Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder

L A Ajram,D G M Murphy,J Zinkstok,D M Robertson,D J Lythgoe,L P Brennan,A Galanopoulos,R H Wichers,S C Williams,R A E Edden,M D Tricklebank,M Heasman,D Meek,G Ivin,C M Murphy,G J Barker,G M Mcalonan,J Horder,M A Mendez

doi:10.1038/tp.2017.104

Abstract

Currently, there are no effective pharmacologic treatments for the core symptoms of autism spectrum disorder (ASD). There is, nevertheless, potential for progress. For example, recent evidence suggests that the excitatory (E) glutamate and inhibitory (I) GABA systems may be altered in ASD. However, no prior studies of ASD have examined the ‘responsivity’ of the E–I system to pharmacologic challenge; or whether E–I modulation alters abnormalities in functional connectivity of brain regions implicated in the disorder. Therefore, we used magnetic resonance spectroscopy ([1H]MRS) to measure prefrontal E–I flux in response to the glutamate and GABA acting drug riluzole in adult men with and without ASD. We compared the change in prefrontal ‘Inhibitory Index’—the GABA fraction within the pool of glutamate plus GABA metabolites—post riluzole challenge; and the impact of riluzole on differences in resting-state functional connectivity. Despite no baseline differences in E–I balance, there was a significant group difference in response to pharmacologic challenge. Riluzole increased the prefrontal cortex inhibitory index in ASD but decreased it in controls. There was also a significant group difference in prefrontal functional connectivity at baseline, which was abolished by riluzole within the ASD group. Our results also show, for we believe the first time in ASD, that E–I flux can be ‘shifted’ with a pharmacologic challenge, but that responsivity is significantly different from controls. Further, our initial evidence suggests that abnormalities in functional connectivity can be ‘normalised’ by targeting E–I, even in adults.

Highlights

Autism spectrum disorder (ASD) is a neurodevelopmental condition, which impacts on three ‘core’ domains of function–social interaction, social communication and repetitive behaviours or interests
All autism spectrum disorder (ASD) individuals had a consensus clinical diagnosis of ASD led by a consultant psychiatrist using ICD10 research criteria;[42] and reached Autism Diagnostic Observation Schedule (ADOS)[43] algorithm cut-offs in both communication and social domains
Men with ASD have significant differences in E–I responsivity At baseline, there were no group differences in the inhibitory index, or absolute levels of GABA or glutamate in the medial prefrontal cortex region

Summary

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental condition, which impacts on three ‘core’ domains of function–social interaction, social communication and repetitive behaviours or interests. ASD has its origins in very early (prenatal) development, and persists through to adulthood.[1] It is clinically diverse; the core difficulties can range in severity from mild to severe, and they are often accompanied by secondary conditions, such as anxiety and depression, especially in adulthood.[2] This phenotypic variability likely reflects the marked aetiological heterogeneity of the disorder, and has made the identification of a common underlying pathology challenging. There is hope as genetic, post-mortem and preclinical laboratory studies indicate that the differences in the balance between the brain’s excitatory (E) glutamate and inhibitory (I) GABA systems may be one of the final ‘common pathways’ in ASD.[3] This is perhaps especially true for GABA. Genetic studies have consistently implicated genes regulating GABAA receptor expression with ASD,[4,5] whereas environmental risk factors for ASD, such as exposure to maternal inflammation in prenatal life, have been shown to disrupt gene expression across GABA pathways.[6,7,8]

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