Juarez-Martinez Erika L, van Andel Dorinde M, Sprengers Jan J, Avramiea Arthur-Ervin, Oranje Bob, Scheepers Floortje E, Jansen Floor E, Mansvelder Huibert D, Linkenkaer-Hansen Klaus, Bruining Hilgo
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands.
Child and Adolescent Psychiatry and Psychosocial Care, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Front Neurosci. 2022 May 12;16:879451. doi: 10.3389/fnins.2022.879451. eCollection 2022.
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 (E/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 E/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.
EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.
神经元兴奋-抑制（E/I）失衡被认为是神经发育障碍中的一种重要病理生理机制。结节性硬化症（TSC）的临床前研究表明，氯离子稳态改变可能会损害γ-氨基丁酸能抑制作用，从而影响E/I平衡调节。因此，纠正氯离子稳态可能构成缓解行为症状的治疗靶点。最近，我们在开放标签研究“布美他尼改善结节性硬化症过度兴奋行为试验”（BATSCH试验；欧盟临床试验注册号：2016-002408-13）中发现，布美他尼（一种调节氯离子的药物）改善了行为症状。在此，我们展示静息态脑电图作为BATSCH试验的二次分析，以研究对E/I平衡网络水平变化敏感的脑电图测量指标与布美他尼临床反应之间的关联。我们获取了10名TSC患者（年龄8 - 21岁）的脑电图。比较了治疗91天前后α频段的频谱功率、长程时间相关性（LRTC）和功能性E/I比值（E/I）。将治疗前的测量结果与29名发育正常儿童（TDC）进行比较。脑电图测量指标与异常行为检查表-易激惹分量表（ABC-I）、社会反应量表-2（SRS-2）和重复行为量表-修订版（RBS-R）进行相关性分析。在基线时，TSC患者的α频段绝对功率和E/I比值低于TDC。布美他尼治疗后绝对功率增加，这与RBS-R的改善呈中度（尽管不显著）相关。有趣的是，基线脑电图测量指标与临床结果之间的相关性表明，在E/I平衡点附近具有网络特征的儿童可能对治疗反应最为敏感。总之，TSC患者存在指向抑制主导网络 的E/I失衡。我们确定了布美他尼的神经生理效应，尽管其与临床改善的关系尚无定论。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。这些发现突出了对E/I敏感的脑电图测量指标在TSC新治疗干预中的潜在应用价值。
欧盟临床试验注册库，EudraCT 2016-002408-13（www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL）。于2016年7月25日注册。
