GABA Concentration in the Left Ventral Premotor Cortex Associates With Sensory Hyper-Responsiveness in Autism Spectrum Disorders Without Intellectual Disability

Abstract

Individuals with autism spectrum disorder (ASD) often exhibit abnormal processing of sensory inputs from multiple modalities and higher-order cognitive/behavioral response to those inputs. Several lines of evidence suggest that altered γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, is a central characteristic of the neurophysiology of ASD. The relationship between GABA in particular brain regions and atypical sensory processing in ASD is poorly understood. We therefore employed 1 H magnetic resonance spectroscopy (1 H-MRS) to examine whether GABA levels in brain regions critical to higher-order motor and/or multiple sensory functions were associated with abnormal sensory responses in ASD. We evaluated atypical sensory processing with a clinically-validated assessment tool. Furthermore, we measured GABA levels in four regions: one each in the primary visual cortex, the left sensorimotor cortex, the left supplementary motor area (SMA), and the left ventral premotor cortex (vPMC). The latter two regions are thought to be involved in executing and coordinating cognitive and behavioral functions in response to multisensory inputs. We found severer sensory hyper-responsiveness in ASD relative to control participants. We also found reduced GABA concentrations in the left SMA but no differences in other regions of interest between ASD and control participants. A correlation analysis revealed a negative association between left vPMC GABA and the severity of sensory hyper-responsiveness across all participants, and the independent ASD group. These findings suggest that reduced inhibitory neurotransmission (reduced GABA) in a higher-order motor area, which modulates motor commands and integrates multiple sensory modalities, may underlie sensory hyper-responsiveness in ASD.

Associations between sensory processing and electrophysiological and neurochemical measures in children with ASD: an EEG-MRS study

“…Contrary to prior research that has demonstrated associations between GABA levels and sensory processing in ASD [ 33 – 35 ], no associations were found between GABA+ values in any VOI and sensory processing symptoms across all participants or within TD or ASD groups. Nevertheless, our results are consistent with a recent study that found no association between GABA+ concentrations and behavioral and fMRI measures of visual spatial suppression [ 67 ].…”

“…They hypothesize that this pattern of ASD-related power differences may reflect atypical patterns of excitatory (glutamate) and/or inhibitory (GABA; E/I) neurotransmitters, which is consistent with models that have proposed that ASD may result from atypically increased cortical excitation (Hussman [ 30 ]; Rubenstein and Merzenich [ 31 ]). Although in vivo measurement of GABA and glutamate concentrations using magnetic resonance spectroscopy (MRS) has provided mixed results (see [ 32 ], for review), region-specific differences in GABA concentrations in ASD have been linked to sensory processing differences [ 33 – 35 ]. However, it is currently unclear whether differences in regional patterns of neurotransmitter concentrations are associated with atypical oscillary activity in ASD, and whether inter-individual differences in alpha power and E/I measures may be related to hyper- and/or hypo-sensory sensitivity in ASD.…”

Temporal resolution relates to sensory hyperreactivity independently of stimulus detection sensitivity in individuals with autism spectrum disorder

“…The gap-detection task that we employed in this study would be associated with a relatively earlier stage of temporal processing since the participants simply judged whether the stimuli were perceived as a singlet or a doublet. Given that a previous study (Ide et al 2019) severer sensory hyperreactivity estimated by AASP (Umesawa et al 2020). Considering these findings, we assume that decreased neural inhibition by GABA-mediated atypical neural function, which has been broadly reported across ASD studies (see, Cellot and Cherubini 2014;Pizzarelli and Cherubini 2011), in the brain circuits of temporal resolution might associate with extraordinarily high perceptual processing cycle and result in frequent experience of sensory hyperreactivity.…”

“…However, little detailed explanation has been provided. We proposed that a higher frequency of sensory processing resulting from high firing rates of neurons is associated with a higher temporal resolution of sensory stimuli as atypical synaptic inhibitory functions in the brain have been suggested as a core symptomatic condition of sensory motor dysfunction in ASD (for references of human studies, Foss-Feig et al 2017;Gaetz et al 2014;Sapey-Triomphe et al 2019;Umesawa et al 2020). The strength of subjective impressions of stimuli would increase with a longer stimulus duration (temporal summation in perception; Barlow 1972), and such threshold reduction may be mediated at the neuronal level (Heil and Neubauer 2003).…”

A single- and paired-pulse TMS-EEG investigation of the N100 and long interval cortical inhibition in autism spectrum disorder

“…In line with this, neuroimaging studies using magnetic resonance spectroscopy (MRS) commonly indicate that GABA concentration is reduced among individuals with ASD compared to neurotypical controls. This reduction has been identified at various frontal/motor (6)(7)(8)(9)(10)(11), temporal (8,12,13), occipital (14), and cerebellar (10) voxels. There are, however, also MRS reports of no differences in GABA indices between individuals with and without ASD at these, and other, sites (11,(15)(16)(17)(18), or when using alternative approaches to quantifying GABA concentration (13).…”