Traumatic brain injury commonly impairs attention and executive function, and disrupts the large-scale brain networks that support these cognitive functions. Abnormalities of functional connectivity are seen in corticostriatal networks, which are associated with executive dysfunction and damage to neuromodulatory catecholaminergic systems caused by head injury. Methylphenidate, a stimulant medication that increases extracellular dopamine and noradrenaline, can improve cognitive function following TBI. In this experimental medicine add-on study to a randomised, double-blind, placebo-controlled clinical trial, we test whether administration of methylphenidate alters corticostriatal network function and influences drug response. 43 moderate-severe traumatic brain injury patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. 28 patients were included in the neuropsychological and functional imaging analysis (4 females, mean age 40.9±12.7, range 20-65) and underwent functional MRI and neuropsychological assessment after each block. 123I-Ioflupane SPECT Dopamine Transporter (DAT) scans were performed, and specific binding ratios were extracted from caudate subdivisions. Functional connectivity and the relationship to cognition was compared between drug and placebo conditions. Methylphenidate increased caudate to anterior cingulate cortex functional connectivity compared to placebo and decreased connectivity from the caudate to default mode network. Connectivity within the default mode network was also decreased by methylphenidate administration and there was a significant relationship between caudate functional connectivity and DAT binding during methylphenidate administration. Methylphenidate significantly improved executive function in TBI patients, and this was associated with alterations in the relationship between executive function and right anterior caudate functional connectivity. Functional connectivity is strengthened to brain regions including the anterior cingulate that are activated when attention is focused externally. These results show that methylphenidate alters caudate interactions with cortical brain networks involved in executive control. In contrast, caudate functional connectivity reduces to default mode network regions involved in internally focused attention and that deactivate during tasks that require externally focused attention. These results suggest that the beneficial cognitive effects of methylphenidate may be mediated through its impact on the caudate. Methylphenidate differentially influences how the caudate interacts with large-scale functional brain networks that exhibit co-ordinated but distinct patterns of activity required for attentionally demanding tasks.

中文翻译：

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哌醋甲酯差异性地改变创伤性脑损伤后的皮质纹状体连接


创伤性脑损伤通常会损害注意力和执行功能，并破坏支持这些认知功能的大规模大脑网络。功能连接异常见于皮质纹状体网络，这与头部损伤引起的执行功能障碍和神经调节儿茶酚胺能系统损伤有关。哌醋甲酯是一种增加细胞外多巴胺和去甲肾上腺素的兴奋剂药物，可以改善 TBI 后的认知功能。在这项随机、双盲、安慰剂对照临床试验的实验性医学附加研究中，我们测试了哌醋甲酯的给药是否会改变皮质纹状体网络功能并影响药物反应。43 名中重度创伤性脑损伤患者接受 0.3 mg/kg 哌醋甲酯或安慰剂，每天两次，分 2 周。28 例患者被纳入神经心理学和功能影像学分析 （4 例女性，平均年龄 40.9±12.7，范围 20-65），并在每次阻滞后接受功能 MRI 和神经心理学评估。进行 123I-碘氟烷 SPECT 多巴胺转运蛋白 （DAT） 扫描，并从尾状核细分中提取特异性结合比。比较药物和安慰剂条件之间的功能连接和与认知的关系。与安慰剂相比，哌醋甲酯增加了尾状核到前扣带回皮层的功能连接，并减少了从尾状核到默认模式网络的连接性。哌醋甲酯给药也降低了默认模式网络内的连接性，并且在哌醋甲酯给药期间尾状核功能连接与 DAT 结合之间存在显着关系。 哌醋甲酯显著改善了 TBI 患者的执行功能，这与执行功能与右前尾状核功能连接之间关系的改变有关。与大脑区域的功能连接得到加强，包括当注意力集中在外部时，前扣带回会被激活。这些结果表明，哌醋甲酯改变了尾状核与参与执行控制的皮层脑网络的相互作用。相比之下，尾状核功能连接减少到默认模式网络区域，涉及内部集中注意力，并在需要外部集中注意力的任务中停用。这些结果表明，哌醋甲酯的有益认知作用可能是通过其对尾状核的影响来介导的。哌醋甲酯对尾状核与大规模功能性大脑网络的相互作用方式产生差异，这些大脑网络表现出对注意力要求高的任务所需的协调但不同的活动模式。