# From Nerve to Brain: Toward a Mechanistic Understanding of Spinal Cord Stimulation in Human Subjects

> **NIH NIH RM1** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $7,114,690

## Abstract

PROJECT SUMMARY
Spinal cord stimulators (SCS) and related devices are commonly used to treat refractory pain conditions,
although mechanisms underlying pain reduction remain unclear. Improved understanding of SCS and the
development of biomarkers are critical for improving device design and stimulation patterns and optimizing
patient selection for device treatment. The main hypothesis of this proposal is that SCS devices reduce pain
by modulating the excitability of peripheral sensory nerve fibers that project within the spinal dorsal
columns, and this effect can be leveraged for biomarker development. The rationale for this hypothesis is
that first order low-threshold mechanoreceptors project from the periphery through the dorsal column/medial
lemniscus system to the brainstem. These are the neurons that (1) have closest proximity to the epidural
space, the location of stimulation, and (2) have processes in both the periphery and spinal cord tracts. We
will apply specialized tests of peripheral nerve excitability, threshold tracking nerve conduction studies, to
detect changes in the excitability exerted on these neurons by SCS. We will also perform secondary
measurements to determine other potential mechanisms of SCS in the peripheral and central nervous
systems: microneurography, to detect modulation of primary nociceptor neuron excitability; PET-MRI, to
measure changes in brain neuroinflammation; plasma cytokines and chemokines, to detect systemic
neuroinflammatory effects due to SCS. We will perform sensory phenotyping to identify mechanisms in
specific subgroups and pain and psychometric instruments to quantify responses. Aim 1 will use a multiple
crossover design in subjects who have stably implanted SCS devices, and SCS settings will be toggled
between therapeutic and minimal settings. Crossover intervals will include both two-week periods and rapid
two-hour periods between setting changes. Aim 2 will consist of a prospective assessment of subjects prior
and after implantation of new SCS devices, with a goal of identifying predictors of pain reduction response.
The successful completion of this study will yield new mechanisms by which SCS reduces pain, relevant
biomarkers, and further development of promising outcomes for broad pain research.

## Key facts

- **NIH application ID:** 10518516
- **Project number:** 1RM1NS128741-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ROY FREEMAN
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $7,114,690
- **Award type:** 1
- **Project period:** 2022-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518516

## Citation

> US National Institutes of Health, RePORTER application 10518516, From Nerve to Brain: Toward a Mechanistic Understanding of Spinal Cord Stimulation in Human Subjects (1RM1NS128741-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10518516. Licensed CC0.

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