Sensory over-responsivity is related to GABAergic inhibition in thalamocortical circuits

Abstract

Sensory over-responsivity (SOR), extreme sensitivity to or avoidance of sensory stimuli (e.g., scratchy fabrics, loud sounds), is a highly prevalent and impairing feature of neurodevelopmental disorders such as autism spectrum disorders (ASD), anxiety, and ADHD. Previous studies have found overactive brain responses and reduced modulation of thalamocortical connectivity in response to mildly aversive sensory stimulation in ASD. These findings suggest altered thalamic sensory gating which could be associated with an excitatory/inhibitory neurochemical imbalance, but such thalamic neurochemistry has never been examined in relation to SOR. Here we utilized magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging to examine the relationship between thalamic and somatosensory cortex inhibitory (gamma-aminobutyric acid, GABA) and excitatory (glutamate) neurochemicals with the intrinsic functional connectivity of those regions in 35 ASD and 35 typically developing pediatric subjects. Although there were no diagnostic group differences in neurochemical concentrations in either region, within the ASD group, SOR severity correlated negatively with thalamic GABA (r = -0.48, p < 0.05) and positively with somatosensory glutamate (r = 0.68, p < 0.01). Further, in the ASD group, thalamic GABA concentration predicted altered connectivity with regions previously implicated in SOR. These variations in GABA and associated network connectivity in the ASD group highlight the potential role of GABA as a mechanism underlying individual differences in SOR, a major source of phenotypic heterogeneity in ASD. In ASD, abnormalities of the thalamic neurochemical balance could interfere with the thalamic role in integrating, relaying, and inhibiting attention to sensory information. These results have implications for future research and GABA-modulating pharmacologic interventions.

Fig. 1. Relationship between Sensory Over-Responsivity Severity and Neurometabolites in ASD Youth.

SOR severity scores are significantly correlated with: A Thalamus GABA+/Cr (r = −0.48, p < 0.05, n = 28; plot of partial regression corrected for SCARED); and, B SSC Glx/Cr (r = 0.68, p < 0.01, n = 20; plot of partial regression corrected for SSC voxel tissue fraction and SCARED).

Fig. 2. Thalamus Functional Connectivity Related to Thalamic GABA+/Cr.

Whole-brain resting-state analyses using bilateral thalamus seed with GABA+/Cr as a bottom-up regressor. Within-group and between-group contrasts are thresholded at Z > 2.30 and cluster corrected at p < 0.05 (see eFig. 3.A for unthresholded maps). ASD Autism spectrum disorders, L Left, TD Typically developing.

Fig. 3. Somatosensory Cortex Connectivity Related to SSC Glx/Cr.

Whole-brain resting-state analysis using bilateral precentral gyrus seed with Glx/Cr as a bottom-up regressor. Within-group and between-group contrasts were thresholded at Z > 2.30 and cluster corrected at p < 0.05 (see eFig. 3.B for unthresholded maps), only within ASD demonstrated a significant relationship with Glu/Cr. ASD Autism spectrum disorders, L Left.