ABSTRACT Chronic low back pain (CLBP) is one of the most ubiquitous and intractable problems in medicine and a significant source of patient suffering and disability, leading to opioid misuse and addiction. Previous neuromodulatory therapies for CLBP have focused primarily on spinal etiologies and intra-spinal mechanisms of pain transmission. However, existing pharmacological and neuromodulatory therapies have not been successful in treating CLBP. Potential gaps and opportunities include: (1) a need to better understand the brain networks underlying CLBP, (2) development of DBS devices that can better target the specific brain networks underlying CLBP in a safe and clinically testable manner, and (3) identification of neuroimaging biomarkers of response to DBS for CLBP. Pain can be separated into sensory, cognitive and affect components. Growing neuroimaging evidence shows that chronic pain is associated with widespread changes in brain circuits mediating these components with particular pathological overrepresentation of the affective component. The current proposal aims to address these critical gaps and the unmet therapeutic needs of CLBP patients by using a next- generation DBS device with directional steering capability to engage networks known to mediate the affective component of CLBP. We will use the Abbott Infinity™ DBS System, which offers segmented electrodes capable of providing directional current steering technology. In addition, we will utilize patient- specific probabilistic tractography to target the subgenual cingulate cortex (SCC) in order to engage the major fiber pathways mediating the affective component of chronic pain. The SCC region demonstrates structural connectivity to downstream brain structures also known to be involved in the affective component of chronic pain, and DBS of the SCC has been previously shown to improve affect in patients with intractable depression. The objective of this application is to propose an exploratory first-in-human clinical trial of SCC DBS for the treatment of medically refractory CLBP which leverages our multidisciplinary expertise and technical skills. Specifically, we propose the following aims in order to carry out this trial: (1) Assess the preliminary efficacy of DBS of the SCC in the treatment of medically refractory CLBP; (2) Demonstrate the safety and feasibility of SCC DBS for CLBP; and (3) Develop diffusion tensor imaging (DTI)-based blueprints of response to SCC DBS for CLBP. The overall impact of this proof-of-concept pilot trial includes validation of the concept that suffering from CLBP results from pathological activity in affective brain networks, that these networks can be accurately engaged using a next-generation directional DBS device in a safe and feasible manner, and the discovery of neuroimaging biomarkers of response to SCC DBS for CLBP.

PROJECT NARRATIVE Chronic pain is one of the most ubiquitous and intractable problems in medicine affecting over 50 million people in the United States alone. A current obstacle to developing more effective therapies for chronic low back pain (CLBP) is the lack of clinical trials assessing the feasibility and potential effectiveness of promising new neuromodulatory brain targets. Our long-term goals are to determine whether deep brain stimulation of the subgenual cingulate cortex is beneficial for treating CLBP and to identify: (1) participant characteristics associated with positive response, (2) the potential mechanisms of SCC DBS, and (3) the neuroimaging biomarkers of response to SCC DBS.