Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder

Erika L. Juarez-Martinez, Jan J. Sprengers, Gianina Cristian, Bob Oranje, Dorinde M. van Andel, Arthur Ervin Avramiea, Sonja Simpraga, Simon J. Houtman, Richard Hardstone, Cathalijn Gerver, Gert Jan van der Wilt, Huibert D. Mansvelder, Marinus J.C. Eijkemans, Klaus Linkenkaer-Hansen, Hilgo Bruining

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Scopus)


Background: Mechanism-based treatments such as bumetanide are being repurposed for autism spectrum disorder. We recently reported beneficial effects on repetitive behavioral symptoms that might be related to regulating excitation-inhibition (E/I) balance in the brain. Here, we tested the neurophysiological effects of bumetanide and the relationship to clinical outcome variability and investigated the potential for machine learning–based predictions of meaningful clinical improvement. Methods: Using modified linear mixed models applied to intention-to-treat population, we analyzed E/I-sensitive electroencephalography (EEG) measures before and after 91 days of treatment in the double-blind, randomized, placebo-controlled Bumetanide in Autism Medication and Biomarker study. Resting-state EEG of 82 subjects out of 92 participants (7–15 years) were available. Alpha frequency band absolute and relative power, central frequency, long-range temporal correlations, and functional E/I ratio treatment effects were related to the Repetitive Behavior Scale-Revised (RBS-R) and the Social Responsiveness Scale 2 as clinical outcomes. Results: We observed superior bumetanide effects on EEG, reflected in increased absolute and relative alpha power and functional E/I ratio and in decreased central frequency. Associations between EEG and clinical outcome change were restricted to subgroups with medium to high RBS-R improvement. Using machine learning, medium and high RBS-R improvement could be predicted by baseline RBS-R score and EEG measures with 80% and 92% accuracy, respectively. Conclusions: Bumetanide exerts neurophysiological effects related to clinical changes in more responsive subsets, in whom prediction of improvement was feasible through EEG and clinical measures.

Original languageEnglish
Pages (from-to)251-261
Number of pages11
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
Issue number3
Early online date8 Sept 2021
Publication statusPublished - Sept 2021


  • Autism
  • Bumetanide
  • EEG
  • Excitation-inhibition
  • Machine learning
  • RCT
  • Repetitive behavior

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