Abstracts

Rationale: Dravet syndrome (DS) is a rare, severe infant brain disorder mainly caused by mutations in the SCN1A gene, which encodes the Nav1.1 sodium channel. This channel is essential for depolarization and the function of primary GABAergic inhibitory interneurons. Recent studies link gamma aminobutyric acid (GABA) concentrations with gamma frequency cortical oscillations, measured by Electroencephalography (EEG) and magnetoencephalography (MEG). Since Nav1.1 is crucial for GABAergic neurons, its alteration in DS affects gamma oscillations. The exact mechanisms of DS remain unclear due to the rarity of disease and limited human brain tissue, highlighting the need for noninvasive biomarkers. We propose assessing these measures in children with DS and healthy controls to develop such biomarkers for monitoring brain GABA levels. We hypothesize that GABA depletion in DS disrupts the excitation/inhibition balance and correlates with neurophysiological indices such as the visual and auditory-induced oscillatory activity. Such biomarkers would facilitate early diagnosis, predict disease progression, and guide the development of new therapeutic strategies.


Methods: We recruited eight children with DS (mean age: 4.5 years ± 1.72; 4 females) and five healthy controls (mean age: 5.8 years ± 1.6; 2 females), with no significant age differences. Participants underwent simultaneous HD-EEG and MEG recordings with visual (cartoons on checkerboards; 340 trials) and auditory (beeps; 400 trials) stimuli (Fig.1A). Data were filtered (1-100 Hz), artifact-inspected, and averaged within -200 to 500 ms (visual) and -500 to 1000 ms (auditory) windows (Fig.1B). Boundary Element Method was used for solving the forward model (Fig.1C&E). Cortical activity in the primary visual cortex (V1) and auditory cortex (A1) was localized using dynamic Statistical Parametric Mapping and virtual sensors were reconstructed (Fig. 1D). A cluster-based permutation test compared time-frequency (TF) maps between DS and healthy controls (Fig. 1F). Additionally, plasma metabolites were compared between groups using Wilcoxon rank sum test.


Results: Higher plasma levels of GABA, glutamic acid, argininosuccinic acid, aspartic acid, kynurenine, phenylalanine, and tryptophan were observed in the TD compared to the DS group (p< 0.05) (Fig. 2A). MEG evoked responses revealed suppressed gamma and beta band power in children with DS from ~25 to 160 ms post-stimulus (p< 0.05) and higher gamma power in TD children (800±120 vs.1750±1200%; p=0.043) (Fig. 2C). Similarly, EEG showed lower gamma band power in the DS group from ~15 to 40 ms post-stimulus (p< 0.05) and higher gamma power in TD children (76±20 vs.168±45%; p=0.023) (Fig. 2D). No differences were found in auditory TF-maps or induced responses. Additionally, there were no correlations between gamma power (MEG and EEG) and plasma GABA levels (2C & D).


Conclusions: Our study shows reduced gamma oscillatory activity in the V1 of children with DS compared to controls. These findings align with DS mechanisms and suggest a potential biomarker for early diagnosis and interventions.


Funding: Encoded Therapeutics. Inc, California.