PT698. Shifting Excitation/Inhibition Balance in Autism Spectrum Disorder

Background: Opioid sensitivity is well known to vary widely among individual subject in levels of μ-opioid receptor (MOP) expression, responses to pain and analgesic effect of morphine. Many studies have reported that the single nucleotide polymorphism (SNP), A118G, of the μ-opioid receptor gene (OPRM1) has been shown to be associated with MOP expression levels, as well as pain thresholds, analgesia and alcohol dependence. However, there are large differences in allele frequency and the sensitivity to pain among different ethnicities. Objectives: To elucidate effect of A118G polymorphism of OPRM1 on personality traits as well as function of the brain, as potential endophenotypes of psychiatric disorders, we analyzed the effects of the A118G SNP of the OPRM1 on personality traits and cognitive functions among Japanese population. Methods: All subjects were right-handed university, college, or postgraduate students or subjects who had graduated from these institutions within 1 year before the experiment, and had normal vision (mean age = 20.82 ± 1.84 years). None had a history of neurological or psychiatric illness. High-molecularweight DNA was isolated from saliva, and genotyping of the SNP was carried out using TaqMan assays. Neuropsychological tests of basic cognitive performance and questionnaires for psychological variables relevant to various personality traits were subsequently administered. This study was approved by the Ethics Committee of Tohoku University, and written informed consent was obtained from each subject. Results: Allele frequency (A allele:52.6%, G allele:47.4%) was consistent with previous studies. Carriers of the G allele had negative correlation for trait of anger (P=0.006), loneliness (P=0.083), and neuroticism (P=0.003), whereas there were positive correlation between the G allele with locus of control (P=0.002), intellectual curiosity (P=0.013), and self-directedness (P=0.008). Conclusions: It has been suggested that the minor G allele of the A118G SNP of the OPRM1 may be involved in positive emotions among Japanese population. PT698 Shifting Excitation/Inhibition Balance in Autism Spectrum Disorder Laura Ajram*1, Jamie Horder1, M. Andreina Menzez1, Iulia Dudd2, Anastasios Galanopoulos2, Rob Wichers1, Daniel Meek2, Gareth J Barker3, David J Lythgoe3, Steven C.R Williams3, Richard Edden4, Declan Murphy1,2, Grainne McAlonan1,2. 1 Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry Psychology & Neuroscience, Kings College London, UK 2 Behavioural and Clinical Academic Group, Kings Health Partners, UK 3 Department of Neuroimaging, Institute of Psychiatry Psychology & Neuroscience Kings College London, UK 4 John Hopkins University, USA *Corresponding Author: [email protected] Abstract There are no pharmacological treatments for the core symptoms of Autism Spectrum Disorder (ASD). However, evidence suggests an imbalance between excitatory (E) glutamate and inhibitory (I) GABA in ASD; and may explain the early promise of GABA-glutamate modulating drugs such as riluzole. Here we hypothesised that, compared to controls, individuals with ASD would have differences in the E/I response to a riluzole drug challenge. Adult men with and without ASD received 50mg p.o riluzole or matched placebo in a randomised, double blind, crossover design, 1hr pre-MRI scan. MEGAPRESS proton magnetic resonance spectroscopy was used to measure Glx (glutamate+glutamine) and GABA in the frontal lobe and subcortex and an inhibitory index was calculated as GABA/(GABA+Glx). Whole brain resting-state fMRI data was acquired as an indirect measure of E/I influence on widespread brain networks. A significance threshold of p < 0.05 was adopted for all analyses. Subcortical Glx was significantly lower in men with ASD compared to controls at baseline (placebo); p=0.034. Riluzole significantly increased the inhibitory index in the subcortex of both groups; p=0.048. However, in the frontal lobe, riluzole increased the inhibitory index in the ASD group only; p=0.049. These effects were driven by increases in GABA. The extent to which riluzole increased GABA (or E/I ‘responsivity’) in the prefrontal lobe was negatively correlated with ASD social domain scores; p=0.019. Additionally, differences in frontal lobe connectivity in ASD appeared ‘normalized’ by riluzole. We have shown that brain E/I balance in adults with ASD can be shifted; and that this has widespread effects on brain functional connectivity. The glutamate-GABA system may therefore be a tractable treatment target in ASD. Future work will examine E/I ‘responsivity’ as a means of ‘fractionating’ the ASD sample into pharmacologically homogeneous sub-groups; and determine if this approach can predict who will be most responsive to glutamate-GABA treatments (e.g. riluzole).There are no pharmacological treatments for the core symptoms of Autism Spectrum Disorder (ASD). However, evidence suggests an imbalance between excitatory (E) glutamate and inhibitory (I) GABA in ASD; and may explain the early promise of GABA-glutamate modulating drugs such as riluzole. Here we hypothesised that, compared to controls, individuals with ASD would have differences in the E/I response to a riluzole drug challenge. Adult men with and without ASD received 50mg p.o riluzole or matched placebo in a randomised, double blind, crossover design, 1hr pre-MRI scan. MEGAPRESS proton magnetic resonance spectroscopy was used to measure Glx (glutamate+glutamine) and GABA in the frontal lobe and subcortex and an inhibitory index was calculated as GABA/(GABA+Glx). Whole brain resting-state fMRI data was acquired as an indirect measure of E/I influence on widespread brain networks. A significance threshold of p < 0.05 was adopted for all analyses. Subcortical Glx was significantly lower in men with ASD compared to controls at baseline (placebo); p=0.034. Riluzole significantly increased the inhibitory index in the subcortex of both groups; p=0.048. However, in the frontal lobe, riluzole increased the inhibitory index in the ASD group only; p=0.049. These effects were driven by increases in GABA. The extent to which riluzole increased GABA (or E/I ‘responsivity’) in the prefrontal lobe was negatively correlated with ASD social domain scores; p=0.019. Additionally, differences in frontal lobe connectivity in ASD appeared ‘normalized’ by riluzole. We have shown that brain E/I balance in adults with ASD can be shifted; and that this has widespread effects on brain functional connectivity. The glutamate-GABA system may therefore be a tractable treatment target in ASD. Future work will examine E/I ‘responsivity’ as a means of ‘fractionating’ the ASD sample into pharmacologically homogeneous sub-groups; and determine if this approach can predict who will be most responsive to glutamate-GABA treatments (e.g. riluzole). PT699 A case of acute necrotizing encephalopathy over bilateral basal ganglion associated with Klüver–Bucy syndrome Yu-Jui Huang1, Ching-Yun Wang2 1Department of Psychiatry, Taipei Medical University Hospital, Taipei, Taiwan 2Department of Pediatrics, Taipei Medical University Hospital,