Neurophysiological predictors for successful SCS 1.0
Research type
Research Study
Full title
Neurophysiological predictors for therapeutic success of spinal cord stimulation in patients with neuropathic pain. A one year observational study exploring changes in cortical oscillation, temporal summation of pain as well as structural and connectivy changes in the somatosensory system.
IRAS ID
224218
Contact name
Andrej Stancak
Contact email
Sponsor organisation
The University of Liverpool
Duration of Study in the UK
4 years, 0 months, 1 days
Research summary
Research Summary
The main goal of this PhD project is to investigate the neurophysiological factors underlying long-term pain relief in patients with neuropathic pain undergoing spinal cord stimulation (SCS) therapy. Patients are referred for SCS treatment after other forms of treatment, such as pharmacological therapy, prove to be ineffective. SCS for pain relief involves large initial costs (about £20,000 per patient). Although recent cost-benefit analyses confirmed the return of funds in two years in successful cases, the therapy is effective in only about 50% of patients. It is therefore essential to understand the factors hindering therapeutic success in patients who show little pain relief or cessation of therapeutic effects after several months.
The proposed research will be split into two studies. Study 1 will involve repeated experiments over a period of one year starting with the initial trial period of the temporary spinal cord stimulator to achieve significant pain relief via a pleasant mode of stimulation. Patients will attend two more experimental sessions, at 6 months and 12 months after implantation. We will record magnetic resonance imaging (MRI) scans of the brain prior to the trial and implantation of the stimulator. Electrophysiological and psychophysical data will be acquired both prior to the use of the spinal cord stimulator and during two follow-up periods (6 and 12 months). Therapeutic success of SCS will be evaluated using routine outcome data collected by the neuromodulation team. Study 2 will investigate effects of three different intensities of SCS on ongoing brain electrical activity to explore the neurophysiological mechanisms of burst SCS. This research problem is important as burst SCS only works in a relatively narrow range of intensities, and determination of the correct stimulation intensity is of critical importance in this therapy.
Data will allow the comparison of patients responding or not-responding to SCS in term of brain structure and function, immediate brain response to trains of spinal cord stimuli, and the sensitivity of the spinal cord neurons. The measures of brain and spinal cord activation will be used to build a mathematical prediction model which in future can be used by neuromodulation teams in their therapeutic decisions.
Summary of Results
Neuropathic pain is defined as pain caused by a lesion or disease in the somatosensory system (Treede et al., 2008). Neuropathic pain syndromes affect approximately 7–10% of the general population (van Hecke et al., 2014), with negative impacts on quality of life and functioning (Smith & Torrance, 2012). Spinal cord stimulation (SCS) is an established intervention for reducing neuropathic pain symptoms. However, only 62% of patients who undergo permanent SCS implantation experience adequate pain relief (Taylor et al., 2014), and an estimated 30% of all implanted devices are removed (Simopoulos et al., 2019). A lack of effectiveness could be partly due to our limited understanding of the therapeutic mechanisms of SCS (Jensen & Brownstone, 2019).
Previous studies have highlighted spinal and supraspinal mechanisms in the therapeutic effects of SCS. Conventional tonic SCS has been proposed to work via multiple mechanisms, including inhibition of somatosensory processing (Linderoth & Foreman, 2017). Mechanisms underlying the newer burst waveform are still under debate. Limited studies point towards alternative mechanisms for tonic and burst waveforms which are reflected in the spine (Crosby et al., 2015b; Tang et al., 2014) and in the brain. Examination of the effects of burst and tonic SCS on spontaneous oscillations and the processing of somatosensory input is necessary to investigate the therapeutic mechanisms underlying the two waveforms.
This research aimed to investigate both spinal cord and supraspinal mechanisms of SCS and predictors of SCS effectiveness. The research consisted of two studies. Firstly, we conducted a longitudinal study (Study 1) to identify factors predicting pain relief during SCS therapy. This research problem is important as the current method to identify patients suitable for SCS therapy is not entirely effective, and many patients who undergo SCS implantation do not experience long-term pain relief. Secondly, we investigated the effects of four different intensities of SCS on ongoing brain electrical activity (Study 2). This research problem is important as burst SCS only works in a relatively narrow range of intensities, and determination of the correct stimulation intensity is of critical importance in this therapy.
The research was conducted by a team of researchers at the University of Liverpool in collaboration with clinicians at The Walton Centre NHS Foundation Trust. The research was funded by a Medical Research Council Industrial CASE studentship in partnership with Abbott. Study 1 investigated differences in brain structure and function, changes in cortical oscillations during rest, and suppression of tactile stimulus processing during SCS, as a function of treatment response. The target population for the study was patients with unilateral or bilateral neuropathic lower limb pain aged between 18-80 years of age with no history of neurological or psychiatric conditions, who were due to undergo SCS implantation. Data were collected from patients during four visits: one before SCS implant, and at 1-month, 6-months and 12 months following implant. This study was not completed due to complications arising from the COVID-19 pandemic.
Study 2 investigated the effects of different modes of SCS and of varying intensities of SCS and LFS on resting oscillatory activity and in response to somatosensory stimuli, measured using EEG. The target population for the study was patients aged 18-80 years with no history of neurological or psychiatric conditions who were using burst or tonic SCS as a treatment for unilateral or bilateral neuropathic lower limb pain. Data were collected from patients during a single visit where EEG was recorded at rest and during brushing of the leg at four SCS: no stimulation, low, medium, and therapeutic intensities. The use of EEG measures allowed investigation of the underlying cortical processes relating to varying intensities and types of SCS.
