Functional and histological changes to peripheral innervation following spinal cord stimulation in patients with painful diabetic neuropathy

PROJECT ABSTRACT Diabetes is the most common cause of peripheral neuropathy, a condition that impacts over 30 million Americans. Often, this condition occurs as painful diabetic peripheral neuropathy (PDPN), which is particularly challenging to treat in the clinic, in part due to the lack of effective treatments and the risk of dependency for opioid analgesics. Spinal cord stimulation (SCS) is a treatment that stimulates nerve electrical activity in the spine, and is proven to be effective for pain conditions, including PDPN, for which SCS is now FDA approved through multiple device manufacturers. However, the mechanisms by which SCS improves pain are not yet known, and may involve promoting neural plasticity and small fiber nerve regeneration. We hypothesize that the electrical activity in stimulated spinal nerves with SCS treatment improves pain due to, or in parallel to, improvements in peripheral tissue innervation. This is based on decades of research evidence that electrical stimulation can promote nerve plasticity and regeneration. We will compare 3 PDPN treatment groups (N=15 each) across an 18mo longitudinal study: conventional medical management (CMM), SCS treatment, or SCS with a delayed activation of the device at 3mo post-surgery (to control for placebo effect of the surgery or device implantation). A team comprised of neuroscientists, neurologists, a neuromodulation surgeon, and computational/biostatistical experts will collect an 8-point dataset across this study timeline, in order to rigorously compare pain improvement scores with small and large fiber neuropathy assessments, quality of life scores, and metabolic parameters. The innovation of this study is further driven by the inclusion of a new functional measure of small fiber nerve electrical activity, using the Detecting Early Neuropathy (DEN) device, which employs a microneedle array to collect data on nerve activity up to 4mm deep from the skin surface. This is the first device capable of measuring small nerve fiber activity as a diagnostic test for small fiber peripheral neuropathy, such as diabetic neuropathy. Taken together, this study will provide important new data on PDPN improvements with SCS treatment and whether mechanisms include changes to small fiber tissue innervation or nerve activity.