Development and Evaluation of Computerized Chemosensory-Based Orbitofrontal Networks Training for Treatment of Pain (CBOT-P)

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 odorant phytochemicals to stimulate the secondary olfactory cortex (i.e. the OFC) repetitively, with established micro-controller- regulated stimulation parameter settings that maintain persistent activation of the OFC and medial temporal regions, without habituation; paired with digitally-administered olfactory psychophysical training tasks that activate same regions, for synergistic effect on long-term neuroplasticity changes that prevents CP-induced shrinkage. As a second mechanism of action, the olfactory stimulants were fortified with proprietary components, such as beta-caryophyllene (BCP), a selective endocannabinoid-2 receptor agonist, which has strong anti-inflammatory and antinociceptive effects, and scalable for acute positive affect. In the Phase I of this Fast-Track SBIR application, we will (a) configure CBOT-P regimen and stimulation parameters for faster onset of mood elevating and analgesic effects, focusing on Chronic Low Back Pain populations and (b) establish its neural mechanism of action through target-engagement studies of OFC activity and functional connectivity with other pain regulating regions at baseline. In Phase II, we will perform a powered randomized trial of the refined CBOT-P from Phase I, compared to sham CBOT in CLBP, to determine its short- and long-term effectiveness on Pain, Affect, Cognition and cortical brain Structure (PACS), long-term safety, and indications. We will also collect user experiences to help refine a final marketable CBOT product, enter the FDA breakthrough designation program for pain that would lead to Medicare/Medicaid reimbursement, engage a wider network of pain stakeholders, and establish marketing for commercial success. Project success will be enhanced through strong collaborations between Evon Medics, Johns Hopkins (JHU) Pain Center, Howard University investigators, community pain providers and collaborating manufacturers. To the best of our knowledge this will be the first home-based combinatorial digital- chemosensory neuromodulatory product for stimulation of deep brain regions for CP management.