PDF(Pubmed)
Abstract：
Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide-a chloride-regulating agent-improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8-21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio (fE/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and fE/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC.
UNASSIGNED: EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.
UNASSIGNED: EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.
摘要：
神经元兴奋抑制（E/I）失衡被认为是神经发育障碍的重要病理生理机制。结节性硬化症（TSC）的临床前研究，表明改变的氯化物稳态可能会损害GABA能抑制，从而损害E/I平衡调节。因此，纠正氯化物稳态可能构成缓解行为症状的治疗目标。最近,我们在“布美他尼改善结节性硬化症患者过度兴奋行为试验”(BATSCH试验;Eudra-CT:2016-002408-13)的开放标签研究中显示,氯调节剂布美他尼改善了行为症状.这里,我们将静息态EEG作为BATSCH的辅助分析,以研究对网络水平E/I平衡变化敏感的EEG测量值与对布美他尼的临床反应之间的关联.10名TSC参与者（8-21岁）的EEG可用。光谱功率,长程时间相关性(LRTC)，在治疗前和治疗91天后比较α频率带的功能E/I比（fE/I）。将治疗前的措施与29名典型发育儿童（TDC）进行了比较。EEG测量值与异常行为检查表-易怒子量表（ABC-I）相关，社会反应量表-2(SRS-2)，和重复行为量表修订(RBS-R)。在基线,TSC显示出比TDC更低的α带绝对功率和fE/I。绝对功率增加通过布美他尼治疗，显示出适度的，尽管不重要，与RBS-R改善的相关性有趣的是,基线脑电图测量值与临床结果之间的相关性表明，在具有E/I平衡点周围网络特征的儿童中，大多数反应可能是预期的。总之,在TSC中存在指向抑制主导网络的E/I失衡。尽管与临床改善的关系尚无定论，但我们确定了布美他尼的神经生理学作用。尽管如此，我们的结果进一步表明,基线网络特征可能会影响治疗反应.这些发现强调了E/I敏感的EEG措施在TSC新的治疗干预措施中的可能实用性。
■欧盟临床试验注册，EudraCT2016-002408-13(www.临床试验登记。欧盟/ctr-search/trial/2016-002408-13/NL)。2016年7月25日注册
■欧盟临床试验注册，EudraCT2016-002408-13(www.临床试验登记。欧盟/ctr-search/trial/2016-002408-13/NL)。2016年7月25日注册
