Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control
Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control
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DOI：
10.1093/brain/awz007
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发表时间：
2019-03-01
期刊：
影响因子：
14.5
通讯作者：
van Eimeren, Thilo
中科院分区：
文献类型：
--
作者：
Hammes, Jochen;Theis, Hendrik;van Eimeren, Thilo
冲动强迫行为，如病态赌博或性欲亢进是帕金森病患者多巴胺替代疗法的常见副作用。多项影像学研究表明，突触前多巴胺转运蛋白在脑桥核的显着减少是一个诱发因素，反映了减少的中脑边缘投射，或者，作为替代，一个较低的突触前多巴胺转运蛋白表达本身。在这里，我们的目的是测试的假设，较少的中脑边缘系统的预测作为一个危险因素，通过使用多巴胺合成能力作为多巴胺能神经末梢密度的代理。此外，以前的研究已经证明，额纹状体连接的减少与帕金森病患者冲动强迫行为风险的增加有关。因此，本研究的另一个目的是探讨冲动强迫行为的严重程度，多巴胺合成能力和额-纹状体连接之间的关系。80名参与者接受了静息状态功能性MRI和解剖T-1加权图像[平均年龄：68 +/- 9.9岁，67%为男性（患者）]。在59名参与者中，获得了F-18-DOPA-PET，并计算了指示多巴胺合成能力的体素Patlak斜率。所有参与者都完成了QUIP-RS问卷，这是一项经过充分验证的测试，用于量化帕金森病患者冲动强迫行为的严重程度。计算纹状体区域多巴胺合成能力和QUIP-RS评分之间的体素相关性分析。为了研究症状严重程度和功能连接之间的关系，进行了体素相关性分析。多巴胺合成能力和QUIP-RS评分之间呈负相关（r =-0.57，P = 0.001），在延髓核，一个区域的功能连接到喙前扣带皮层。连接强度受QUIP-RS的调制，即具有更严重的冲动-强迫行为的患者具有更弱的前扣带皮层和背核之间的功能连接。此外，皮质厚度和冲动强迫行为的严重程度呈正相关，在膝下喙前扣带皮层。我们发现有三个因素与冲动-强迫行为的严重程度相关：（i）前扣带核多巴胺合成能力降低;（ii）前扣带皮质吻侧与前扣带核功能连接性降低;（iii）前扣带皮质吻侧下的皮质厚度增加。而不是多巴胺转运蛋白的下调，减少中脑边缘多巴胺能投射与功能障碍的喙前扣带皮层地区已知发挥关键作用的冲动控制可能是最重要的神经生物学危险因素的发展下帕金森氏病患者的多巴胺替代治疗的冲动强迫行为。
Impulsive-compulsive behaviours like pathological gambling or hypersexuality are a frequent side effect of dopamine replacement therapy in patients with Parkinson's disease. Multiple imaging studies suggest a significant reduction of presynaptic dopamine transporters in the nucleus accumbens to be a predisposing factor, reflecting either a reduction of mesolimbic projections or, alternatively, a lower presynaptic dopamine transporter expression per se. Here, we aimed to test the hypothesis of fewer mesolimbic projections as a risk factor by using dopamine synthesis capacity as a proxy of dopaminergic terminal density. Furthermore, previous studies have demonstrated a reduction of fronto-striatal connectivity to be associated with increased risk of impulsive-compulsive behaviour in Parkinson's disease. Therefore, another aim of this study was to investigate the relationship between severity of impulsive-compulsive behaviour, dopamine synthesis capacity and fronto-striatal connectivity. Eighty participants underwent resting state functional MRI and anatomical T-1-weighted images [mean age: 68 +/- 9.9 years, 67% male (patients)]. In 59 participants, F-18-DOPA-PET was obtained and voxel-wise Patlak slopes indicating dopamine synthesis capacity were calculated. All participants completed the QUIP-RS questionnaire, a well validated test to quantify severity of impulsive-compulsive behaviour in Parkinson's disease. A voxel-wise correlation analysis between dopamine synthesis capacity and QUIP-RS score was calculated for striatal regions. To investigate the relationship between symptom severity and functional connectivity, voxel-wise correlations were performed. A negative correlation was found between dopamine synthesis capacity and QUIP-RS score in the nucleus accumbens (r = -0.57, P = 0.001), a region functionally connected to the rostral anterior cingulate cortex. The connectivity strength was modulated by QUIP-RS, i.e. patients with more severe impulsive-compulsive behaviours had a weaker functional connectivity between rostral anterior cingulate cortex and the nucleus accumbens. In addition, cortical thickness and severity of impulsive-compulsive behaviour were positively correlated in the subgenual rostral anterior cingulate cortex. We found three factors to be associated with severity of impulsive-compulsive behaviour: (i) decreased dopamine synthesis capacity in the nucleus accumbens; (ii) decreased functional connectivity of the rostral anterior cingulate cortex with the nucleus accumbens; and (iii) increased cortical thickness of the subgenual rostral anterior cingulate cortex. Rather than a downregulation of dopamine transporters, a reduction of mesolimbic dopaminergic projections in conjunction with a dysfunctional rostral anterior cingulate cortexa region known to play a key role in impulse control-could be the most crucial neurobiological risk factor for the development of impulsive-compulsive behaviours in patients with Parkinson's disease under dopamine replacement therapy.