Funded Projects

Project # Project Title Sort descending Research Focus Area Research Program Administering IC(s) Institution(s) Investigator(s) Location(s) Year Awarded
1UG3NS115637-01
Clinical Translation of Ultrasonic Ketamine Uncaging for Non-Opioid Therapy of Chronic Pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS STANFORD UNIVERSITY AIRAN, RAAG D; WILLIAMS, NOLAN R Stanford, CA 2019
FOA Title: HEAL Initiative: Translational Devices to Treat Pain (UG3/UH3 Clinical Trial Optional)
FOA Number: RFA-NS-19-016
Summary:

The research team has developed ultrasonic drug uncaging for neuroscience, in which neuromodulatory agents are uncaged from ultrasound-sensitive biocompatible and biodegradable drug-loaded nanocarriers. This project will clinically translate ultrasonic ketamine uncaging for chronic pain therapy. In the UG3 phase, the research team will scale our nanoparticle production processes to human scales and adapt them to pharmaceutical standards. In the UH3 phase, they will complete a first-in-human evaluation of the safety and efficacy of ultrasonic ketamine uncaging by quantifying how much ketamine is released relative to the ultrasound dose and assessing whether the uncaged ketamine can modulate the sensitivity and affective response to pain, in patients suffering from chronic osteoarthritic pain. This project aims to yield a novel, noninvasive, non-opioid therapy for chronic pain that maximizes the therapeutic efficacy of ketamine over its side effects, by targeting its action to a critical hub of pain processing.

1UH3NS113661-01
Deep Brain Stimulation of the Subgenual Cingulate Cortex for the Treatment of Medically Refractory Chronic Low Back Pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS UNIVERSITY OF CALIFORNIA LOS ANGELES BARI, AUSAF Los Angeles, CA 2019
FOA Title: HEAL Initiative: Clinical Devices to Treat Pain (UH3 Clinical Trial Optional)
FOA Number: RFA-NS-19-018
Summary:

This study aims to address critical gaps and unmet therapeutic needs of chronic low back pain (CLBP) patients using a next-generation deep brain stimulation (DBS) device with directional steering capability to engage networks known to mediate the affective component of CLBP. Researchers will utilize patient-specific probabilistic tractography to target the subgenual cingulate cortex (SCC) to engage the major fiber pathways mediating the affective component of chronic pain. The objective is to conduct an exploratory first-in-human clinical trial of SCC DBS for treatment of medically refractory CLBP. The research team aims to: (1) assess the preliminary efficacy of DBS of SCC in treatment of medically refractory CLBP; (2) demonstrate the safety and feasibility of SCC DBS for CLBP; and (3) develop diffusion tensor imaging–based blueprints of response to SCC DBS for CLBP.

1U18EB029351-01
Development of an MRgFUS system for precision-targeted neuromodulation of pain circuits with simultaneous functional MRI Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NIBIB VANDERBILT UNIVERSITY MEDICAL CENTER CASKEY, CHARLES F; CHEN, LI MIN; GRISSOM, WILLIAM A Nashville, Tennessee 2019
FOA Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
FOA Number: RFA-EB-18-003
Summary:

This project aims to develop a next-generation noninvasive neuromodulation system for non-addictive pain treatments. The research team will build an integrated system that uses magnetic resonance image-guided focused ultrasound (MRgFUS) stimulation to target pain regions and circuits in the brain with high precision. The system will use MR imaging to locate three pain targets commonly used in clinical pain treatments, to stimulate those targets with ultrasound, and to monitor responses of nociceptive pain circuits using a functional MRI readout. Three collaborating laboratories will tackle the goals of this project: (Aim 1) Develop focused ultrasound technology for neuromodulation in humans, compatible with the high magnetic fields in an MRI scanner. (Aim 2) Develop MRI technology to find neuromodulation targets, compatible with focused ultrasound transducers. (Aim 3) Validate the complete MRgFUS neuromodulation system in brain pain regions in nonhuman primates. By the end of the project, the research team will have a fully developed and validated MRgFUS system that is ready for pilot clinical trials in pain management.

1U18EB029353-01
Development of a Wireless Endovascular Nerve Stimulator for Treatment of Refractory Neuropathic Pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NIBIB BAYLOR COLLEGE OF MEDICINE KAN, PETER TZE MAN; ROBINSON, JACOB T; SHETH, SUNIL Houston, TX 2019
FOA Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
FOA Number: RFA-EB-18-003
Summary:

For patients with neuropathic pain refractory to therapy using small molecules, modulation of specific neural structures in the central or peripheral nervous system can provide effective alternative treatments. While current Food and Drug Administration–approved devices for dorsal root ganglion (DRG) stimulation are safe and effective, there have been an unfortunate number of adverse events associated with pulse generator infections and lead migration. The research team will develop a wireless, millimeter-sized nerve stimulator that can be delivered through the vasculature and stimulate the DRG to alleviate symptoms of neuropathic pain and the associated minimally invasive delivery method. This endovascular nerve stimulation (EVNS) system depends on development and integration of key novel technologies into an endovascular stent. The magnetoelectric transducers and electronic circuits will convert wireless power and data into stimulus patterns that can trigger neural activity in the DRG via miniature electrodes. After chronic demonstration of safety and functionality in large animal models, the team will prepare for regulatory discussions with the FDA. If successful, the EVNS will provide a technology platform for treating other neuropathic pain syndromes. 

