Funded Projects

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.

The Medical University of South Carolina (MUSC) Specialized Clinical Center (Hub) of the Early Phase Pain Investigation Clinical Network (EPPIC-Net) will provide a robust and readily accessible infrastructure for rapid implementation and performance of high-quality comprehensive studies of novel treatments for patients with a wide variety of pain conditions. The MUSC-Hub will harness multidisciplinary clinical, research, statistical, and data management expertise to provide the scientific leadership and infrastructure required to design and conduct multisite Phase II clinical trials, biomarker validation studies, and deep phenotyping of patient populations as part of the EPPIC-Net with the overall goal of accelerating the development of new therapies for patients with acute and/or chronic pain.

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.

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.

Hesperos uses microphysiological systems in combination with functional readouts to establish systems capable of analysis of chemicals and drug candidates for toxicity and efficacy during pre-clinical testing, with initial emphasis on predictive toxicity. The team constructed physiological systems that represent cardiac, muscle and liver function, and demonstrated a multi-organ functional cardiac/liver module for toxicity studies as well as metabolic activity evaluations. In addition, the team demonstrated multi-organ toxicity in a 4-organ system composed of neuronal, cardiac, liver and muscle components. While much is known about the cells and neural circuitry regulating pain modulation there is limited knowledge regarding the precise mechanism by which peripheral and spinal level antinociceptive drugs function, and no available human-based model reproducing this part of the pain pathway. The ascending pain modulatory pathways provide a well characterized neural architecture for investigating pain regulatory physiology. In this project, the research team propose a human-on-a-chip neuron tri-culture system composed of nociceptive neurons, GABAergic interneurons and glutamatergic dorsal projection neurons (DPN) integrated with a MEMS construct. Using this model, investigators will interrogate pain signaling physiology at three levels, 1) at the site of origin by targeting nociceptive neurons with pain modulating compounds including noxious stimuli and inflammatory mediators, 2) at the inhibitory GABAergic interneuron, and 3) at the ascending spinal level by targeting glutamatergic DPNs. These circuits will be integrated utilizing expertise in patterning neurons as well as integration with BioMEMs devices. This system provides scientists with a better understanding of ascending pain pathway physiology and enable clinicians to consider alternative indications for treating pain at peripheral and spinal levels. 

Chronic low back pain (cLBP) is recurrent and often nonresponsive to conservative treatments. Biomechanists, physical therapists, and surgeons each utilize a variety of tools and techniques to assess and interpret qualitative movement changes to understand potential mechanical and neurological sources of low back pain and as critical elements in their treatment paradigm. However, objectively characterizing and communicating this information is currently impossible, since clinically feasible (i.e., cost-effective, objective, and accurate) tools and quantitative benchmarks do not exist. This research addresses the challenge to improve cLBP outcomes through the use of unique, inexpensive, screen-printable, elastomer-based, nanocomposite, piezoresponsive sensors, which will be integrated into a SPInal Nanosensor Environment (SPINE) sense system to measure lumbar kinematics and provide an objective, quantitative platform for diagnosis, monitoring, and follow-up assessment of cLBP.

EPPIC-Net will provide a robust and readily accessible infrastructure for the rapid implementation and performance of high-quality comprehensive studies of patients with well-defined pain conditions, and the rapid design and performance of high-quality Phase 2 clinical trials to test promising novel therapeutics for pain. Using the Hospital of the University of Pennsylvania as a hub and five additional centers that are part of the UPenn Health System and the Children’s Hospital of Philadelphia (CHOP) as spokes, studies will be conducted as designed by the expertise of the EPPIC Network, which intends to bring intense focus to relatively small numbers of patients with clinically well-defined pain conditions and high unmet therapeutic needs. The UPenn Specialized Clinical Center (SCC) will test novel, efficient study designs including adaptive and platform designs, validation studies of biomarkers, and biomarker-informed proof of principle or target engagement studies in Phase 2 trials of interventions from academic and industry partners.

The study team developed an mHealth pain self-management intervention for the perioperative period (SurgeryPal) to target psychosocial risk factors and teach pain self-management skills. The goal of this proposal is to establish the effectiveness of the SurgeryPal psychosocial intervention to improve clinically meaningful outcomes in adolescents undergoing major musculoskeletal surgery, and to identify the optimal timing of intervention delivery. The study team will plan for the efficient implementation of a multisite randomized clinical trial at 25 centers in 500 youth ages 12–18 years undergoing spinal fusion surgery and their parents. Participants will be randomized to receive SurgeryPal or attention control condition during the preoperative and postoperative phases. Self-reported pain severity and interference and secondary outcomes will be assessed at baseline, 3-, and 6-months. If effective, this scalable, low cost intervention will allow broad implementation to prevent chronic postsurgical pain in youth.

