Development and Evaluation of Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT) for Opioid Use Disorder

项目摘要 Evon Medics LLC建议评估和优化便携式家庭产品， 基于化学感觉的眶额皮层训练（CBOT），作为预防复发的替代策略 阿片类药物使用（OUD）和其他物质使用障碍（SUD）患者。类阿片和其他形式的药物 成瘾可以被定义为未能控制寻求药物的行为，并反映了一种夸大的驱动力， 消费药物，和/或无法参与涉及非药物奖励的结果导向行为，如 食物健康社会地位和金钱与过度学习的药物相关性相反， 通常不太确定，需要推断或心理模拟。眶额皮质（OFC） 通过提供关联结构（即认知图）在成瘾调节中起重要作用 进行心理模拟。此外，眶额皮层通过增强的运动神经元功能在情绪调节中起着重要作用。 负性情感线索的认知重新评价;负性情感是物质复吸的强预测因子。 OUD患者眶额皮层体积和功能减少，海洛因和可卡因剂量依赖性减少 OFC神经元功能，从而助长了反复使用药物。 CBOT是一种可编程的、便携式的、安全的、用户友好的用于联合化学传感器的装置。 用克服OFC脱敏的刺激参数刺激OFC神经活动， 管理嗅觉认知任务，这些任务协同地以足够的高保真度参与OFC， 引起眶额皮层功能的持久变化。第一阶段的研究和开发达到或超过规定 技术里程碑：CBOT干预导致结果导向行为任务的表现增加， 在12周随访期间，增加了OUD患者在治疗中的保留率，并降低了复发率。 与假治疗相比，CBOT治疗的OUD患者也经历了较轻的阿片类药物戒断 和渴望，减少睡眠中断和负面影响评级，独立于严重程度和持续时间， 吸毒Evon Medics正在寻求SBIR第二阶段的资金，以证明其在非家庭应用中的实用性。 寻求治疗和寻求治疗的OUD人群，参与长期，成功的阿片类药物治疗 复苏这一建议将使产品进一步完善，以便广泛实施， 增加长期OUD治疗保留和戒断的器械的商业化， 通过急剧降低戒断严重程度和负面影响来增加恢复的参与度。在 与此同时，Evon Medics正在建立战略合作伙伴关系， 制造、监管备案、销售和分销。Evon Medics的科学家、工程师和商业 专家们以使命为导向，积极主动地对全世界的精神和社会健康产生影响。 第二阶段项目的主要技术目标是：（1）确定CBOT的有效性， 在大样本OUD受试者中改善保留和复发预防;（2）确定其对以下方面的有效性： 急性减少戒断严重程度和恢复早期的负面影响;（3）配置和优化 CBOT的商业版本，以提高效率，用户友好性和可接受性。这些目标 将导致一个优化的CBOT产品，克服了传统的嗅觉疗法和其他 治疗药物成瘾和预防复发的非侵入性神经调节方法。后 完成第二阶段后，我们将准备将研究扩展到第三阶段疗效研究，或 通过建立商业伙伴关系，对实际环境中的有效性进行研究 在这个项目的过程中据我们所知，这将是第一次评估一个家庭为基础的， 可扩展的，计算机化的，基于化学传感器的脑刺激，对两种治疗都有潜在的广泛影响- 寻求和不寻求治疗的OUD人群。

PROJECT SUMMARY Evon Medics LLC proposes to evaluate and optimize the portable, home-based product, Computerized Chemosensory-Based Orbitofrontal Cortex Training (CBOT), as an alternative strategy for relapse prevention in patients with Opioid Use (OUD) and other substance use disorders (SUD). Opioid and other forms of drug addiction can be defined as a failure to control drug-seeking behavior, and reflect an exaggerated drive to consume drugs, and/or an inability to engage in outcome-guided behaviors involving non-drug rewards such as food, health, social status and money. In contrast to overlearned drug-related associations, non-drug outcomes are often less well established and need to be inferred or mentally simulated. The orbitofrontal cortex (OFC) plays important role in regulation of addiction through provision of an associative structure (i.e. cognitive map) for these mental simulations. Additionally, the OFC plays critical role in emotion regulation through enhanced cognitive reappraisal of negative affective cues; and negative affect is a strong predictor of substance relapse. People with OUD have reduced OFC volume and function, and heroin and cocaine dose-dependently diminish OFC neuronal functions, thereby fueling recurrent drug use. The CBOT is a programmed, portable, safe, user-friendly device for conjoined chemosensory stimulation of OFC neural activity with stimulation parameters that overcome OFC desensitization, and for administration of olfactory cognitive tasks that synergistically engage the OFC with high fidelity sufficient to induce lasting changes in OFC functions. Phase I research and development met or exceeded stated technical milestones: CBOT intervention led to increased performance in outcome-guided behavior tasks, increased retention of OUD patients in treatment and reduced relapse rate during 12 weeks follow-up. Compared to sham treatment, CBOT-treated OUD patients also experienced less severe opioid withdrawal and cravings, and less sleep disruptions and negative affect rating, independent of severity and duration of drug use. Evon Medics is seeking SBIR Phase II funding to demonstrate its utility for home application by non- treatment seeking and treatment-seeking OUD populations, to engage in long-term, successful opioid recovery. This proposal will enable additional product refinement to allow broad implementation and commercialization of the device that increases long-term OUD treatment retention and abstinence and increases engagement in recovery through acute reduction of withdrawal severity and negative affect. At the same time, Evon Medics is engaging strategic partnerships that will be used to drive development through manufacturing, regulatory filings, sales, and distribution. Evon Medics scientists, engineers and commercial experts are mission-driven and highly motivated to make an impact on mental and social health worldwide. Key technical objectives of this Phase II project are to: (1) establish the effectiveness of CBOT for improved retention and relapse prevention in a large sample of OUD subjects; (2) establish its effectiveness for acute reduction of withdrawal severity and negative affect early in recovery; and (3) configure and optimize a commercial-ready CBOT version for improved efficacy, user-friendliness and acceptability. These objectives will lead to an optimized CBOT product that overcomes the drawbacks of traditional olfactory therapy and other noninvasive neuromodulation approaches in the treatment of drug addictions and prevention of relapses. Upon completion of Phase II, we will be poised to expand the research to Phase III efficacy study, or an implementation study of effectiveness in the real-world setting through commercial partnerships developed over the course of this project. To the best of our knowledge, this will be the first evaluation of a home-based, scalable, computerized, chemosensory-based brain stimulation with potential broad impact for both treatment- seeking and non-treatment seeking OUD populations.