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

Abstract

Individuals on the autism spectrum are often reported as being hyper- and/or hypo-reactive to sensory input. These sensory disturbances 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 excitation and inhibition respectively. In the current study, we found region-specific elevations of Glx elevated in the sensorimotor cortex but not thalamus) but not GABA+ in ASD. Higher levels of Glx were associated with more parent reported difficulties of hyper- and hypo-reactivity to sensory input, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Together, these results provide strong empirical support for increased excitation by way of elevated Glx in ASD. Critically, our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

Association between increased anterior cingulate glutamate and psychotic-like symptoms, but not autistic traits

“…As the TE of our MRS data varied, we simulated six different PRESS basis sets for each TE (36,37,38,39,40,41) segmentation. The structural T1-image was segmented into gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF).…”

“…Horder and colleagues (35) for example found reduced levels of glutamate in the striatum to be associated with the severity of social symptoms in ASD. Interestingly, Page and colleagues (36) found increased concentrations of glutamate/glutamine in the amygdala/hippocampus, but not in parietal regions, while others found increased glutamate in the inferior frontal gyrus (37), the sensory motor cortex (children (38)) or the putamen (39). Another study (40) found reduced glutamate concentrations in the auditory cortex and increased concentrations in the ACC.…”

GABAergic regulation of auditory repetition suppression in adults with and without Autism Spectrum Disorder

“…Sensory circuits in which GABA has a key role mature in early postnatal periods and subsequent brain development 'cascades' through multiple sensitive periods as more and more complex cognitive and behavioral skills are acquired (73). Indeed, atypical sensory processing has been flagged very early in development of infants who go on to receive a diagnosis of ASD (2,74). Thus, the atypical GABAergic auditory processing in ASD observed here is likely to reflect earlier alterations in neural circuit maturation.…”

EEG resting-state functional connectivity: evidence for an imbalance of external/ internal information integration in Autism

“…In particular, alpha desynchronization may be linked to increased neural excitability/decreased neural inhibition (6). Previous studies in ASD reported abnormal cortical inhibitory interneurons (79,80) and altered glutamatergic levels (81,82), associated with atypical sensory processing in ASD (73,83). The excitation/inhibition imbalance increases neural noise in ASD and may lead to atypical sensory processing and under-responsiveness to behaviorally relevant stimuli in participants with ASD (72).…”