Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders

Jason L He,Deana Crocetti,Mark Mikkelsen,Stewart H Mostofsky,Alyssa Deronda,Ericka L Wodka,Nicolaas A J Puts,Georg Oeltzschner,Richard A E Edden,Ashley D Harris

doi:10.1038/s41398-021-01525-1

Jason L He, Deana Crocetti + Show 8 more

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Individuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA + (GABA + macromolecules) and Glx (glutamate + glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

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While the phenotypical expression of autism spectrum disorders (ASD) is heterogeneous, ~95% of individuals with ASD present as being either hyper- and/or hyporeactive to sensory stimuli [1,2,3,4]
Subsequent simple slope analyses revealed that while there was no meaningful association between SM1 Glx and Thal Glx in the typically developing controls (TDC) group (r = 0.01, pBonferroni = 0.999), there was a moderate to strong positive correlation in the ASD group (r = 0.55, pBonferroni = 0.007) (Fig. 3g)
In contrast to previous work showing altered GABA+ in ASD [29, 30, 42, 79, 80], and in contrary to our hypotheses, GABA+ levels in both SM1 and Thal were comparable between children in the ASD and TDC groups

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Introduction

While the phenotypical expression of autism spectrum disorders (ASD) is heterogeneous, ~95% of individuals with ASD present as being either hyper- and/or hyporeactive to sensory stimuli [1,2,3,4]. Given the proposed importance of sensory processing to neurodevelopment and functioning in ASD, many studies conducted over the last two decades attempt to both characterize the nature of sensory symptoms of ASD [7,8,9] and to understand their underlying neurobiological causes [10, 11]. Parent, and/or teacher questionnaires to characterize sensory symptoms in ASD have generally found that when compared to children with other neurodevelopmental disorders, as well as typically developing controls (TDC), children with ASD are far more likely to present with symptoms of both hyperreactivity and hyporeactivity, with the evidence for the presence of the latter being more heterogeneous [15]. Individuals with ASD who are either hyper- and/or hyporeactive to stimuli in one sensory domain tend to be hyper- and/or hyporeactive to stimuli in other domains (e.g., a child who is hyperreactive to auditory stimuli tends to be hyper-reactive to tactile stimuli), suggesting these symptoms to be domain-general rather than domain-specific [16]

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