Effect of Conventional Spinal Cord Stimulation on Serum Protein Profile in Patients With Persistent Spinal Pain Syndrome: A Case-Control Study.

BACKGROUND: Spinal cord stimulation (SCS) provides pain relief for most patients with persistent spinal pain syndrome type 2 (PSPS 2). Evidence is mounting on molecular changes induced by SCS as one of the mechanisms to explain pain improvement. We report the SCS effect on serum protein expression in vivo in patients with PSPS 2. MATERIALS AND METHODS: Serum proteins were identified and quantified using mass spectrometry. Proteins with significantly different expression among patients with PSPS 2 relative to controls, responders, and nonresponders to SCS, or significantly modulated by SCS relative to baseline, were identified. Those most correlated with the presence and time course of pain were selected using multivariate discriminant analysis. Bioinformatic tools were used to identify related biological processes. RESULTS: Thirty patients with PSPS 2, of whom 23 responded to SCS, were evaluated, together with 14 controls with no pain who also had undergone lumbar spinal surgery. A significant improvement in pain intensity, disability, and quality of life was recorded among responders. Five proteins differed significantly at baseline between patients with PSPS 2 and controls, with three proteins, mostly involved in immune processes and inflammation, being downregulated and two, mostly involved in vitamin metabolism, synaptic transmission, and restorative processes, being upregulated. In addition, four proteins, mostly related to immune processes and inflammation, decreased significantly, and three, mostly related to iron metabolism and containment of synaptic sprouting, increased significantly during SCS. CONCLUSION: This study identifies various biological processes that may underlie PSPS 2 pain and SCS therapeutic effects, including the modulation of neuroimmune response and inflammation, synaptic sprouting, vitamin and iron metabolism, and restorative processes.

Predictive Clinical Decision Support System Using Machine Learning and Imaging Biomarkers in Patients With Neurostimulation Therapy: A Pilot Study.

BACKGROUND: Chronic pain is correlated with alterations in brain structure and function. The selection process for the ideal candidate for spinal cord stimulation (SCS) therapy is based on functional variables analysis and pain evaluation scores. In addition to the difficulties involved in the initial selection of patients and the predictive analysis of the trial phase, the large rate of explants is one of the most important concerns in the analysis of the suitability of implanted candidates. OBJECTIVE: To investigate the usefulness of imaging biomarkers, functional connectivity (FC) and volumetry of the whole brain in patients with Failed back surgery syndrome (FBSS) and to create a clinical patient-based decision support system (CDSS) combining neuroimaging and clinical data for predicting the effectiveness of neurostimulation therapy after a trial phase. STUDY DESIGN: A prospective, consecutive, observational, single center study. SETTING: The Multidisciplinary Pain Management Department of the General University Hospital in Valencia, Spain. METHODS: A prospective, consecutive, and observational single-center study. Using Resting-state functional magnetic resonance imaging (rs-fMRI) and Region of interest (ROI) to ROI analysis, we compared the functional connectivity between regions to detect differences in FC and volume changes. Basal magnetic resonance images were obtained in a 1.5T system and clinical variables were collected twice, at the basal condition and at 6-months post-SCS implant. We also conducted a seed-to-voxel analysis with 9 items as seed-areas characterizing the functional connectivity networks. A decreased in 10 units in the Pain Detect Questionnaire (PD-Q) score was established to define the subgroup of Responders Group (R-G) to neurostimulation therapy. The clinical variables collected and the imaging biomarkers obtained (FC and volumes) were tested on a set of 6 machine learning approaches in an effort to find the best classifier system for predicting the effectiveness of the neurostimulator. RESULTS: Twenty-four patients were analyzed and only seven were classified in the R-G. Volumetric differences were found in the left putamen, F = 34.06, P = 0.02. Four pairwise brain areas showed statistical differences in the rs-fMRI including the right insular cortex. Linear Discriminant Analysis showed the best performance for building the CDSS combining clinical variables and significant imaging biomarkers, the prediction increased diagnostic accuracy in the R-G patients from 29% in current practice to 96% of long-term success. CONCLUSION: These findings confirm a major role of the left putamen and the four pairs of brain regions in FBBS patients and suggest that a CDSS would be able to select patients susceptible to benefitting from SCS therapy adding imaging biomarkers.

