Electrical neuromodulation is an important strategy for treating chronic pain conditions that are refractory to pharmacotherapies. However, currently available neurostimulation pain therapies are associated with limited efficacy and side effects. We created novel Safe Direct Current Stimulation (SDCS) that enables implantable neuroelectronic prostheses to safely modulate neuronal activity by using ionic direct current (iDC). Our preliminary studies provide promising evidence that iDC applied at peripheral nerves induces effective and reversible inhibition of neural activity in pain pathways. Intriguingly, iDC may be optimized to preferentially inhibit ?pain? signals, while allowing the other nerve signals to pass. The central goal of our study is to uncover neurophysiologic mechanisms, optimize stimulation parameters, and establish the experimental framework for advancing the development of novel SDCS-based neuroelectronic prostheses for precision pain treatment.
In Aim 1, we will examine how iDC modulates the conduction and excitability of different subtypes of afferent sensory neurons in a rat model of neuropathic pain. By recording compound action potentials and activity in teased nerve fibers, we will determine how to optimize the polarity, intensity, and duration of iDC in a way that preferentially suppresses propagation of ?pain? signals in the peripheral nervous system.
In Aim 2, we will uncover spinal neurophysiologic mechanisms for pain inhibition by iDC. Specifically, we will record local field potential in dorsal horn to examine if iDC differentially affects spinal transmission of sensory inputs from nociceptive C-fibers and non-nociceptive A?-fibers. Single-unit recording will be used to further determine how iDC affects responses of individual pain-processing dorsal horn neurons to peripheral stimuli. If iDC induces neuronal excitation, we will determine if the excitation can be reduced by using multipolar and phasic-array iDC paradigms.
In Aim 3, we will conduct animal behavior tests to optimize the suppression of pain manifestations by iDC and examine potential side effects. Histologic and immunocytochemical studies will be used to evaluate the biosafety of iDC with short- and long-term use. Novel non-pharmacologic strategies are greatly needed for chronic pain treatment, and the performance of SDCS in biological systems is just now being explored. Our findings will help to conceptualize the biological basis of SDCS techniques for precision pain inhibition. Based on iDC mechanisms, our findings will provide rationales and critical insights for the development of testable SDCS-based ?electroceuticals? that may revolutionize current approaches to chronic pain treatment.

Public Health Relevance

Currently available neurostimulation therapies for chronic pain are associated with limited efficacy and side effects. We developed novel Safe Direct Current Stimulation (SDCS) technology, which enables implantable neuroelectronic devices to safely modulate neuronal activity by using ionic direct current. We will uncover important neurophysiologic mechanisms, optimize stimulation parameters, and establish the experimental framework to advance the development of novel SDCS-based ?electroceuticals? for precise pain inhibition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS099879-01
Application #
9227078
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Oshinsky, Michael L
Project Start
2016-09-01
Project End
2018-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Stephens, Kimberly E; Chen, Zhiyong; Sivanesan, Eellan et al. (2018) RNA-seq of spinal cord from nerve-injured rats after spinal cord stimulation. Mol Pain 14:1744806918817429
Yang, Fei; Anderson, Michael; He, Shaoqiu et al. (2018) Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current. Sci Adv 4:eaaq1438
Sdrulla, Andrei D; Guan, Yun; Raja, Srinivasa N (2018) Spinal Cord Stimulation: Clinical Efficacy and Potential Mechanisms. Pain Pract 18:1048-1067
Huang, Qian; Duan, Wanru; Sivanesan, Eellan et al. (2018) Spinal Cord Stimulation for Pain Treatment After Spinal Cord Injury. Neurosci Bull :
Sivanesan, Eellan; Maher, Dermot P; Raja, Srinivasa N et al. (2018) Supraspinal Mechanisms of Spinal Cord Stimulation for Modulation of Pain: Five Decades of Research and Prospects for the Future. Anesthesiology :
Tiwari, Vinod; Anderson, Michael; Yang, Fei et al. (2018) Peripherally Acting ?-Opioid Receptor Agonists Attenuate Ongoing Pain-associated Behavior and Spontaneous Neuronal Activity after Nerve Injury in Rats. Anesthesiology 128:1220-1236
He, Shao-Qiu; Xu, Qian; Tiwari, Vinod et al. (2018) Oligomerization of MrgC11 and ?-opioid receptors in sensory neurons enhances morphine analgesia. Sci Signal 11:
Chakravarthy, Krishnan; Richter, Hira; Christo, Paul J et al. (2018) Spinal Cord Stimulation for Treating Chronic Pain: Reviewing Preclinical and Clinical Data on Paresthesia-Free High-Frequency Therapy. Neuromodulation 21:10-18
Shu, Bin; Yang, Fei; Guan, Yun (2017) Intra-spinal microstimulation may alleviate chronic pain after spinal cord injury. Med Hypotheses 104:73-77
Li, Zhe; Tseng, Pang-Yen; Tiwari, Vinod et al. (2017) Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain. Proc Natl Acad Sci U S A 114:E1996-E2005