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

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.

Abnormal spectral and scale-free properties of resting-state EEG in girls with Rett Syndrome

“…Increased DFA coe cient in RTT suggests non-optimal state of neuronal networks that have more predictable activity. This novel result for RTT ts well with previous reports in neurodevelopmental disorders, such as idiopathic ASD 20 as well as in patients with STXBP1 syndrome 21 that have increased DFA as well. Among common features of these disorders is comorbidity with epilepsy, which is also characterized by increased DFA measure with intracranial recordings near the epileptogenic region 22,23 .…”

Resting-state oscillations reveal disturbed excitation–inhibition ratio in Alzheimer’s disease patients

“…In contrast to an average whole-brain fE/I value of ~ 1 in healthy adults as previously observed in EEG data 34 , both the HE and HY subjects showed a median fE/I < 1.0 in both the parieto-occipital cortex (median(Q1–Q3): HY, 0.86 (0.79–0.94); HE, 0.88 (0.72–0.95)) and hippocampi (median(Q1–Q3): HY ( n = 18), 0.85 (0.69–0.89); HE, 0.79 (0.69–0.91)). An fE/I < 1.0 has been previously related to pathological network imbalance, and an inhibition-dominated regime specifically 34 , 40 . fE/I values were not calculated for ROIs with a DFA < 0.55 34 .…”

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

“…Indeed, signs of cortical dysfunction, dysmaturity, and epilepsy [e.g., as reflected by slowing of activity ( Krsek et al, 2010 ; Terney et al, 2010 ; Tao et al, 2011 ; Stoner et al, 2014 ; Britton et al, 2016 )] have been described in EEG recordings in TSC ( De Ridder et al, 2020 ). Importantly, we have previously associated EEG abnormalities to low f E/I in ASD ( Bruining et al, 2020 ) and in children with STXBP1 syndrome, which is another genetic disorder with a high prevalence of epilepsy ( Houtman et al, 2021 ). Furthermore, low f E/I values in TSC could be an expression of both, an excess in inhibition, e.g., as a protective mechanism against epileptogenicity ( Terney et al, 2010 ; Bruining et al, 2020 ), increased GABA concentration (i.e., in cortical tubers) compensating for reduced GABA receptors ( Taki et al, 2009 ; Mori et al, 2012 ), or an overall reduced excitation as a compensatory change for a primary aberrant (excitatory) GABA transmission ( Nelson and Valakh, 2015 ).…”