Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

Frontiers in Neuroscience

Erika L. Juarez-Martinez¹  Klaus Linkenkaer-Hansen²  Huibert D. Mansvelder²  Arthur-Ervin Avramiea²  Floor E. Jansen³  Dorinde M. van Andel⁴  Jan J. Sprengers⁴  Floortje E. Scheepers⁴  Bob Oranje⁴  Hilgo Bruining⁵ 

[1] Child and Adolescent Psychiatry and Psychosocial Care, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands;Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands;Department of Pediatric Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, Netherlands;Department of Psychiatry, UMC Utrecht Brain Center, University Medical Centre Utrecht, Utrecht, Netherlands;Levvel, Academic Center for Child and Adolescent Psychiatry, Amsterdam, Netherlands;N=You Neurodevelopmental Precision Center, Amsterdam Neuroscience, Amsterdam Reproduction and Development, Amsterdam UMC, Amsterdam, Netherlands;

关键词: tuberous sclerosis complex (TSC);    bumetanide;    EEG;    excitation-inhibition balance;    repetitive behavior;    irritability;   

DOI  :  10.3389/fnins.2022.879451

来源: DOAJ

【 摘 要 】

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.Clinical Trial RegistrationEU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.

【 授权许可】

Unknown