Direct investigation of the excitatory/inhibitory imbalance in autism spectrum disorder

Summary

The pathophysiology of autism spectrum disorder (ASD), a common neurodevelopmental disorder, is still relatively unknown. One highly influential hypothesis states that ASD is due to an imbalance between glutamatergic and GABAergic signalling, respectively the most abundant excitatory and inhibitory neurotransmitters in the brain. This excitatory/inhibitory (E/I) imbalance hypothesis, however, is rather unspecified, lacks concrete evidence and has never been properly tested. Individuals with ASD have shown a robust deficit in binocular rivalry, a basic visual function thought to rely on E/I balance in the visual cortex (V1) and deficits in cognitive control, regulated by the anterior cingulate cortex (ACC). These deficits are associated with respectively the sensory processing abnormalities and restricted repetitive patterns of behaviour, an understudied ASD symptom domain.
The most often used approach to study neural mechanisms underlying ASD in vivo harnesses the BOLD-effect in functional MRI (fMRI) studies; however, this is an indirect measure of the neuronal response and does not differentiate whether altered excitation, altered inhibition or both are underlying E/I imbalance.
In this proposal I will rigorously test the E/I imbalance hypothesis by for the first time directly investigating both excitatory (glutamate) neurotransmission, inhibitory (GABA) neurotransmission, and the BOLD-response during binocular rivalry and cognitive control. Thereby, I will implement a newly developed sequence for simultaneous magnetic resonance spectroscopy (1H-MRS) and fMRI for a 7-Tesla scanner in a carefully phenotyped sample of adults with ASD. I hypothesize glutamate and GABA concentrations to be predictive of neural functioning during binocular rivalry and cognitive control. I will further examine the imbalance hypothesis in two large existing data sets using MRI/1H-MRS, cognition and genetics data. In this way I will be able to really, directly test the E/I imbalance hypothesis and deliver readouts and biomarkers for future proof of concept in drug testing for individuals with ASD.

Details

Project number

VI.Veni.194.032

Main applicant

Dr. J. Naaijen

Affiliated with

Radboud Universiteit Nijmegen, Donders Institute, Cognitive Neuroimaging

Duration

01/01/2020 to 31/12/2022