A primary factor contributing to acute or recurrent back injury is overexertion via excessive peak and cumulative forces on the back and the primary factors involved in the progression of acute low back injury to chronic low back pain (cLBP) include maladaptive motor control strategies, muscle hyperactivity, reduced movement variability, and the development of fear cognitions. This project will focus on the development of robotic apparel with integrated biofeedback components that can reduce exertion; encourage safe, varied movement strategies; and promote recovery. Robotic apparel will be capable of providing supportive forces to the back and hip joints through adaptive control algorithms that respond to dynamic movements and becoming fully transparent when assistance is no longer needed. This technology can be used to prevent cLBP caused by overexertion and provide a new tool to physical therapists and the clinical community to enhance rehabilitation programs.

The objective of the Early Phase Pain Investigation Clinical Network (EPPIC-Net) and EPPIC- Net initiatives is to rapidly and efficiently translate advances in the neurobiology of pain into treatments for people with chronic and acute pain, conditions associated with a significant burden to both patients and society. The Clinical Coordinating Center (CCC) for EPPIC-Net will promote and facilitate, from initial conception through final analysis, clinical trials in adult and pediatric populations with acute or chronic pain by providing efficient methodological, organizational, and logistical support. The EPPIC-Net-CCC will adopt and establish processes aimed at dramatically increasing the efficiency of multicenter clinical trials, improving the overall quality of clinical trials, promoting patient recruitment and retention as well as increasing the number of clinical investigators and research staff well trained and passionate about leading and conducting multicenter clinical trials.

Pain Coping Skills Training (PCST) uses a cognitive behavioral therapy (CBT) approach to teach patients cognitive and behavioral coping skills shown to reduce pain and pain interference (e.g., relaxation, distraction, cognitive restructuring, activity pacing). Randomized controlled trials show that PCST and similar CBT-based interventions, when delivered in a traditional in-person format, can improve pain and functioning in people with cancer and other conditions. Yet these interventions are underused in clinical care due to barriers such as high resource costs, a shortage of therapists trained to deliver them, and travel requirements for patients. This trial aims to deliver evidence-based behavioral pain interventions such as PCST with methods capable of overcoming barriers currently limiting patient access. This will be investigated using a two-arm trial comparing pain relief with the following interventions: painTRAINER in clinic with eight web-based follow-up sessions; enhanced usual care.

This project's goal is to develop a completely noninvasive, precise, and durable treatment option for low back pain (LBP). Focused ultrasound (FUS) is a lower-risk, completely noninvasive modality that enables the delivery of spatially confined acoustic energy to a small tissue region (dorsal root ganglion [DRG]) under magnetic resonance (MR) imaging guidance to treat axial low back pain by neuromodulation. The central goal of this study is to demonstrate neuromodulation of the DRG with FUS to decrease nerve conduction; this treatment can be used to attenuate pain sensation. This exploratory study will demonstrate FUS neuromodulation of the DRG in pigs as assessed by somatosensory evoked potential and perform unique behavioral assessments indicative of supraspinal pain sensation, with the ultimate goal of translating this technology to patients with LBP. FUS could potentially replace current invasive or systemically detrimental treatment modalities.

This project focuses on identifying and validating a new central analgesic circuit in the brain, based on a highly innovative hypothesis that the strong analgesic effects of general anesthesia (GA) are in part carried out by GA-mediated activation of the endogenous analgesic circuits. Preliminary discovery studies found that a subset of GABAergic neurons located in the central amygdala (CeA) become strongly activated and express high levels of the immediate early gene Fos under GA (hereafter referred to as CeAGA neurons). Furthermore, activation of these neurons exert profound pain-suppressing effects in an acute pain model and a chronic orofacial neuropathic pain model in mice. Based on these exciting preliminary findings, this project will identify and validate CeAGA neurons’ analgesic functions utilizing multiple mouse pain models. Identification of these shared common pathways that need to be suppressed by specific subtypes of CeAGA analgesic neurons will be highly critical for developing precise CeAGA-targeted therapies to treat chronic pain.