Martins Daniel, Veronese Mattia, Turkheimer Federico E, Howard Matthew A, Williams Steve C R, Dipasquale Ottavia
Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK.
Brain Commun. 2021 Dec 22;4(1):fcab302. doi: 10.1093/braincomms/fcab302. eCollection 2022.
Chronic pain is a world-wide clinical challenge. Response to analgesic treatment is limited and difficult to predict. Functional MRI has been suggested as a potential solution. However, while most analgesics target specific neurotransmission pathways, functional MRI-based biomarkers are not specific for any neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response. Here, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets to investigate whether neurotransmission-enriched functional connectivity mapping can provide insights into the brain mechanisms underlying chronic pain and inter-individual differences in analgesic response after a placebo or duloxetine. We performed secondary analyses of two openly available resting-state functional MRI data sets of 56 patients with chronic knee osteoarthritis pain who underwent pre-treatment brain scans in two clinical trials. Study 1 ( = 17) was a 2-week single-blinded placebo pill trial. Study 2 ( = 39) was a 3-month double-blinded randomized trial comparing placebo to duloxetine, a dual serotonin-noradrenaline reuptake inhibitor. Across two independent studies, we found that patients with chronic pain present alterations in the functional circuit related to the serotonin transporter, when compared with age-matched healthy controls. Placebo responders in Study 1 presented with higher pre-treatment functional connectivity enriched by the dopamine transporter compared to non-responders. Duloxetine responders presented with higher pre-treatment functional connectivity enriched by the serotonin and noradrenaline transporters when compared with non-responders. Neurotransmission-enriched functional connectivity mapping might hold promise as a new mechanistic-informed biomarker for functional brain alterations and prediction of response to pharmacological analgesia in chronic pain.
慢性疼痛是一项全球性的临床挑战。对镇痛治疗的反应有限且难以预测。功能磁共振成像被认为是一种潜在的解决方案。然而，虽然大多数镇痛药针对特定的神经传递途径，但基于功能磁共振成像的生物标志物并非针对任何神经递质系统具有特异性，这限制了我们对它们如何有助于预测治疗反应的理解。在此，我们试图通过应用基于靶点的功能连接富集分析来弥合这一差距，以研究神经传递富集的功能连接图谱是否能够为慢性疼痛的脑机制以及安慰剂或度洛西汀治疗后镇痛反应的个体差异提供见解。我们对两个公开可用的静息态功能磁共振成像数据集进行了二次分析，这些数据集来自56名患有慢性膝骨关节炎疼痛的患者，他们在两项临床试验中接受了治疗前的脑部扫描。研究1（n = 17）是一项为期2周的单盲安慰剂药丸试验。研究2（n = 39）是一项为期3个月的双盲随机试验，比较安慰剂与度洛西汀（一种5-羟色胺-去甲肾上腺素再摄取双重抑制剂）。在两项独立研究中，我们发现，与年龄匹配的健康对照相比，慢性疼痛患者在与5-羟色胺转运体相关的功能回路中存在改变。在研究1中，与无反应者相比，安慰剂反应者在治疗前具有更高的由多巴胺转运体富集的功能连接。与无反应者相比，度洛西汀反应者在治疗前具有更高的由5-羟色胺和去甲肾上腺素转运体富集的功能连接。神经传递富集的功能连接图谱可能有望成为一种新的基于机制的生物标志物，用于功能性脑改变以及慢性疼痛中药理学镇痛反应的预测。
