Brain effects of long-term anabolic-androgenic steroid use:Multimodal imaging and cognition studies

总结/摘要 合成代谢雄激素类固醇（AAS）的使用是一个重大的公共卫生问题，近400万美国人 使用AAS。大约30%的AAS使用者发展为AAS依赖，是最高依赖之一。 所有滥用药物的比率。多种药物滥用在AAS使用者中非常普遍。AAS使用导致急性 精神影响，如侵略和暴力，正如我们过去所报道的，长期使用AAS是 与视觉空间记忆功能障碍有关的早期痴呆症的预测测试。迄今为止，人类大脑 长期使用AAS的相关性在很大程度上尚未探索。我们在长期AAS使用者中的初步成像研究 产生了3个令人信服的发现。首先，杏仁核被AAS放大，与对照临床前一致。 问题研究第二，AAS减少了杏仁核和背侧前扣带回之间的功能连接 皮质（dACC），一个认知控制区域。第三，在磁共振波谱研究中，AAS用户 dACC中谷氨酰胺/谷氨酸比值升高和鲨肌醇水平降低，提示持续功能障碍 以及可能的神经毒性由于杏仁核参与情绪调节，视觉空间处理， 感觉整合/食欲/厌恶刺激的处理，成本/收益决策，以及药物奖励， 寻找和线索反应，并与dACC一起调节接近/回避学习和监测 情绪冲突、杏仁核和dACC异常可能损害所有这些过程。因为 通常使用的AAS增加β-淀粉样蛋白水平和scyllo-inositol防止β-淀粉样蛋白结块，我们的scyllo- 肌醇发现可能特别重要。在此R 01应用程序中，我们的目标是通过以下方式在初步调查结果的基础上再接再厉： 直接探测杏仁核和海马功能与任务为基础的BOLD功能磁共振成像范例，包括 来源记忆范式和哈里里情绪面孔范式。我们还将获得MRS光谱， dACC和顶枕皮质，后者是早期β-淀粉样蛋白积累的靶点，以确定 是否谷氨酰胺/谷氨酸和鲨肌醇/肌酸代谢物比例异常也发生在后 扣带皮质，一个通常表现出早期β-淀粉样蛋白积聚的区域。拟议的研究涉及大量 样本量足以检验先验假设。由此产生的数据将有助于确定 AAS使用者精神和认知异常的神经基础，以衡量大脑影响的严重程度 从长期AAS使用，并告知未来研究的设计，以检查这种影响的进展 持续使用AAS和/或老化，包括使用诸如鲨肌醇或 NMDA受体拮抗剂。我们可以访问特征良好的AAS用户和控件， 即将完成的NIDA资助的心血管研究，以及招募新受试者的能力， 入选/排除标准。我们的团队对这些人群和建议的 评估方法，因此是独一无二的准备进行这项研究。因此，该方案是 这是可行的，如果成功的话，可能会对实地产生持续和强大的影响。

Summary/Abstract Anabolic-androgenic steroids (AAS) use is a significant public health problem, with nearly 4 million Americans having used AAS. Roughly 30% of AAS users develop AAS dependence, among the highest dependence rates of all abused drugs. Polydrug abuse is highly prevalent among AAS users. AAS use causes acute psychiatric effects such as aggression and violence, and as we reported in past, long-term AAS use is associated with visuospatial memory dysfunction on tests predictive of early dementia. To date, human brain correlates of long-term AAS use are largely unexplored. Our pilot imaging studies in long-term AAS users produced 3 compelling findings. First, the amygdala is enlarged by AAS, consistent with controlled preclinical studies. Second, AAS reduced functional connectivity between the amygdala and dorsal anterior cingulate cortex (dACC), a cognitive control region. Third, in magnetic resonance spectroscopy studies, AAS users had elevated glutamine/glutamate ratios and lower scyllo-inositol levels in dACC, suggestive of ongoing dysfunction and possible neurotoxicity. As the amygdala participates in emotion regulation, visuospatial processing, sensory integration/processing of appetitive/aversive stimuli, cost/benefit decision-making, and drug reward, seeking, and cue reactivity, and together with the dACC modulates approach/avoidance learning and monitors emotional conflicts, amygdala and dACC abnormalities could impair all of these processes. Because commonly used AAS increase β-amyloid levels and scyllo-inositol prevents β-amyloid clumping, our scyllo- inositol finding may be particularly important. In this R01 application, we aim to build upon initial findings by directly probing amygdala and hippocampal function with task-based BOLD fMRI paradigms, including a source memory paradigm and the Hariri emotional face paradigm. We also will acquire MRS spectra from dACC and parieto-occipital cortex, the latter of which is a target for early β-amyloid accumulation, to determine whether glutamine/glutamate and scyllo-inositol/creatine metabolite ratio abnormalities also occur in posterior cingulate cortex, a region normally exhibiting early β-amyloid accumulation. Proposed studies involve large sample sizes that are adequately powered to test a priori hypotheses. Resulting data will help to identify the neural bases for psychiatric and cognitive abnormalities in AAS users, to gauge the severity of brain effects from long-term AAS use, and to inform the design of future studies to examine the progression of such effects with continued AAS use and/or aging, including interventional studies with agents such as scyllo-inositol or NMDA receptor antagonists. We have access to well-characterized AAS users and controls, recruited for our nearly-completed NIDA-funded cardiovascular studies, and the ability to recruit new subjects meeting inclusion/exclusion criteria. Our team is highly experienced with these populations and with proposed assessment methods, and thus is uniquely poised to conduct this research. Accordingly, this program is feasible and, if successful, likely will exert a sustained and powerful influence on the field.