Vansina Eline, Douw Linda, Kaiser Antonia, van der Pal Zarah, Boucherie Daphne E, De Vries Taco J, Pattij Tommy, Cohen Jessica R, Hoekstra Pieter J, Reneman Liesbeth, Schrantee Anouk
Department of Radiology and Nuclear Medicine, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands.
Department of Anatomy and Neurosciences, Amsterdam UMC, location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
medRxiv. 2025 Aug 29:2025.08.27.25334547. doi: 10.1101/2025.08.27.25334547.
Methylphenidate is effective in reducing ADHD symptoms in the short term, but long-term benefits are inconsistent, possibly due to the development of tolerance. Moreover, little is known about its sustained effects on brain functional connectivity. We examined whether a 4-month methylphenidate treatment leads to sustained alterations in resting-state functional connectivity, and whether acute brain responses to methylphenidate decrease after treatment, as a potential marker of neurobiological tolerance.
This is a secondary analysis of the ePOD-MPH RCT in which 50 boys and 49 men with ADHD were randomized to methylphenidate or placebo. Resting-state fMRI data were collected before, and one week after, a 4-month treatment period. At both visits, participants were scanned before and after an acute oral methylphenidate challenge. We computed whole-brain and default mode network (DMN) global efficiency, and DMN-whole-brain connectivity strength.
In adults, methylphenidate (but not placebo) led to sustained increases in whole-brain efficiency (p=0.01) and DMN-whole-brain connectivity strength (p=0.03). No significant effects were observed in children (all p>0.17). Exploratory analyses indicated that whole-brain efficiency increases related to decreasing cognitive performance in methylphenidate-treated children, but improving performance in placebo-treated children, suggesting treatment-dependent moderation (p<0.01). Acute connectivity responses remained stable in adults across visits (all p>0.15), but increased in children, regardless of treatment (all p<0.04).
Four months of methylphenidate treatment led to sustained functional connectivity changes in adults with ADHD, without evidence of neurobiological tolerance. These findings emphasize the importance of studying longer treatment durations, considering that methylphenidate treatments typically span multiple years.
哌甲酯在短期内可有效减轻注意力缺陷多动障碍（ADHD）症状，但长期疗效并不一致，这可能是由于耐受性的产生。此外，对于其对脑功能连接的持续影响知之甚少。我们研究了为期4个月的哌甲酯治疗是否会导致静息态功能连接的持续改变，以及治疗后对哌甲酯的急性脑反应是否会降低，以此作为神经生物学耐受性的潜在标志。
这是对ePOD-MPH随机对照试验（RCT）的二次分析，该试验将50名患有ADHD的男孩和49名男性随机分为哌甲酯组或安慰剂组。在为期4个月的治疗期之前和之后一周收集静息态功能磁共振成像（fMRI）数据。在两次就诊时，参与者在接受急性口服哌甲酯激发前后均进行扫描。我们计算了全脑和默认模式网络（DMN）的全局效率以及DMN与全脑的连接强度。
在成年人中，哌甲酯（而非安慰剂）导致全脑效率（p = 0.01）和DMN与全脑的连接强度持续增加（p = 0.03）。在儿童中未观察到显著影响（所有p>0.17）。探索性分析表明，全脑效率的提高与哌甲酯治疗的儿童认知表现下降有关，但与安慰剂治疗的儿童表现改善有关，提示存在治疗依赖性调节（p<0.01）。在成年人中，急性连接反应在各次就诊时保持稳定（所有p>0.15），但在儿童中增加，无论治疗情况如何（所有p<0.04）。
为期4个月的哌甲酯治疗导致患有ADHD的成年人静息态功能连接发生持续变化，且没有神经生物学耐受性的证据。这些发现强调了研究更长治疗疗程的重要性，因为哌甲酯治疗通常持续数年。
