STXBP1 Syndrome Is Characterized by Inhibition-Dominated Dynamics of Resting-State EEG

Simon J. Houtman, Hanna C.A. Lammertse, Annemiek A. van Berkel, Ganna Balagura, Elena Gardella, Jennifer R. Ramautar, Chiara Reale, Rikke S. Møller, Federico Zara, Pasquale Striano, Mala Misra-Isrie, Mieke M. van Haelst, Marc Engelen, Titia L. van Zuijen, Huibert D. Mansvelder, Matthijs Verhage, Hilgo Bruining, Klaus Linkenkaer-Hansen*

*Corresponding author for this work

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Abstract

STXBP1 syndrome is a rare neurodevelopmental disorder caused by heterozygous variants in the STXBP1 gene and is characterized by psychomotor delay, early-onset developmental delay, and epileptic encephalopathy. Pathogenic STXBP1 variants are thought to alter excitation-inhibition (E/I) balance at the synaptic level, which could impact neuronal network dynamics; however, this has not been investigated yet. Here, we present the first EEG study of patients with STXBP1 syndrome to quantify the impact of the synaptic E/I dysregulation on ongoing brain activity. We used high-frequency-resolution analyses of classical and recently developed methods known to be sensitive to E/I balance. EEG was recorded during eyes-open rest in children with STXBP1 syndrome (n = 14) and age-matched typically developing children (n = 50). Brain-wide abnormalities were observed in each of the four resting-state measures assessed here: (i) slowing of activity and increased low-frequency power in the range 1.75–4.63 Hz, (ii) increased long-range temporal correlations in the 11–18 Hz range, (iii) a decrease of our recently introduced measure of functional E/I ratio in a similar frequency range (12–24 Hz), and (iv) a larger exponent of the 1/f-like aperiodic component of the power spectrum. Overall, these findings indicate that large-scale brain activity in STXBP1 syndrome exhibits inhibition-dominated dynamics, which may be compensatory to counteract local circuitry imbalances expected to shift E/I balance toward excitation, as observed in preclinical models. We argue that quantitative EEG investigations in STXBP1 and other neurodevelopmental disorders are a crucial step to understand large-scale functional consequences of synaptic E/I perturbations.

Original languageEnglish
Article number775172
JournalFrontiers in Physiology
Volume12
ISSN1664-042X
DOIs
Publication statusPublished - 23. Dec 2021

Keywords

  • aperiodic exponent
  • EEG
  • excitation-inhibition balance
  • fE/I
  • MUNC18-1
  • SNAREopathies

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