Authors :
Presenting Author: Joanne Hall, M.Sc. – Boston Children's Hospital
Shahid Bashir, PhD – King Fahad Specialist Hospital Dammam; Melissa Tsuboyama, MD – Boston Children’s Hospital; Raidah Al-Bradie, MD – King Fahad Specialist Hospital Dammam; Mona Ali, MD – King Fahad Specialist Hospital, Dammam; Ali Mir, MD – King Fahad Specialist Hospital, Dammam; Annapurna Poduri, PhD – Boston Children’s Hospital; Alexander Rotenberg, MD, PhD – Boston Children's Hospital
Rationale:
Dravet Syndrome (DS) is an epileptic encephalopathy typically caused by heterozygous variants in the SCN1A gene that lead to loss of function. SCN1A haploinsufficiency leads to reduced firing rates of fast-spiking parvalbumin-positive (PV+) inhibitory interneurons, which comprise a large proportion of the GABAergic inhibitory neuron system. We hypothesized that the resultant deficiency in fast-firing inhibitory interneuron signaling should be detectable through aggregate network oscillatory EEG recordings from the human scalp. Published work using metrics related to
power and
phase-amplitude coupling (PAC) in DS are lacking. We evaluated such metrics as potential biomarkers for drug (or gene therapy) target engagement for future therapeutic intervention.
Methods:
EEG data were collected from six patients with DS and eleven age-matched control participants from the King Fahad Specialist Hospital Dammam (KFSHD) and Boston Children’s Hospital (BCH). Segments of seven through fifteen minutes of artifact-free N2/N3 sleep EEG were extracted and analyzed for power and PAC. Welch’s method was applied to extract the cumulative power spectrum for delta (1-4 Hz), theta ( >4-7 Hz), alpha (8-12 Hz), sigma (12-16 Hz), beta (13-30 Hz), and gamma (30-80 Hz) ranges, log-transformed and normalized by the sum of total power to produce a relative power spectrum. PAC was analyzed using the Kullback-Leibler (KL) modulation index (MI), verified via surrogate bootstrapping. Data were then normalized and aggregated to compare groups for PAC.
Results:
Cumulative
delta and
theta power were significantly reduced in the DS group, compared to age-matched control participants. For Delta, p = 0.001. For Theta, p = 0.02. Gamma showed marginal significance, at p = 0.08.
PAC analysis revealed significantly lower PAC between 1-2 Hz phase and 63-80 Hz amplitude in the DS group compared to the control group, p = 0.003.
Conclusions:
Lower delta-theta power and reduced PAC appear to be relatively different between, DS and healthy participants during N2/N3 sleep. Taken together, these metrics are consistent with preclinical studies, and likely reflect compromised GABAergic inhibitory tone that corresponds to a lowered seizure threshold in DS. Notably, while we did not see a significant difference in the EEG gamma frequency band in this pilot study, a larger study powered to assess this metric should be undertaken before drawing definitive conclusions regarding this metric.
Funding:
This work was funded by Encoded Therapeutics (Protocol P00034206).