal gyrus. CONCLUSION: Suprathreshold stimulation resulted in greater activity (both activation and deactivation) of the frontal brain regions; the sensory, limbic, and motor cortices; and the diencephalon in comparison with subthreshold stimulation. Each type of frequency at suprathreshold stimulation was characterized by an individual activation pattern.

Is the Self-Reporting of Failed Back Surgery Syndrome Patients Treated With Spinal Cord Stimulation in Line With Objective Measurements?

OBJECTIVES: To understand the subjective pain experience of patients, healthcare providers rely heavily on self-reporting. However, to quantify this unique pain experience, objective parameters are not yet available in daily clinical practice. With regard to patients with failed back surgery syndrome (FBSS) treated with spinal cord stimulation (SCS), pain therapists may recover the individual functional information about the patient's posture from the implantable pulse generator (IPG) of the stimulator. The aim of this study is to investigate whether subjective self-reporting is in correlation with the functional capacities of a patient. MATERIALS AND METHODS: Thirty-nine patients with FBSS, treated with SCS were included. The accelerometer in the IPG detects positional changes and provides an objective output of seven functional positions (lying back, lying prone, lying left, lying right, transition, upright, and upright + mobile). The Oswestry Disability Index (ODI), VAS-diary, and the Pittsburgh Sleep Quality Index (PSQI) were assessed to evaluate physical functioning, pain intensities, and subjective sleep quality. Additionally, 21 patients wore a wearable actigraph device to objectify sleep quality. The agreement and Spearman correlations between objective and subjective parameters were assessed. RESULTS: Spearman rank correlations revealed no significant correlations between the ODI (subscales walking, sitting, standing, and sleeping) and the output of the IPG (percentage upright + mobile, transition, upright, and lying, respectively). Sleep parameters measured with the Actiwatch and the PSQI were not in agreement. CONCLUSIONS: This study demonstrated that self-reporting questionnaires do not correlate with the findings of objective measurements. Therefore, we recommend using both subjective and objective parameters when determining treatment options for FBSS patients.