Results from the study indicated that SCS induced changes in cortical excitability which were modulated by stimulation intensity. Inspection of oscillatory activity during burst and tonic SCS supports different underlying mechanisms which are engaged during somatosensory input. The varying effects of burst and tonic SCS on tactile somatosensory processing and spontaneous cortical oscillations were investigated based on evidence of alternative mechanisms (De Ridder et al., 2013; De Ridder & Vanneste, 2016; Yearwood et al., 2019). Burst and tonic SCS were found to modulate tactile somatosensory processing differently, although no significant difference in spontaneous cortical oscillations was found. In accordance with the Gate Control Theory, tonic SCS has been shown to stimulate the dorsal column pathway (Holsheimer, 2002; Joosten & Franken, 2020; Melzack & Wall, 1965; Shealy et al., 1967) and inhibit somatosensory processing (Bentley et al., 2016; Sankarasubramanian et al., 2019). Results in patients using tonic SCS align with these findings. Comparatively, burst SCS is proposed to engage the spinothalamic tract without the involvement of the dorsal column pathway (De Ridder & Vanneste, 2016; Joosten & Franken, 2020). In line with this theory, results showed that burst SCS did not attenuate somatosensory processing during brushing of the leg, pointing towards alternative mechanisms (Gandevia et al., 1983; Kakigi & Jones, 1986; Mancini et al., 2015).
Findings from this research have important implications for theory and clinical practice. Strong interference with the transmission of afferent impulses at SCS intensities as much as one-third lower than the therapeutic level suggests that lower intensities may be equally or more effective than the clinically programmed settings. SCS intensity is one facet of electrical dose and electrical charge transfer. Lower electrical charge transfer preserves battery life and reduces any unpleasant paraesthesia sensations (Miller et al., 2016; Paz-Solís et al., 2022). Optimising electrical dose is crucial for effective pain relief with SCS (Chakravarthy et al., 2021; Paz-Solís et al., 2022). Currently, the method for SCS dose titration is a process of trial and error between the programmer and the patient. Further understanding of the SCS therapeutic window, particularly for paraesthesia-free waveforms, is of vital importance. Therefore, these preliminary findings suggest that EEG may have a valuable role in determining optimal stimulation parameters for managing neuropathic pain.
The findings demonstrated that stimulation intensity is a critical factor determining response to SCS, with greater intensities inhibiting activity in somatosensory processing regions. Tonic and burst stimulation have different and shared mechanisms which were highlighted during somatosensory stimulation, and greater suppression of parallel inputs from brushing during tonic stimulation supports the gating effect of SCS. Effects of stimulation at less than therapeutic intensities warrant further investigation but suggest the possibility of implementing SCS at lower intensities to maximise treatment effectiveness. These findings may have important clinical implications for the treatment of neuropathic pain which has not been adequately managed with first-line pharmacological treatments.
A subset of these findings will be published in a peer-reviewed scientific journal. Additionally, the studies formed part of a PhD thesis, the final version of which is available on the University of Liverpool repository.References
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Treede, R.-D., Jensen, T. S., Campbell, J. N., Cruccu, G., Dostrovsky, J. O., Griffin, J. W., Hansson, P., Hughes, R., Nurmikko, T. J., & Serra, J. (2008). Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology, 70(18), 1630–1635. https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbZxmW28CQkjRxNmV-2Bm3eYU1V-2F9r-2BuNbOyfEQxKS4R1lRsGKqcIwcgJFFULUk40p-2Fvg-3D-3DU7Lj_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJ-2FMD89dhYOhkcRz0aIGJTFId2cV88RQ2zS5hOeOVDNuxC32LQnxfZLtg9rkK7aA61F-2BXX1LS-2BxU93A7fUUwvTkITlmlL5Kr7XiZw5xCJzwu5EBVB0trL3Iqr-2BTTPOWOzPm7hw70vjFSmBhXgIk0LWDoIiSRnt-2B0fO2qn8W-2Fi68vQ-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C95b327ba44394e5a91f608db58635c31%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638200955995853605%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=pCIop4wORco7Frd2eyB45%2FnXtYBHOf6HFBQUTI86KXM%3D&reserved=0
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Yearwood, T., Ridder, D. De, Yoo, H. Bin, Falowski, S., Venkatesan, L., To, W. T., Vanneste, S., De Ridder, D., Yoo, H. Bin, Falowski, S., Venkatesan, L., Ting To, W., & Vanneste, S. (2019). Comparison of Neural Activity in Chronic Pain Patients During Tonic and Burst Spinal Cord Stimulation Using Fluorodeoxyglucose Positron Emission Tomography. Neuromodulation: Technology at the Neural Interface, 2019(1), 56–63. https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbSu94g-2Fw7XUVx4K3PFSk7euG3LnAhAXYjCa6Wj7tkxCcZmgg_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJ-2FMD89dhYOhkcRz0aIGJTF42M1d7XdwIsB5SzPIB617C8J7lN0hkWb3HhZJkzgZBUEn72Ks-2FE5j-2BM11-2FFmIcaEIcnd2u2N6EV2tF6pgbjs7TfbpvG5WjblRYpYK7N50TFPIu4GQeCus48zAJq5vmT3AQHRrh-2FlECQCBAfhtYYkkg-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C95b327ba44394e5a91f608db58635c31%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638200955995853605%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=Cnc4mKqVzhrrQRBpgCLTp%2FOrLOd8OthsjkPcI9FOnUI%3D&reserved=0REC name
North West - Liverpool Central Research Ethics Committee
REC reference
17/NW/0676
Date of REC Opinion
18 Jan 2018
REC opinion
Further Information Favourable Opinion