Towards treatment for the complex patient: investigations of low-intensity focused ultrasound.

针对复杂患者的治疗：低强度聚焦超声的研究。

• 批准号: 10775216
• 负责人: MARY LEE
• 金额: $ 77.88万
• 依托单位: INSTITUTE FOR CLINICAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10775216
• 关键词: Adverse event; Anterior; Anxiety; Anxiety Disorders; Attenuated; Behavior; Behavioral; Brain; Brain region; Clinical; Clinical Research; Clinical Treatment; Combined Modality Therapy; Communities; Complex; Cues; Data; Decision Making; Disease; District of Columbia; Dose; Double-Blind Method; Down-Regulation; Emotional; Equilibrium; Evoked Potentials; Focused Ultrasound; Generalized Anxiety Disorder; Government; Hour; Hyperactivity; Individual; Insula of Reil; Interoception; Investigation; Laboratories; Location; Longevity; MRI Scans; Measures; Mediating; Mental disorders; Methods; Motivation; Neurobiology; Neuropsychology; Opioid; Outcome; Outcome Measure; Pain; Pain Disorder; Pain Threshold; Pain intensity; Patients; Penetration; Phase; Physiological; Physiological Processes; Physiology; Population; Post-Traumatic Stress Disorders; Process; Protocols documentation; Regulation; Role; Safety; Sampling; Signal Transduction; Site; Social Anxiety Disorder; Specificity; Structure; Symptoms; Techniques; Transcranial magnetic stimulation; Treatment Efficacy; Treatment outcome; Veterans; addiction; anxiety states; anxiety symptoms; biological adaptation to stress; brain dysfunction; brain magnetic resonance imaging; central sensitization; chronic back pain; chronic pain; clinical examination; comorbidity; conditioned pain modulation; cranium; craving; efficacy evaluation; healthy volunteer; heart rate variability; high risk; improved; innovation; millimeter; neurobehavioral; neurobiological mechanism; neuroregulation; novel; opioid overdose; opioid use disorder; overdose death; pain processing; pain score; pain symptom; patient population; persistent symptom; programs; recruit; reduce symptoms; repaired; research clinical testing; response; reward processing; safety assessment; sensory stimulus; sham-controlled study; symptomatology; therapeutic target

Opioid use disorder with co-morbid chronic pain and anxiety (OCpA) is a clinical triad associated with the highest risk of opiate overdose deaths. Co-occurrence of these three disorders amplifies symptoms of each and results in poorer treatment outcomes. There are shared neurobiological substrates for these disorders such as reward processing and stress response. The anterior insula (AI) is a brain region involved in these processes as well as in clinical disorder of pain, addiction, and anxiety. The AI is upregulated in pain, addiction and anxiety disorders and is therefore a potential therapeutic target for neuromodulation. Low-intensity focused ultrasound (LIFU) is a noninvasive method to inhibit cortical and deep brain regions. LIFU can reach deep brain regions such as the AI with spatial specificity, unlike traditional noninvasive neuromodulation methods which lack spatial specificity and depth penetration. LIFU can selectively target the insula and its subregions and provides a potentially transformative method to reduce symptoms of pain, opiate craving, and anxiety in a complex patient population such as OCpA. In the UG3 phase of this study, we will administer one session of inhibitory LIFU to the AI in individuals with OCpA [opiate use disorder, chronic back pain, and anxiety disorders (generalized anxiety disorder, post-traumatic stress disorder, or social anxiety disorder)]. The aim of this phase of the study is to establish that LIFU vs sham LIFU to AI is safe and well tolerated as measured by adverse events, clinical evaluation and repeated structural brain magnetic resonance imaging scans. We will also gather preliminary data on the effect of LIFU to AI on opiate cue-induced craving and laboratory measures of central sensitization(CS) which occurs with pain chronicity such as temporal summation of pain and conditioned pain modulation. In the second phase of this project (UH3), we will examine the efficacy, in a larger sample of individuals with OCpA, of repeated LIFU delivery on measures of pain and opiate cue-induced craving, anxiety symptoms, interoception and autonomic reactivity as these outcomes are dysregulated in OCpA and are mediated by the AI. LIFU will be delivered for 10 minutes each hour for 4 hours on a single day. We hypothesize that repeated sessions of LIFU will reduce measures of CS, opiate cue-induced craving, state anxiety symptoms, increase heart rate variability and normalize measures of interoception. We will examine the durability and effect of 1 vs 2 sessions of repeated LIFU on these outcome measures. Repeated sessions of other forms of neuromodulation result in increased magnitude and longer lasting effects. We hypothesize that 2 sessions vs 1 of repeated LIFU will result in greater magnitude of change in the outcome measures. Lastly, we will examine the safety and tolerability of repeated LIFU sessions. There is a need for improved treatments for complex patients such as OCpA beyond combining treatments for each disorder. LIFU provides an ability to transiently and selectively inhibit AI to determine its causal role in OCpA symptoms which then may lead to improved treatments for this clinical triad which is associated with poor treatment outcomes.

