Neurophysiological mechanisms underlying rTMS treatment of addiction

rTMS 治疗成瘾的神经生理机制

• 批准号: 9507661
• 负责人: C. DANIEL SALZMAN
• 金额: $ 24.3万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9507661
• 关键词: Amygdaloid structure; Animals; Anterior; Area; Behavior; Behavior Therapy; Behavioral; Biological Models; Brain; Cell physiology; Cells; Chronic; Clinical; Cocaine; Color; Decision Making; Disease remission; Drops; Drug abuse; Economics; Electrophysiology (science); Exhibits; Frequencies; Future; Genetic; Grant; Hour; Human; Internal Granular Layer; Juice; Lead; Left; Long-Term Effects; Macaca mulatta; Measures; Monkeys; Mono-S; Motor; Neurons; Nucleus Accumbens; Pathway interactions; Phase; Physiological; Prefrontal Cortex; Primates; Probability; Process; Property; Protocols documentation; Rest; Rewards; Rodent; Rodent Model; Saccades; Self Administration; Stimulus; Structure; Surface; Synapses; Testing; Therapeutic; Training; Translating; Update; Ventral Tegmental Area; Work; addiction; base; behavior test; cingulate cortex; cocaine use; craving; human subject; improved; in vivo; insight; multi-electrode arrays; neurophysiology; neuroregulation; nonhuman primate; optogenetics; preference; relating to nervous system; repetitive transcranial magnetic stimulation; response; restoration; substance abuse treatment; treatment strategy; trial design

Neuromodulatory treatments, such as repetitive transcranial magnetic stimulation (rTMS) applied to dorsolateral prefrontal cortex (DLPFC), have shown efficacy in reducing cocaine craving. This grant seeks to understand the neurophysiological mechanisms underlying rTMS efficacy in reducing cocaine induced behaviors at a circuit level, and, more broadly, the effects of rTMS on single cell physiology. Two rhesus monkeys will perform a decision-making task in which they choose between iv cocaine and a natural reward. Parametric manipulations of reward amounts or probability will enable quantification of how monkeys value cocaine in relation to natural rewards. As the monkey develops a preference for cocaine, we will record simultaneously in DLPFC and two brain areas known to represent the values of rewards during economic decision-making, the orbitofrontal cortex (OFC) and amygdala. We will test the hypothesis that neuronal activity recorded in DLPFC, OFC and amygdala is correlated with how monkeys value cocaine. As monkeys escalate cocaine self-administration, reflecting an increase in how cocaine is valued, we hypothesize that OFC and amygdala will update neural representations of the value of cocaine (Aim 1). Monkeys will then enter a cross-over rTMS vs. sham trial design. They will receive either rTMS at 15Hz, 100% RMT (resting motor threshold) or sham, every other day for 20 sessions in left DLPFC (area 9/46d). The days without rTMS, monkeys will undergo a recording session with the same choice paradigm. We hypothesize that rTMS will cause a decline in preference for cocaine, a parallel shift in the encoding of relative value in OFC and amygdala, and restoration of baseline activity in DLPFC for monkeys undergoing rTMS vs. sham monkeys (Aim 2). Recordings will continue for 3 months after the last treatment to assess the duration of rTMS induced electrophysiological changes. Different frequencies and different networks will be tested if needed. This grant will be the first to characterize directly neuronal responses in relation to rTMS hours and days after applications. This will advance rTMS treatment of substance abuse by elucidating the circuits and mechanisms responsible for conferring clinical benefits, which in turn may provide key insights for developing and targeting improved therapeutics in the future.

神经调节治疗，例如应用于 背外侧前额叶皮层（DLPFC）在减少可卡因渴望方面表现出疗效。这笔赠款试图 了解降低可卡因诱导的RTMS功效的神经生理机制 在电路水平上的行为，更广泛地是RTM对单细胞生理学的影响。两个恒河 猴子将执行一项决策任务，其中他们在静脉可卡因和自然奖励之间进行选择。 奖励金额或概率的参数操作将能够量化猴子的价值 可卡因与自然奖励有关。随着猴子对可卡因的偏爱，我们将记录 同时在DLPFC和两个大脑区域中代表经济期间的奖励价值 决策，眶额皮质（OFC）和杏仁核。我们将测试神经元的假设 在DLPFC，OFC和杏仁核中记录的活动与猴子的价值可卡因如何相关。作为猴子 升级可卡因自我管理，反映了可卡因的重视方式的增加，我们假设OFC 杏仁核将更新可卡因价值的神经表示（AIM 1）。然后，猴子将进入 交叉RTMS与假试设计。他们将在15Hz，100％RMT（静止电动机）收到RTM 阈值）或假，每隔一天在左DLPFC（9/46D区域）进行20次会议。没有RTM的日子， 猴子将与相同选择范式进行录音会议。我们假设RTM会 导致对可卡因偏爱的偏好下降，在OFC和OFC中相对值编码的平行转移 杏仁核，以及在RTMS与假猴的DLPFC中基线活性的恢复 （目标2）。最后一次治疗后，记录将持续3个月，以评估RTMS的持续时间 电生理变化。如果需要，将测试不同的频率和不同的网络。这笔赠款 将是第一个与RTMS相关的直接表征神经元反应的数小时。 申请。这将通过阐明电路和机制来推动RTMS治疗药物滥用 负责赋予临床益处，这又可能为开发和定位提供关键见解 将来改善了治疗剂。