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Modulating Excitation: Inhibition Imbalance in ASD As a Means of ‘Fractionating the Spectrum'; An In Vivo, Clinical [1H]-MRS Assay

Friday, May 13, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
L. A. Ajram1, J. Horder2, R. H. Wichers3, S. C. Williams4, R. A. Edden5, C. M. Murphy3, D. G. Murphy3 and G. M. McAlonan6, (1)Institute of Psychiatry, London, United Kingdom, (2)Institute of Psychiatry, King's College London, London, England, United Kingdom of Great Britain and Northern Ireland, (3)Sackler Institute for Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Sciences,, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom, (4)Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom, (5)Johns Hopkins University School of Medicine, Baltimore, MD, (6)Department of Forensic and Neurodevelopmental Science, IoPPN, KCL, London, United Kingdom
Background:  There are no pharmacological treatments for the core symptoms of Autism Spectrum Disorder (ASD). However, accumulating evidence suggests an imbalance between excitatory (E) glutamate and inhibitory (I) GABA in ASD; and may explain the early promise of proGABA and anti-glutamate drugs such as riluzole. Here we tested the hypothesis that, compared to unaffected controls, individuals with ASD have differences in the E/I response to a riluzole drug challenge.

Objectives:  There are no pharmacological treatments for the core symptoms of Autism Spectrum Disorder (ASD). However, accumulating evidence suggests an imbalance between excitatory (E) glutamate and inhibitory (I) GABA in ASD; and may explain the early promise of proGABA and anti-glutamate drugs such as riluzole. Here we tested the hypothesis that, compared to unaffected controls, individuals with ASD have differences in the E/I response to a riluzole drug challenge.

Methods:  Subcortical Glx was significantly lower in men with ASD compared to controls at baseline (placebo, p=0.03). Riluzole significantly increased the inhibitory index in the subcortex of both groups (p = 0.04). However, in the prefrontal cortex, riluzole increased the inhibitory index in the ASD group only (p=0.04). Post-hoc testing suggested that increases in inhibitory indices in both groups were driven by increased GABA. Differences in frontal lobe connectivity in ASD appeared normalized by riluzole. The difference in the effect riluzole has on E:I balance in the ASD cohort is significantly associated with baseline E:I levels and symptom presentation. 

Results:  Subcortical Glx was significantly lower in men with ASD compared to controls at baseline (placebo, p=0.03). Riluzole significantly increased the inhibitory index in the subcortex of both groups (p = 0.04). However, in the prefrontal cortex, riluzole increased the inhibitory index in the ASD group only (p=0.04). Post-hoc testing suggested that increases in inhibitory indices in both groups were driven by increased GABA. Differences in frontal lobe connectivity in ASD appeared normalized by riluzole. The difference in the effect riluzole had on E:I balance in the ASD cohort was significantly associated with baseline E:I levels and symptom presentation. 

Conclusions:  Individuals with ASD have differences in E/I balance (lower subcortical Glx in ASD) and responsivity (Riluzole increases inhibition in the cortex of ASD patients only), at regional (shown by MRS) and whole-brain levels (shown by fMRI). Thus, the glutamate-GABA system may be a tractable treatment target in ASD. This MRS/rs-fMRI approach may provide a safe means to fractionate the ASD sample into more biologically homogeneous sub-groups, for example prior to clinical trial. Baseline E:I levels are potentially predictive of E:I ‘responsivity’, therefore this approach may also help predict who will be responsive to glutamate-GABA treatments (such as riluzole).

See more of: Animal Models
See more of: Animal Models