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，如重复经颅磁刺激（rTMS），应用于 背外侧前额叶皮层（DLPFC），已显示出减少可卡因渴望的功效。该补助金旨在 了解rTMS在减少可卡因诱导的 在电路水平上的行为，以及更广泛地说，rTMS对单细胞生理学的影响。两只恒河猴 猴子将执行一项决策任务，其中它们在静脉注射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使猴子如何量化价值 可卡因与自然奖赏的关系当猴子对可卡因产生偏好时，我们将记录 同时在DLPFC和两个已知代表经济期间奖励价值的大脑区域中， 决策，眶额皮质（OFC）和杏仁核。我们将检验神经元 记录在前外侧前额叶皮层、眶额皮层和杏仁核中的活动与猴子对可卡因的评价有关。如猴 可卡因自我给药增加，反映了可卡因的价值增加，我们假设OFC 杏仁核将更新可卡因价值的神经表征（目标1）。然后猴子会进入一个 交叉rTMS与假手术试验设计。他们将接受15 Hz的rTMS，100% RMT（静息运动） 阈值）或假手术，每隔一天在左侧DLPFC（区域9/46 d）进行20次治疗。没有rTMS的日子， 猴子将经历具有相同选择范例的记录会话。我们假设rTMS将 导致对可卡因的偏好下降，OFC中相对价值编码的平行变化， 接受rTMS的猴与假手术猴相比，杏仁核和DLPFC的基线活性恢复 (Aim 2）。记录将在末次治疗后持续3个月，以评估诱导的rTMS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 将是第一个直接表征神经元反应与rTMS小时和天后， 应用.这将通过阐明回路和机制来推进rTMS治疗药物滥用 负责赋予临床益处，这反过来又可以为开发和靶向 在未来改进治疗方法。