Neurophysiological mechanisms underlying rTMS treatment of addiction

神经调节治疗，如重复经颅磁刺激(RTMS)应用于 背外侧前额叶皮质(DLPFC)，已显示出减少可卡因渴求的效果。这笔赠款旨在 了解rTMS减少可卡因诱导的神经生理学机制 电路水平的行为，以及更广泛地说，rTMS对单细胞生理学的影响。两只恒河猴 猴子将完成一项决策任务，在静脉注射可卡因和自然奖励之间做出选择。 对奖励金额或概率的参数操作将使量化猴子的价值成为可能 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和两个已知的代表经济活动中奖励价值的大脑区域 决策，眶前叶皮质(OFC)和杏仁核。我们将测试神经细胞的假设 记录在DLPFC、OFC和杏仁核的活动与猴子对可卡因的评价有关。就像猴子一样 升级可卡因自我管理，反映出可卡因价值的增加，我们假设OFC 杏仁核将更新神经对可卡因价值的表示(目标1)。然后猴子们将进入一个 交叉rTMS与假试验设计。他们将接受15赫兹、100%RMT(静止电机)的rTMS 阈值)或假手术，每隔一天在左侧DLPFC(9/46d区)进行20次治疗。没有rTMS的日子， 猴子们将用同样的选择范式进行录音。我们假设rtms会 导致对可卡因的偏好下降，OFC和OFC的相对值编码的平行变化 杏仁核，以及接受rTMS的猴子与假手术猴DLPFC基线活动的恢复 (目标2)。记录将在最后一次治疗后持续3个月，以评估诱发rTMS的持续时间 电生理改变。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与rTMS相关的神经元反应的人 申请。这将通过阐明电路和机制来推进rTMS治疗药物滥用 负责授予临床益处，这反过来可能为开发和确定目标提供关键见解 在未来改进治疗方法。

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.