Abstracts

Rationale: Infantile spasms (IS) occur early postnatally and often lead to devastating developmental outcomes. The pathomechanisms of its neurological deterioration is unknown, uncontrolled spasms and associated electrical derangement of brain is hypothesized as a cause. To identify the role of uncontrolled spasms on brain, we analyzed the brain metabolite changes after clusters of N-methyl-D-aspartate (NMDA)-triggered spasms in a rat model using MR spectroscopy. Methods: Prenatally betamethasone-exposed pups were subjected to 3 times of intraperitoneal NMDA-induced spasms (n=11) or saline injections (controls, n=10) on postnatal days (P) 12, 13, and 15. ¹H-MRI/MRS were performed at a 9.4T MR system and MR spectra were acquired using the signal voxel localization (PRESS; 1.5 x 2 x 2.5 mm³) in the cingulate cortex at P9 (baseline), P16, P23, and P30 and the quantification of metabolites was processed with LC Model. Additionally, fear conditioning was conducted on P27-29 with the same animals. The concentrations of metabolites and behavioral responses were compared between groups and times using linear mixed model or repeated measure ANOVA. Results: There was no significant morphological difference on serial MRI between groups. At P16 (a day after the last NMDA injection), GABA and taurine levels were significantly increased (p = 0.010 and p = 0.046) in rats with NMDA-triggered spasms. Two weeks after NMDA-spasms (P30), N-acetylaspartate (NAA; p = 0.036), taurine (Tau; p = 0.045), glutamine-plus-glutamate (Glx; p = 0.029), macromolecules-plus-lipids (MM+Lip; p = 0.034) were significantly decreased. The changes of GABA (p = 0.024), NAA (p = 0.044), taurine (p = 0.012), and total choline (tCho; p = 0.029) with time were significantly different between two groups. In fear conditioning responses, rats with NMDA-triggered spasms showed persistently elevated freezing behavior to sound and light after several conditioning period without shock (p = 0.016). Conclusions: NMDA-triggered spasms acutely elevated inhibitory neurotransmitter GABA and taurine in cingulate cortex of rats. Markers for neuronal density markers, neurotransmitters, and cellular proliferation were significantly reduced in rats with multiple spasms at juvenile period with impaired adaptive responses to sound and light conditioning. These age-dependent alterations of neurometabolites after spasms can be suggested as the biomarkers of IS sequela.