PHASE I/II (FAST/TRACK) ABSTRACT The Development and Evaluation of Computerized Chemosensory-Based Orbitofrontal Networks Training for Treatment of Pain (CBOT-P) is a project to develop an effective, scalable, user-friendly, and home- based neuromodulatory platform for broad-spectrum treatment of chronic pain conditions with associated negative affect and cognitive impairments. Chronic pain (CP) affects 1.5 billion people globally, and causes severe human suffering, disability, and high financial burden. Clinical and neuroscience studies show that CP over time leads to shrinkage in the prefrontal cortex (PFC) regions and their deep brain connections critical to emotion, motivation, and cognitive functions. As a result, more than 40% of CP patients suffer negative affect (i.e., anxiety and depression), cognitive and decision-making problems and reduced drive. Chronic pain with negative affect (CP-N) is more debilitating, harder to treat, costlier to payers and significantly more associated with opioid use, overdose, and deaths. In a stakeholder value canvassing exercise CP sufferers and pain doctors unanimously desire new non-invasive, home-based, safe, and effective interventions that can reduce pain severity by more than 10%, suggesting that current treatments have limitations. Anterograde and retrograde anatomical tracings have been used to demonstrate direct (monosynaptic) anatomical connection between the OFC and the descending inhibitory pain nodes at the midbrain periaqueductal gray matter (PAG). Transition to CP is marked by weakened modulation of the PAG-descending inhibition. Evon Medics, a small business specializing in olfactory neurotherapeutics, developed an innovative chemosensory-based orbitofrontal cortex (OFC) stimulation device, called CBOT-P, for home use, to increase OFC plasticity and effect OFC-induced regulation of pain and negative affect. We now plan to refine this product for broad pain conditions and quickly make it available to the population. OFC is the part of the prefrontal cortex that plays key roles in multisensory integration, affect regulation, and decision-making. The lateral OFC, which is consistently activated by pain, is connected to other cortical brain regions that process pain; and the medial OFC, which networks with medial temporal affect networks, is engaged by mindfulness therapy for pain and plays important role in positive affect and drive. Unfortunately, CP and opioid analgesics are associated with OFC shrinkage, which amplifies pain through increased negative affect (NA) and cognitive impairment. The success of CBOT-P in acute relief of NA and pain in our pilot studies is not surprising because single-pulsed electrical stimulations with OFC-placed electrodes acutely relieved NA in humans in invasive deep brain stimulation, and experimentally induced stimulation of the OFC in animal models and humans activates the PAG to reduce pain sensitization. The CBOT-P uses Evon’s proprietary regimen of 10 od...