Influence of the natural hormonal milieu on perfusion fMRI smoking cue responses

然而，吸烟是美国可预防死亡的头号原因，尽管众所周知， 吸烟对健康的影响，五分之一的美国人继续吸烟。大多数吸烟者希望戒烟， 成功率很低。女性戒烟困难更大， 比男性的健康更重要。更多地了解妇女的复发脆弱性有助于确定 治疗目标，并导致改善健康和拯救生命的干预措施。对此的指导假设是 建议是，性腺性激素[雌二醇（E）和孕酮（P）]在整个过程中的波动， 月经周期（MC）可能通过其对强复发的作用极大地影响复发脆弱性 动机，吸烟相关线索（SC）暴露。这一假说来自动物研究，表明性腺 性激素显著影响奖励系统和奖励相关行为。具体来说，E抬高腹侧 纹状体多巴胺，并加速药物提示和药物引发的恢复，而P具有相反的作用 关于吸毒行为相应地，当女性有高E水平时，例如发生在 在MC的卵泡晚期，他们可能会发现药物更有回报，与药物相关的线索更有动力， 这可能会显著削弱女性在戒烟方面的成功。我们的初步 神经成像结果显示，内侧眶额皮质对SC的反应增强，该区域已知是 参与编码的奖励幅度，在妇女在卵泡期相比，黄体期，但 激素环境对SC的神经反应的直接影响仍未得到验证，使我们失去了关键的， 治疗相关信息。因此，本提案的总体目标是描述 大脑的自然激素环境和对SC的行为反应。具体来说，在AIM 1中，将激素 在3个月MC的过程中，在重复测量计数器中， 平衡设计，我们将比较一组健康的，自然的， 骑自行车的女性是慢性吸烟者，在3个不同的时间点，在他们的自然MC。鉴于早期 卵泡期与极低水平的E和P有关，它提供了一个自然和理想的比较器 条件会议将仔细定时发生在高E，这对应于后期卵泡阶段， 在高P期间，这对应于黄体中期，以及在MC期间，当E和P 低（LEP）。E/P浓度将用于验证条件，并作为协变量检查其 与大脑反应的联系在AIM 2中，将激素状态和大脑反应与行为联系起来， 对SC的偏见，与成像会议同步，来自Aim 1的女性也将参加3个实验室 由神经行为电池组成的会议，包括探测情感和注意力偏差的任务 在这两个时间点，SC。这项研究解决了我们知识中的一个关键空白：即， 激素环境对脑对SC反应的影响，这是一个重要的复发触发因素。其结果可能会指导临床- 知情的治疗战略，有可能减少复发，从而改善健康和挽救生命。

Cigarette smoking is the number one cause of preventable death in the U.S. however, despite the known health consequences of smoking, 1 in 5 Americans continues to smoke. Most smokers desire to quit but success rates are low. Women have greater difficulty quitting smoking and suffer greater smoking-related health consequences than men. Greater knowledge of relapse vulnerabilities in women could help to identify treatment targets and result in interventions that improve health and save lives. The guiding hypothesis for this proposal is that fluctuations in gonadal sex hormones [estradiol (E) and progesterone (P)] over the course of the menstrual cycle (MC) may greatly impact relapse vulnerability through their actions on a powerful relapse motivator, smoking-related cue (SC) exposure. This hypothesis arises from animal studies showing that gonadal sex hormones dramatically affect reward systems and reward-related behavior. Specifically, E elevates ventral striatal dopamine and accelerates both drug-cued and drug-primed reinstatement, while P has opposite effects on drug-seeking behavior. Correspondingly, when women have high E levels, such as those occurring during the late follicular phase of the MC, they may find drugs more rewarding and drug-related cues more motivating, which could markedly undermine women's success in quitting smoking at that time. Our preliminary neuroimaging results show enhanced responses to SCs in the medial orbitofrontal cortex, a region known to be involved in the coding of reward magnitude, in women during the follicular compared to the luteal phase, but the direct effects of the hormonal milieu on neural responses to SCs remains untested, divesting us of critical, treatment-relevant information. Thus, the overarching goal of this proposal is to characterize the influence of the natural hormonal milieu on brain and behavioral responses to SCs. Specifically, in AIM 1, to link hormonal status to the brain responses to SCs, over the course of 3 monthly MCs, in a repeated measures counter- balanced design, we will compare the brain responses to highly appetitive SCs in a group of healthy, naturally- cycling females who are chronic smokers at 3 distinct time points within their natural MC. Given that the early follicular phase is associated with extremely low levels of both E and P, it offers a natural and ideal comparator condition. Sessions will be carefully timed to occur during high E, which corresponds to the late follicular phase, during high P, which corresponds to the mid-luteal phase, and during the time of the MC when both E and P are low (LEP). E/P concentrations will be used to verify conditions and as covariates to examine their associations with brain responses. In AIM 2, to link hormonal status and brain responses to the behavioral biases to SCs, in synchrony with the imaging sessions, women from Aim 1 will also participate in 3 laboratory sessions consisting of a neuro-behavioral battery that includes tasks to probe affective and attentional biases to SCs at both time points. This research addresses a critical gap in our knowledge: namely, the impact of the hormonal milieu on brain response to SCs, an important relapse trigger. The results may guide hormonally- informed treatment strategies with the potential to reduce relapse, thus improving health and saving lives.