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，妇女的药物使用率有所提高，完成了 美国的主要公共卫生问题。但是，女性在神经影像学上的人数大大不足 研究，以及在上瘾人群中明确靶向性比较的研究很少有助于 在研究药物成瘾的性别特异性神经生物学机制研究中的差距。最后 十年，在一系列磁共振成像（MRI）研究中（以先前的支持进行了 R01DA023579，R01DA020949），我们将可卡因成瘾的临床症状彻底映射到了 在响应抑制和显着归因（IRISA）中损害的基础神经网络（IRISA）。这个模型 该药物以非毒品相关的强化为代价的提议提高了显着性 与奖励处理和抑制控制下伴随下降的异常相关，共同 易感人士的成瘾严重程度增加（包括渴望，救济）。 IRISA模型 突出了多巴胺能支配的前额叶皮层（PFC）的作用及其与中唇的连接 以及在功能和结构上评估的纹状体下皮层区域。但是，大多数 在可卡因使用障碍（ICUD）的雄性个体中，神经影像学研究已经完成。在 当前的项目我们旨在通过比较相等数量的男性与女性ICUD来扩大IRISA的影响力； 测试该模型的推广性（与药物特异性效应），我们还将包括使用阿片类药物的人 疾病（IOUD）。我们将在奖励处理，抑制性控制和提示反应性过程中进行功能性MRI 任务，以及在静止状态期间检查与任务相关的激活以外的结果的普遍性。超过 功能激活和连通性，解剖学扫描将评估潜在的灰质完整性。 在所有目标中，都将包括健康的控制措施以建立规范。我们假设女性与不同 来自男性ICUD或女性控制 结构措施中的补偿性PFC激活和异常； ICUD与IOUD比较将是 探索性。通过探索性的目的比较，在 受试者设计，月经周期（和荷尔蒙）效应以及通过开发复杂的机器学习 算法合并所有成像方式的数据以产生自动组分类和 成瘾的严重程度（包括渴望）预测工具。考虑到大多数成瘾研究 发生在男性中，澄清irisa神经基础的性别差异可能会加强 研究这两个性别的重要性并暗示不同的治疗策略可能对女性有效 （相对于月经周期的定时时，可能会产生最大的影响），有助于开发量身定制 （基于性别的）治疗选择。包括相等数量的男女将进步基础研究 在未来的临床试验中最大程度地减少成本和不利影响，最终可以节省资源。