Differences in Gene Expression of Endogenous Opioid Peptide Precursor, Cannabinoid 1 and 2 Receptors and Interleukin Beta in Peripheral Blood Mononuclear Cells of Patients With Refractory Failed Back Surgery Syndrome Treated With Spinal Cord Stimulation: Markers of Therapeutic Outcomes?

OBJECTIVE: The use of spinal cord stimulation for patients with failed back surgery syndrome (FBSS) is very common. In order to better understand the mechanisms of action of spinal cord stimulation (SCS), our aim was to determine potential changes in relative gene and protein expression in the peripheral blood mononuclear cells (PBMCs) of patients as potential biomarkers of disease outcomes and potential new targets for therapy. METHODS: Twenty-four patients with diagnosis of FBSS refractory to conservative therapy for at least six months were included in the study. Clinical evaluation in this study included validated questionnaires. Blood samples (10 mL) were collected five times from baseline until two months after implant of the leads. Proenkephalin (PENK), cannabinoid receptors CB1 and CB2, and interleukin 1ß (IL 1ß) were analyzed. Each patient served as his/her own control by comparing the samples collected at different time points against the baseline sample collected at T0. RESULTS: A total of 16 patients met all relevant criteria during the whole study and were assessed. Only PENK showed significant changes over time (Friedman p = 0.000). A positive correlation was observed between changes in visual analog scale (VAS) scores and PENK and a negative correlation between changes in PENK and Short Form-12 (SF-12) mental component score (MCS) scores, as well as between changes in IL 1ß and Pain Detect Questionnaire (PD-Q) scores. As PENK changes increased, so did pain (VAS). As changes in PENK increased, SF-12 MCS health worsened. As changes in IL 1ß increased, PD-Q values decreased. No severe adverse events occurred. CONCLUSIONS: Previously unknown effects of SCS on levels of PBMCs biomarkers are demonstrated. The findings of our research suggest a potential for useful integration of genome analysis and lymphocyte expression in the daily practice of neurostimulation for pain management and represent a novel road map in the light of the important questions that remain unanswered.

Prospective, Randomized Blind Effect-on-Outcome Study of Conventional vs High-Frequency Spinal Cord Stimulation in Patients with Pain and Disability Due to Failed Back Surgery Syndrome.

OBJECTIVES: Spinal cord stimulation (SCS) for patients with failed back surgery syndrome (FBSS) show variable results and limited to moderate evidence. In the last years the stimulation of high frequency (HF) has been considered as a better alternative in this pathology for its supposed benefits compared to the stimulation with conventional frequency (CF). To compare in one year follow-up, the efficacy of high-frequency SCS (HF) versus conventional frequency SCS (CF) on the patients with FBSS. DESIGN: Prospective, Randomized blind trial. SETTING: Academic University Pain Medicine Center. SUBJECT: Seventy eight patients with FBSS diagnosis based on internationally recognized criteria, and refractory to conservative therapy for at least 6 months, have been initially recruited, and. METHODS: Sixty subjects met the eligibility criteria and were randomized and scheduled for the trial phase.The patients were randomly assigned in either, one of the two groups: CF SCS or HF SCS. Within the study methods, special attention was paid to standardizing patient programming, so that these parameters would not impact the results.The trial period was considered successful if there was ?50% reduction in the NRS from baseline. RESULTS: A total of 55 subjects successfully completed all assessments during one year follow-up. Change patterns in scores do not differ based on high versus conventional frequency, with significant global average reduction at 1 year similarly for both groups. Among all the items included in the Short Form-12 questionnaire (SF-12), only the variations in the social function score between the instants t1 and t2 are somewhat higher in the high frequency group. CONCLUSION: The evolutionary pattern of the different parameters studied in our patients with FBSS does not differ according to their treatment by spinal stimulation, with conventional or high frequency, in one year follow-up.