EPV002 - MECHANISM-BASED THERAPY DESIGN: ROLE OF BASIC SCIENCE IN NEUROMODULATION TECHNOLOGY DEVELOPMENT (ID 376)
- Leo Litvak, United States of America
- Melanie Goodman Keiser, United States of America
- Lawrence Poree, United States of America
- Krishnan Chakravarthy, United States of America
- Jeffrey Kramer, United States of America
- Leo Litvak, United States of America
Abstract
Introduction
The mechanisms of action (MoAs) of spinal cord stimulation (SCS) remain unknown for the past 50 years; however, our fundamental understanding of SCS has often followed clinical application of new technology and therapies. Current trends towards stimulation patterns that do not illicit paresthesias, often referred to as subthreshold, subsensory, or paresthesia-free stimulation. There are opportunities to utilize our understanding of underlying MoAs to help drive therapy development and outcome improvements with subthreshold stimulation.
Methods/Materials
A systematic literature review was performed using the PubMed and EMBASE databases. Search criteria included “spinal cord stimulation” and the following terms: subparesthesia, subthreshold, subsensory, sub-sensory, paresthesia-independent, paresthesia-free, paresthesia free, “mechanisms of action”, “mechanisms of action for burst”, and “mechanisms for 10 kHz”.
Results
A total of 508 individual articles was found. One hundred thirty-one articles hypothesized or reviewed proposed mechanisms of action of SCS and 20 articles presented data to support a hypothesized mechanism. Preclinical and clinical methodologies were used to explain and support MoA theories. These include extracellular recordings, behavior and immunohistochemistry experiments in preclinical models. Small clinical studies have used quantitative sensory testing, somatosensory evoked potentials and magnetic resonance imaging to support hypothesized MoAs.
Discussion
It is unclear if the MoA of sub-types of SCS (low dose vs. high dose) differ since most mechanistic preclinical experiments were performed upwards of 90% motor threshold, well above probable sensory thresholds for animal models. It begs to question if subthreshold SCS patterns do not activate the dorsal columns and create paresthesias, what is the target? Also, if subthreshold patterns do activate the dorsal columns then how do the dorsal column fibers track higher frequency patterns when studies have shown following-frequency limitations. Nevertheless, direct effects on dorsal horn cells, non-neuronal cells (immune, glia, etc.) and the potential for supra-spinal mechanisms are all hypothesized MOAs. Thus, animal models may continue to provide a useful model to study MoAs but attention should be paid to the parameters being delivered as an approximation of those used translationally. Moreover, disease model can play a role in response so appropriate models will be an important consideration.
Conclusions
Our understanding of the SCS MoAs, especially subthreshold stimulation, continues to evolve. Neuronal targets, neurotransmitters, and spinal and supraspinal pathways involved remain only partially elucidated or unknown. Nevertheless, mechanistically driven device and therapy design may be a useful pathway to study novel neuromodulation approaches.
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