阿片类药物使用障碍与慢性疼痛和焦虑共病（OCpA）是一种与阿片类药物使用障碍相关的临床三联征。 阿片类药物过量死亡的风险最高。这三种疾病的同时发生放大了每种疾病的症状 并导致较差的治疗结果。这些疾病有共同的神经生物学基础 例如奖励处理和压力反应。前额叶（AI）是一个参与这些活动的大脑区域。 过程以及疼痛、成瘾和焦虑等临床疾病。AI在疼痛、成瘾、 和焦虑症，因此是神经调节的潜在治疗靶点。低强度聚焦 超声波（LIFU）是抑制皮质和脑深部区域的非侵入性方法。LIFU可以到达深处 与传统的非侵入性神经调节方法不同， 缺乏空间特异性和深度渗透。LIFU可选择性靶向靶区及其亚区 并提供了一种潜在的变革性方法，以减少疼痛症状，阿片类药物的渴望，和焦虑， 复杂患者人群，如OCpA。在本研究的UG3阶段，我们将进行一次 在OCpA [阿片类药物使用障碍、慢性背痛和焦虑症]患者中， （广泛性焦虑症、创伤后应激障碍或社交焦虑症）]。本阶段的目标是 研究的目的是确定LIFU与假LIFU相比，AI是安全的，并且耐受性良好，通过不良反应来衡量。 事件、临床评价和重复的结构性脑磁共振成像扫描。我们还将 收集LIFU对AI对阿片类线索诱导的渴望和实验室测量的影响的初步数据 中枢致敏（CS），其发生于疼痛慢性化，如疼痛的时间总和， 条件性疼痛调节在该项目的第二阶段（UH3），我们将在一个更大的 OCpA患者样本，重复LIFU给药，测量疼痛和阿片类药物提示诱导的 渴望，焦虑症状，内感受和自主反应，因为这些结果在 OCpA和由AI介导。LIFU将在一天内每小时输送10分钟，持续4小时。 我们假设，重复的LIFU治疗会降低CS、阿片类线索诱导的渴望、状态 焦虑症状，增加心率变异性和内感受的正常化措施。我们将研究 1次与2次重复LIFU对这些结局指标的持久性和影响。重复治疗 其他形式的神经调节导致增加的幅度和更持久的效果。我们假设 2次治疗与1次重复LIFU将导致结局指标发生更大幅度的变化。 最后，我们将检查重复LIFU治疗的安全性和耐受性。需要改进 复杂患者的治疗，如OCpA，超越了每种疾病的联合治疗。LIFU提供 能够短暂和选择性地抑制AI，以确定其在OCpA症状中的因果作用， 可能导致改善这种与不良治疗结果相关的临床三联征的治疗。