Sex differences in the neural correlates underlying impairments in response inhibition and salience attribution in cocaine addiction

神经系统中的性别差异与可卡因成瘾的反应抑制和显着性归因的潜在损伤相关

• 批准号: 9913128
• 负责人: Rita Z Goldstein
• 金额: $ 68.93万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9913128
• 关键词: Abstinence; Address; Adverse effects; Anatomy; Behavioral; Chronic; Classification; Clinical; Clinical Trials; Cocaine Dependence; Cognitive; Corpus striatum structure; Cues; Data; Data Set; Development; Diagnostic; Disease; Dopamine; Drug Addiction; Drug usage; Early treatment; Emotional; Epidemic; Female; Functional Magnetic Resonance Imaging; Future; Gender; Goals; Gonadal Steroid Hormones; Hormonal; Impairment; Impulsivity; Individual; Informal Social Control; Intervention; Intoxication; Luteal Phase; Machine Learning; Magnetic Resonance Imaging; Maps; Measures; Menstrual cycle; Modeling; Monitor; Neurosciences; Opiate Addiction; Participant; Pattern; Performance; Pharmaceutical Preparations; Phase; Population; Prefrontal Cortex; Proxy; Psychological reinforcement; Public Health; Recovery; Recurrent disease; Relapse; Research; Resources; Rest; Rewards; Role; Scanning; Series; Severities; Sex Differences; Signal Transduction; Specificity; Stimulus; Structure; Symptoms; Testing; Withdrawal; Woman; addiction; base; blood oxygen level dependent; cocaine use; cost; craving; cue reactivity; design; drug of abuse; gray matter; imaging modality; imaging study; machine learning algorithm; male; men; neural correlate; neural network; neurobiological mechanism; neuroimaging; neurotransmission; non-drug; opioid use disorder; precision medicine; psychostimulant; recruit; relating to nervous system; response; reward processing; sex; sexual dimorphism; stress reactivity; symptomatology; systematic review; tool; treatment strategy

National studies show that drug use rates have increased in the last decade among women, comprising a major public health concern in the US. However, women are greatly underrepresented in neuroimaging studies, and the paucity of studies that explicitly target sex comparisons in addicted populations contributes to a gap in the study of the sex specific neurobiological mechanisms underlying drug addiction. Over the last decade, in a series of magnetic resonance imaging (MRI) studies (conducted with previous support including R01DA023579, R01DA020949), we have thoroughly mapped the clinical symptoms of cocaine addiction to the neural networks underlying impairments in Response Inhibition and Salience Attribution (iRISA). This model proposes that the drug assumes heightened salience at the expense of non-drug related reinforcement as associated with abnormalities in reward processing and concomitant decreases in inhibitory control, together increasing addiction severity (including craving, a proxy of relapse) in susceptible individuals. The iRISA model highlights the role of the dopaminergically innervated prefrontal cortex (PFC) and its connections to mesolimbic and striatal subcortical regions as assessed functionally and structurally. However, the majority of this neuroimaging research has been accomplished in male individuals with cocaine use disorders (iCUD). In the current project we aim to expand the reach of iRISA by comparing equal numbers of male to female iCUD; to test this model’s generalizability (vs. drug specificity effects), we will also include individuals with opioid use disorder (iOUD). We will conduct functional MRI during reward processing, inhibitory control and cue-reactivity tasks, and, to inspect generalizability of results beyond task-related activations, during resting-state. Beyond functional activations and connectivity, anatomical scans will assess the underlying gray matter integrity. Across all aims, healthy controls will be included to establish norms. We hypothesize female iCUD to differ from male iCUD, or female controls, in a pattern indicative of enhanced vulnerability to iRISA inclusive of compensatory PFC activations and abnormalities in structural measures; iCUD vs. iOUD comparisons will be exploratory. The novelty of this proposal is further enhanced by an exploratory aim to compare, in a within- subjects design, menstrual cycle (and hormonal) effects and by developing sophisticated machine-learning algorithms to incorporate data from all imaging modalities to yield an automated group classification and addiction severity (including craving) prediction tool. Considering that the majority of research in addiction occurs in males, clarification of the sex differences in the neural underpinnings of iRISA could reinforce the importance of studying both genders and suggest that different treatment strategies may be effective in women (potentially of most impact when timed vis-à-vis menstrual cycle), contributing to the development of tailored (gender-based) treatment options. Including equal numbers of women and men would advance basic studies of drug addiction and ultimately save resources by minimizing cost and adverse effects in future clinical trials.

国家研究表明，在过去十年中，女性的吸毒率有所上升，其中包括 美国的主要公共卫生问题。然而，女性在神经成像方面的代表性严重不足。 研究，以及明确针对成瘾人群中的性别比较的研究的缺乏有助于 在药物成瘾的性别特异性神经生物学机制研究方面存在空白。在过去的几年里 十年，在一系列磁共振成像(MRI)研究中(在之前的支持下进行，包括 R01DA023579、R01DA020949)，我们已经将可卡因成瘾的临床症状彻底映射到 反应抑制和显著归因中损害的神经网络(IRSA)。这款车 建议以牺牲与药物无关的强化为代价，使药物具有更高的显着性 与奖赏加工异常和伴随的抑制性控制能力下降有关 易感个体的成瘾严重程度增加(包括渴望，复发的指标)。Irisa模型 重点介绍多巴胺支配的前额叶皮质(PFC)的作用及其与中脑边缘的联系 和纹状体皮质下区域，作为功能和结构评估。然而，这其中的大部分 神经成像研究已经在患有可卡因使用障碍(ICUD)的男性个体中完成。在 目前的项目，我们的目标是通过比较同等数量的男性和女性iCUD来扩大irisa的覆盖范围； 测试此模型的泛化能力(与药物特异性效果相比)，我们还将包括使用阿片类药物的个体 精神障碍(IOUD)。我们将在奖赏加工、抑制控制和线索反应过程中进行功能磁共振成像。 任务，以及在休息状态期间，检查结果的概括性，超出与任务相关的激活。超越 功能激活和连接，解剖扫描将评估潜在的灰质完整性。 在所有目标中，将包括健康控制，以建立规范。我们假设女性iCUD会有所不同 来自男性iCUD或女性对照，其模式表明对IRSA的易感性增强，包括 补偿性PFC激活和结构措施异常；iCUD与iOUD的比较将是 探索性的。这项建议的新颖性通过探索性目标进一步增强，目的是在一个内部比较- 受试者通过设计、月经周期(和荷尔蒙)影响以及开发复杂的机器学习 合并来自所有成像设备的数据的算法，以产生自动化的组分类和 成瘾严重程度(包括渴求)预测工具。考虑到大多数关于成瘾的研究 在男性中发生，澄清IRSA神经基础中的性别差异可能会加强 研究两性的重要性，并建议不同的治疗策略可能对女性有效 (当计时相对于月经周期时，可能影响最大)，有助于开发定制的 (基于性别的)治疗选择。包括同等数量的女性和男性将促进基础研究 在未来的临床试验中，通过将成本和不良反应降至最低，可以减少药物成瘾并最终节省资源。