Neuroimaging response inhibition and salience attribution changes during mindfulness-based treatment of human heroin addiction

摘要 在过去的15年里，美国一直受到越来越多的处方和非法阿片类药物/阿片类药物滥用的影响， 成瘾和过量关于增加阿片剂/类阿片使用者治疗选择的研究 iOUD（iOUD）显然是一个优先事项。神经科学行为疗法的发展， 作为提高iOUD中药物辅助干预措施有效性的替代品， 应对鸦片危机8周的正念导向恢复增强（MORE）减少阿片类药物 滥用，渴望和线索反应，并增强自然奖励反应，效果归因于重组 在滥用阿片类药物的患者中，改善相关大脑的功能和增加灰质 区域[例如，前额叶皮层（PFC）]已被证明与其他8周的正念干预， 上瘾的人。然而，iOUD中MORE相关变化的神经机制尚不清楚。 受损反应抑制和突出归因（iRISA）模型强调了以下方面的重要性： 中皮质纹状体区域，包括PFC，以增强药物相对于自然奖励的显着性 伴随着抑制控制的降低，药物成瘾的核心底物。鉴于这些 共同点，我们建议研究iRISA的神经相关性，以促进和预测 更多关于iOUD的成瘾结果。采用前后随机治疗设计，随访3个月，我们 将检查MORE [与常规治疗（TAU）相比，作为美沙酮维持治疗的附加治疗]对神经系统的影响。 功能和结构可塑性，以及临床结果（包括日常生态瞬时评估）， 寻求治疗的iOUD（主要使用海洛因）。寻求治疗的iOUD将被随机分配至8周的 MORE或心理社会TAU，并在治疗前后立即进行磁共振成像扫描。 将以相似的时间间隔对健康对照进行扫描。我们假设，与对照组相比，TAU或 MORE前、MORE后受试者将显示以下方面的正常化或变化： 处理（即，增强的自然奖赏和减少的药物线索处理）和抑制控制; B）中- 皮质纹状体静息状态功能连接;和c）与奖赏处理相关的区域中的灰质 和抑制性控制。将在MORE或TAU期间、立即和3个月后评估临床结局。我们 假设MORE后> MORE前或TAU后大脑变化将预测临床改善（治疗 保留、戒断、阿片类药物使用量/频率和渴望），使得神经变化越多越好 结果（健康对照提供结果方向）。在全脑分析中，我们考虑了以下可能性： 恢复需要在其他网络中产生补偿缺陷的影响。结果将有助于识别个体差异 在支持奖励处理的大脑区域/回路中，包括线索反应和抑制控制， 可以随着对MORE的反应而改变，并预测对MORE的反应，最终有助于OUD的精准医学。

ABSTRACT Over the past 15 years, the US has been affected by increasing prescription and illicit opiate/opioid abuse, addiction, and overdose. Research into the enhancement of treatment options for individuals with opiate/opioid use disorder (iOUD) is clearly a priority. The development of neuroscience-informed behavioral therapies that could be used as adjuncts to improve effectiveness of medication-assisted interventions in iOUD is a national priority, a response to the opiate crisis. The 8-week Mindfulness-Oriented Recovery Enhancement (MORE) decreases opioid misuse, craving, and cue-reactivity, and enhances natural reward responsiveness, effects attributed to restructuring of hedonic dysregulation, in opioid misusing patients. Improved function and increased gray matter in relevant brain regions [e.g., the prefrontal cortex (PFC)] have been shown with other 8-week mindfulness interventions in non- addicted individuals. However, the neural mechanisms underlying MORE-related changes in iOUD are unknown. The Impaired Response Inhibition and Salience Attribution (iRISA) model highlights the importance of mesocorticostriatal regions, including the PFC, to enhanced salience of drugs relative to natural rewards concomitant with decreased inhibitory control, core substrates underlying drug addiction. Given these commonalities, we propose to study the neural correlates of iRISA as contributing to and predictive of the impact of MORE on addiction outcome in iOUD. Using a pre-post randomized treatment design with a 3-months follow-up, we will examine the impact of MORE [vs. treatment-as-usual (TAU), as add-ons to methadone maintenance] on neural functional and structural plasticity, and clinical outcomes (including daily ecological momentary assessments), in treatment-seeking iOUD (with primary use of heroin). Treatment-seeking iOUD will be randomized to 8-weeks of MORE or psychosocial TAU and scanned with magnetic resonance imaging immediately before and after treatment. Healthy controls will be scanned at similar time intervals. We hypothesize that compared with the controls, TAU or pre-MORE, post-MORE subjects will show normalizations or changes in: a) frontostriatal function during reward processing (i.e., enhanced natural reward and reduced drug cue processing) and inhibitory control; b) meso- corticostriatal resting-state functional connectivity; and c) gray matter in regions associated with reward processing and inhibitory control. Clinical outcome will be assessed during, immediately and 3-months after MORE or TAU. We hypothesize that brain changes post-MORE>pre-MORE or TAU will predict clinical improvement (treatment retention, abstinence, amount/frequency of opiate use and craving) such that the more the neural change, the better the outcomes (healthy controls provide direction of results). In whole-brain analyses we consider the possibility that recovery entails effects in other networks that compensate for deficits. Results will help identify individual variability in the brain regions/circuits that support reward processing, including cue reactivity, and inhibitory control and that could change with, and predict, response to MORE, ultimately contributing to precision medicine in OUD.