Modeling mechanisms of interindividual variation in pain modulation by spinal cord stimulation

Project Summary Approximately 20% of Americans live with chronic pain, the underlying causes of which are often unknown. Spinal cord stimulation (SCS) is a therapy that successfully alleviates chronic pain symptoms in many patients; however, the efficacy of SCS across individuals can vary widely. Recently, clinicians have begun exploring a larger range of SCS frequencies, from more conventional values of 50 Hz (cSCS) up to values as high as 10 kHz (HF-SCS). While some patients receive significant reductions in pain with HF-SCS, others have optimal pain relief with cSCS or other forms of SCS. The mechanisms by which these protocols lead to pain relief in patients with chronic pain remain unclear, especially as concerns the variability across individuals with different chronic pain states. Potential sources of interpatient variability in the efficacy of SCS include variability in the activation of dorsal column (DC) fibers and the corresponding sensory processing of DC input by neural circuitry in the dorsal horn (DH) of the spinal cord. This proposal aims to use biologically-motivated mathematical models at these two scales: a biophysical three-dimensional hybrid field-cable model describing the activity of DC axons due to the electrical potential fields generated from current impulses emitted by an SCS electrode array, and a firing-rate network model of the neural circuitry responsible for sensory processing in the DH. The proposed projects will be in majority be conducted by undergraduate students at Middlebury College, with mentorship by and collaboration with faculty and graduate student trainees in biomedical engineering and applied mathematics at the University of Michigan. This proposal will strengthen the institutional pain research environment at Middlebury College by providing unique opportunities for undergraduate students to not only actively engage in pain multidisciplinary pain research, but also access a cross-organization, vertically-integrated mentorship program. Together, completion of these computational studies will: 1) identify key anatomical features that most robustly contribute to changes in DC axon firing, and 2) predict the mechanism(s) underlying preferential pain-relief responses of projection neurons within dysregulated DH circuitries (i.e., those contributing to chronic pain) to a range of SCS frequencies.