1U44NS115111-01
High-Resolution, Spinal Cord Stimulation for Non-Opioid Treatment of Neuropathic Pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS MICRO-LEADS, INC. MCLAUGHLIN, BRYAN L Somerville, MA 2019
FOA Title: HEAL Initiative: Translational Devices to Treat Pain (U44 Clinical Trial Optional)
FOA Number: RFA-NS-19-017
Summary:

The research team will develop HD64—a high-resolution, 64-channel spinal cord stimulation therapy to provide more pain relief for those suffering from chronic neuropathic pain and opioid dependence. HD64 provides an ultra-thin conformal blanket of stimulation contacts across the width of the spinal cord and enables more precise targeting of the lateral structures of the spinal cord to enhance pain relief. A cadaveric pilot run followed by a non-significant risk intraoperative study will be performed to inform the design parameters of HD64 arrays. The study will evaluate activation of medial and lateral spinal targets. At the end of Phase 1, the clinical feasibility of HD64 surgical leads will be established. In Phase 2, researchers will develop an external active lead pulse generator and charger. They will perform an early feasibility study human trial using active HD64 and mechanical and electrical design verification testing and chronic safety studies in large animals.

1U44NS115632-01
Implantable Peripheral Nerve Stimulator for Treatment of Phantom Limb Pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS RIPPLE, LLC MCDONNALL, DANIEL Salt Lake City, UT 2019
FOA Title: HEAL Initiative: Translational Devices to Treat Pain (U44 Clinical Trial Optional)
FOA Number: RFA-NS-19-017
Summary:

The research team will develop an implantable neural stimulation system to provide natural and intuitive sensation for prosthesis users. The nerve cuff technology meets the requirements for a sensory feedback system capable of providing consistent and controlled electrical stimulation. Coupled with a multichannel implantable stimulator, this electrode array will offer substantial improvement over existing options to treat phantom limb pain (PLP). In Phase I, researchers will finalize array architectures for evaluation in cadaver studies, complete integration of electrodes with our stimulator, conduct benchtop verification of electrical and mechanical performance, send implants for third-party evaluation of system biocompatibility, and complete a Good Laboratory Practice animal study to validate safety and efficacy. In Phase II, researchers will conduct a 5-subject clinical study to test the implantable stimulation system. Each unilateral prosthesis user will be implanted for one year as researchers evaluate the safety and efficacy of this implantable device to treat PLP.

1UH3NS115631-01
Multisite adaptive brain stimulation for multidimensional treatment of refractory chronic pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS UNIVERSITY OF CALIFORNIA, SAN FRANCISCO SHIRVALKAR, PRASAD San Francisco, CA 2019
FOA Title: HEAL Initiative: Clinical Devices to Treat Pain (UH3 Clinical Trial Optional)
FOA Number: RFA-NS-19-018
Summary:

The research team will develop stimulation control algorithms to treat chronic pain using a novel device that allows longitudinal intracranial signal recording in an ambulatory setting. Subjects with refractory chronic pain syndromes will undergo bilateral surgical implant of temporary electrodes in the thalamus, anterior cingulate, prefrontal cortex, insula, and amygdala to identify candidate biomarkers of pain and optimal stimulation parameters. Six patients will proceed to chronic implantation of “optimal” brain regions for long-term recording and stimulation. The team will first validate biomarkers of low- and high-pain states to define neural signals for pain prediction in individuals. They will then use these pain biomarkers to develop personalized closed-loop algorithms for deep-brain stimulation (DBS) and test the feasibility of closed-loop DBS for chronic pain in weekly blocks. Researchers will assess the efficacy of closed-loop DBS algorithms against traditional open-loop DBS or sham in a double-blinded cross-over trial and measure mechanisms of DBS tolerance.

