Introduction: There is still no global consensus into the mechanism of action of spinal cord stimulation (SCS). Chronic neuropathic pain is frequently described as neuroinflammatory with changes in the expression of neuropeptides in the neuroimmune interface. Tonic and burst modes of SCS have demonstrated changes in neuroimmune and inflammatory peptides correlating with improved pain scores in patients with neuropathic pain.  This study examines the dynamic changes of T cells, cytokines, chemokines, neurotrophins and proteomic constituents of cerebrospinal fluid (CSF) after burst SCS. 
Methods: Patients with neuropathic pain selected for SCS had CSF sampled prior to full implant. Baseline and 8 week pain scores with demographics were recorded. All patients were implanted following on the table trial with paraesthesia mapping. Burst SCS was applied to all patients based on paraesthesia mapping for 8 weeks. Patients that reported a 50% reduction in pain had a second CSF sample taken at 8 weeks.  T cell frequencies were analysed using flow cytometry.  Mass spectrometry was utilised for proteomic analysis and secreted cytokines, chemokines and neurotrophins by ELISA. 
Results: 4 patients (2 female) with a mean age of 51 (SEM 2.74, SD 5.48) achieved a >50% reduction in pain after burst SCS. There was a significant reduction in the proteomes: Scavenger receptor cysteine-rich type 1 protein M130, Calbindin, Heat shock cognate 71 kDa protein, Serpin A3 and Alpha-1-B-Glycoprotein. There were also significant increases in: Matrix Gla protein, C-reactive protein, Cadherin-11, Low-density lipoprotein receptor. The majority of the affected proteome were involved in calcium chelation, inflammation and immune response. The proteins significantly altered were also predominately produced by glial cells. The concentrations of secreted chemokines and cytokines and the frequencies of T cells were not significantly affected. 

Conclusion: This study characterised in CSF, the proteomic response to burst SCS in vivo. The affected proteome is predominately involved in inflammation, immune response and calcium-ion chelation. The findings suggest burst SCS modulates CNS cellular function beyond neurons . More research is needed into the modulation of glial cells with SCS to not only determine mechanisms of action but the pathophysiology of neuropathic pain.

CHARACTERISATION OF THE EFFECT OF BURST SPINAL CORD STIMULATION ON CEREBROSPINAL FLUID CELLULAR AND PROTEIN CONSTITUENTS IN PATIENT RESPONDERS WITH CHRONIC NEUROPATHIC PAIN.