Department of Radiology and Nuclear Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Swammerdam Institute for Life Sciences, Center for Neurosciences, University of Amsterdam, Sciencepark 904, 1098 XH Amsterdam, The Netherlands.
Department of Radiology and Nuclear Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Neuroimage Clin. 2017 Jun 2;15:812-818. doi: 10.1016/j.nicl.2017.06.003. eCollection 2017.
Stimulants are the main pharmacological treatment for patients with attention-deficit/hyperactivity disorder (ADHD). Their current prescription rates are rising, both in children, adolescents and adults. Related to the impulse control phenotype, both preclinical and clinical studies have demonstrated lower γ-amino butyric acid (GABA) levels in prefrontal brain regions in ADHD. Whereas stimulant treatment increases GABA levels, preclinical studies have suggested that stimulant treatment effects may be age-dependent. As the long-term consequences of stimulant use in ADHD children and adolescents have so far been poorly studied, we used magnetic resonance spectroscopy to assess GABA+ and glutamate + glutamine (Glx) levels in the medial prefrontal cortex (mPFC) of adult ADHD patients, both before and after an oral methylphenidate (MPH) challenge. Three groups were studied: 1) ADHD patients who were first treated with stimulants before 16 years of age, i.e. during periods of ongoing brain development (early-stimulant-treated, EST); 2) patients first treated with stimulants in adulthood (i.e. > 23 years) (late-stimulant-treated, LST), and 3) stimulant-treatment-naive (STN) ADHD patients. Reduced basal GABA+ levels were found in EST compared to LST patients (p = 0.04), while after an MPH challenge, only the EST patients showed significant increases in GABA+ (p = 0.01). For Glx, no differences were found at baseline, nor after an MPH challenge. First stimulant exposure at a young age is thus associated with lower baseline levels of GABA+ and increased responsivity in adulthood. This effect could not be found in patients that started treatment at an adult age. Hence, while adult stimulant treatment seems to exert no major effects on GABA+ levels in the mPFC, MPH may induce long-lasting alterations in the adult mPFC GABAergic system when treatment was started at a young age.
兴奋剂是治疗注意力缺陷多动障碍（ADHD）患者的主要药物治疗方法。目前，儿童、青少年和成年人的兴奋剂处方率都在上升。与冲动控制表型相关，临床前和临床研究都表明 ADHD 患者前额叶脑区的γ-氨基丁酸（GABA）水平较低。虽然兴奋剂治疗可增加 GABA 水平，但临床前研究表明，兴奋剂治疗效果可能具有年龄依赖性。由于迄今为止对 ADHD 儿童和青少年使用兴奋剂的长期后果研究甚少，我们使用磁共振波谱法评估了内侧前额叶皮质（mPFC）中 GABA+和谷氨酸+谷氨酰胺（Glx）水平，包括 ADHD 成年患者在口服哌甲酯（MPH）挑战前后。我们研究了三组患者：1）16 岁之前就开始接受兴奋剂治疗的 ADHD 患者，即大脑发育仍在进行期间（早期接受兴奋剂治疗，EST）；2）成年后首次接受兴奋剂治疗的患者（即>23 岁）（晚期接受兴奋剂治疗，LST）；3）未接受兴奋剂治疗的 ADHD 患者（STN）。与 LST 患者相比，EST 患者的基础 GABA+水平较低（p=0.04），而在 MPH 挑战后，只有 EST 患者的 GABA+水平显著增加（p=0.01）。对于 Glx，基线时无差异，MPH 挑战后也无差异。因此，早年首次接触兴奋剂与 GABA+基线水平较低和成年后反应性增加有关。在成年后开始治疗的患者中未发现这种影响。因此，虽然成年期的兴奋剂治疗似乎对 mPFC 中的 GABA+水平没有主要影响，但当治疗开始于年幼时，MPH 可能会在成年 mPFC 中诱导 GABA 能系统的长期改变。