1U18EB029257-01
Temporal Patterns of Spinal Cord Stimulation Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NIBIB DUKE UNIVERSITY GRILL, WARREN M Durham, NC 2019
FOA Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
FOA Number: RFA-EB-18-003
Summary:

This project will design and test optimized temporal patterns of stimulation to improve the efficacy of commercially available spinal cord stimulation (SCS) systems to treat chronic neuropathic pain. Researchers will build upon a validated biophysical model of the effects of SCS on sensory signal processing in neurons within the dorsal horn of the spinal cord to better understand how to improve the electrical stimulus patterns applied to the spinal cord. They will use sensitivity analyses to determine the robustness of stimulation patterns to variations in electrode positioning, selectivity of stimulation, and biophysical properties of the dorsal horn neural network. Researchers will demonstrate improvements from these new stimulus patterns by 1) measuring their effects on pain-related behavioral outcomes in a rat model of chronic neuropathic pain and by 2) quantifying the effects of optimized temporal patterns on spinal cord neuron activity. The outcome will be mechanistically derived and validated stimulus patterns that are significantly more efficacious than the phenomenologically derived standard of care patterns; these patterns could be implemented with either a software update or minor hardware modifications to existing SCS products.

1U18EB029251-01
The Injectrode - A Truly Injectable Electrode for Dorsal Root Ganglion Stimulation to Treat Pain Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NIBIB UNIVERSITY OF WISCONSIN-MADISON LUDWIG, KIP A; WEBER, DOUGLAS J Madison, WI 2019
FOA Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
FOA Number: RFA-EB-18-003
Summary:

While traditional epidural spinal cord stimulation (SCS) for intractable pain has been very efficacious for the patients responsive to it, the success rate has held at approximately 55%. Dorsal root ganglion (DRG) stimulation has shown promise in early trials to provide greater pain relief. Although the decrease in back pain at 3 months was significantly greater in the DRG arm vs. SCS, the adverse event rate related to the device or implant procedure was significantly higher in the DRG arm. Researchers will develop the “Injectrode” system to make the procedure simpler and safer by using an alternative to implantation: using an injectable pre-polymer liquid composite that cures quickly after injection adjacent to the DRG. They will compare an Injectrode-based system with traditional electrode stimulation at the DRG as an alternative to opioid administration. Researchers will perform benchtop characterization and refinement as a precursor to a clinical study, use modeling and animal testing to refine the efficiency of energy transfer from a transcutaneous electrical nerve stimulation unit to an Injectrode/Injectrode collector concept, and optimize the procedure for the complex anatomy of the human DRG.

1UH3NS115118-01
Transcranial focused ultrasound for head and neck cancer pain. A pilot study Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NINDS UNIVERSITY OF VIRGINIA ELIAS, WILLIAM JEFFREY Charlottesville, VA 2019
FOA Title: HEAL Initiative: Clinical Devices to Treat Pain (UH3 Clinical Trial Optional)
FOA Number: RFA-NS-19-018
Summary:

Head and neck cancer is particularly susceptible to nociceptive and neuropathic pains because it is dense with sensitive anatomic structures and richly innervated. Transcranial magnetic resonance imaging–guided focused ultrasound (FUS) is a new stereotactic modality capable of delivering high-intensity energy through the intact human skull with submillimeter precision. This clinical trial will target the spinothalamic and spinoreticular pain circuits by unilateral FUS mesencephalotomy, an effective procedure for cancer pain but limited by the accuracy of its era. The primary aim is to assess the safety and preliminary effectiveness in six head and neck cancer patients with opioid-resistant pain. Researchers will investigate the potential mechanism of pain relief as the mesencephalotomy target involves the confluence of the ascending and descending pain systems. Aims 2 and 3 will investigate these systems with electrophysiology specific for the spinothalamic tract and carfentenil positron emission tomography imaging that measures the brain’s endogenous opioids.

1U18EB029354-01
Treating pain in sickle cell disease by means of focused ultrasound neuromodulation Preclinical and Translational Research in Pain Management Translating Discoveries into Effective Devices to Treat Pain NIBIB CARNEGIE-MELLON UNIVERSITY HE, BIN Pittsburgh, PA 2019
FOA Title: HEAL Initiative: Translational Development of Devices to Treat Pain (U18 Clinical Trial Not Allowed)
FOA Number: RFA-EB-18-003
Summary:

Researchers will develop a novel transcranial focused ultrasound (tFUS) device for pain treatment and establish its effectiveness for treating sickle cell disease (SCD) pain in humanized mice. The tFUS will target the specific cortical regions involved in SCD pain using a novel non-invasive electrophysiological source imaging technique. The project’s goals have several aims. Aim 1: Develop tFUS devices for pain treatment. The mouse-scale system will be designed to validate the therapeutic effect of stimulating the anticipated cortical targets. This will inform development of the simpler human-scale system, which will use models of the skull to select cost-effective transducers to reach the targets. Aim 2: Evaluate tFUS effectiveness and optimize stimulation parameters in an SCD mice model. Researchers will determine effective tFUS parameters to chronically reduce SCD pain in mice and validate this using behavioral measures. Aim 3: Use electrophysiological source imaging to target and trigger closed-loop tFUS in animal models. This aim also includes performing safety studies to prepare for human trials. The project will develop a transformative, noninvasive tFUS device to effectively and safely treat pain in SCD.