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

用于治疗疼痛的计算机化化学感应眼眶额网络训练 (CBOT-P) 的开发和评估

• 批准号: 10547925
• 负责人: Charles Chiedu Nwaokobia
• 金额: $ 50万
• 依托单位: EVON MEDICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547925
• 关键词: Acute; Acute Pain; Affect; Affective; Agonist; American; Analgesics; Anatomy; Animal Model; Anti-Inflammatory Agents; Anticonvulsants; Antidepressive Agents; Anxiety; Behavior Therapy; Beta-caryophyllene; Brain; Brain region; Businesses; Cessation of life; Chronic low back pain; Clinical; Cognition; Cognitive; Collaborations; Communities; Data; Decision Making; Deep Brain Stimulation; Development; Devices; Dose; Drug Addiction; Effectiveness; Electric Stimulation; Electrodes; Emotions; Endocannabinoids; Enrollment; Evaluation; Exercise; Feasibility Studies; Financial Hardship; Funding; Home; Human; Impaired cognition; Intervention; Intractable Pain; Lateral; Lead; Long-Term Effects; Manufacturer Name; Marketing; Measures; Medial; Medicare/Medicaid; Mental Depression; Midbrain structure; Mindfulness Training; Moods; Motivation; Narcotics; National Institute of Drug Abuse; Neuronal Plasticity; Neurosciences; Olfactory Cortex; Operative Surgical Procedures; Opioid Analgesics; Outcome; Pain; Pain Clinics; Pain intensity; Pain management; Pathologic; Pathway interactions; Patients; Persons; Phase; Physiologic pulse; Phytochemical; Pilot Projects; Play; Population; Prefrontal Cortex; Prevention; Process; Provider; Psychophysics; Randomized; Randomized Controlled Trials; Regimen; Regulation; Research; Research Personnel; Rewards; Role; Safety; Severities; Site; Small Business Innovation Research Grant; Stimulant; Stimulus; Structure; Subgroup; Technology; Testing; Time; Training; Universities; anatomical tracing; attenuation; base; chronic back pain; chronic pain; chronic pain management; chronic pain patient; chronic painful condition; cognitive function; combinatorial; comorbidity; computerized; cost effective; digital; disability; drug relapse; effective intervention; effective therapy; effectiveness implementation study; efficacy study; emotion regulation; experience; functional loss; gray matter; habituation; improved; innovation; interest; midbrain central gray substance; multisensory; negative affect; nerve damage; neuromechanism; neuroregulation; non-opioid analgesic; opioid misuse; opioid use; opioid use disorder; overdose death; pain chronification; pain patient; pain processing; pain reduction; pain relief; pain sensitivity; patient oriented; prevent; programs; randomized trial; receptor; response; side effect; success; treatment as usual; trend; user-friendly

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.

阶段I/II(快速/跟踪)摘要 基于计算机化学传感的眼眶前额网络的发展与评价 疼痛治疗培训(CBOT-P)是一个旨在开发有效、可扩展、用户友好和家庭- 基于神经调节平台的慢性疼痛的广谱治疗 消极情绪和认知障碍。慢性疼痛(CP)影响着全球15亿人，并导致 严重的人类痛苦、残疾和沉重的经济负担。临床和神经科学研究表明，CP 随着时间的推移，会导致前额叶皮质(PFC)区域及其深部大脑连接的萎缩，这些连接对 情绪、动机和认知功能。因此，超过40%的慢性阻塞性肺病患者受到负面影响 (例如，焦虑和抑郁)、认知和决策问题以及动力减弱。慢性疼痛伴 负面情绪(CP-N)更令人虚弱，更难治疗，对支付者来说代价更高，而且明显更具关联性 阿片类药物的使用，服药过量，以及死亡。在利益相关者价值拉票活动中，CP患者和痛苦 医生们一致希望新的非侵入性、基于家庭的、安全和有效的干预措施可以减少 疼痛严重程度降低了10%以上，这表明目前的治疗方法有局限性。顺行和 逆行解剖示踪已被用来证明直接(单突触)解剖联系 位于中脑导水管周围灰质(PAG)的OFC和下行抑制性痛结之间。 向CP的转变以PAG下行抑制的调制减弱为标志。埃文医护人员，一个小的 企业专门从事嗅觉神经疗法，开发了一种创新的基于化学传感的 眼眶额叶皮质(OFC)刺激装置，称为CBOT-P，家用，以增加OFC可塑性和 FC诱导的疼痛调节和负性情绪的影响。我们现在计划提炼这款产品以适应广泛的疼痛 并迅速将其提供给民众。OFC是前额叶皮质中起作用的部分 在多感官整合、影响调节和决策中的关键作用。横向OFC，这是 持续地被疼痛激活，连接到处理疼痛的大脑其他皮质区域；内侧 OFC与内侧颞叶影响网络建立网络，从事正念疗法治疗疼痛和 在积极的情感和动力方面起着重要的作用。不幸的是，CP和阿片类镇痛剂与 OFC萎缩，它通过增加负面情绪(NA)和认知障碍来放大疼痛。这个 在我们的先导研究中，CBOT-P在急性缓解NA和疼痛方面的成功并不令人惊讶，因为单脉冲 OFC电极电刺激对人侵袭性脑深部NA的强烈缓解作用 刺激，并在动物模型和人类实验中诱导刺激OFC激活 PAG可降低疼痛敏感度。CBOT-P使用Evon的10种气味植物化学物质的专有方案 利用已建立的微控制器，重复刺激次级嗅觉皮质(即OFC)- 可持续激活OFC和内侧颞叶的调节刺激参数设置 没有习惯化的区域；与数字管理的嗅觉心理物理训练任务配对 激活相同的区域，对防止CP诱导的长期神经可塑性变化产生协同效应 缩水。作为第二种作用机制，嗅觉刺激剂得到了专利的强化 成分，如β-石竹烯(BCP)，一种选择性内源性大麻-2受体激动剂，具有 强烈的抗炎和抗伤害作用，并可扩展为急性积极影响。 在此Fast-Track SBIR应用程序的第一阶段中，我们将(A)配置CBOT-P方案和 刺激参数可加快情绪起效和止痛效果，侧重于慢性腰背部 (B)通过OFC的靶点接触研究，建立其神经作用机制 基线时与其他疼痛调节区域的活动和功能连接。在第二阶段，我们将执行一项 一期精制CBOT-P与CLBP中假CBOT的动力性随机试验 确定其对疼痛、情感、认知和大脑皮质结构(PAC)的短期和长期有效性， 长期安全性和适应症。我们还将收集用户体验，以帮助完善最终的适销对路CBOT 产品，进入FDA突破性疼痛指定计划，这将导致联邦医疗保险/医疗补助 报销，吸引更广泛的疼痛利益相关者网络，并建立商业营销 成功。项目的成功将通过Evon医务人员和Johns之间的强大合作而得到加强 霍普金斯疼痛中心、霍华德大学研究人员、社区疼痛提供者和协作 制造商。据我们所知，这将是第一个基于家庭的组合数字- 化学感受性神经调节产品，用于刺激脑深部区域进行脑性瘫痪治疗。