Thalamic GABA:Glutamate Ratio Is Related to Severity of Sensory over-Responsivity in ASD

Background: A better understanding of the underlying neurochemistry of Sensory Over-Responsivity (SOR) is vital for developing potentially groundbreaking and life-altering psychopharmacological interventions for the 50-75% of children with ASD who experience SOR. Parents report that SOR symptoms, ranging from tactile discomfort to distress in loud or complex environments, are among the most disruptive in their children’s everyday life (Ben-Sasson et al., 2007), but the biological mechanisms underlying SOR remain poorly understood, leaving a dearth of effective treatments. Genetic studies of GABA receptor function, biochemical analyses of GABA synthesis and degradation and computational models have suggested that core features of ASD are driven by an excitatory-inhibitory imbalance of neuronal activity (Rosenberg et al., 2015). Neuroimaging research from our laboratory shows reduced modulation of thalamocortical connectivity in autism in response to mildly aversive sensory stimulation, further suggesting that an imbalance of excitation and inhibition in thalamic neuronal populations may play a role in SOR.

Objectives: Examine how GABA, Glutamate, and GABA/Glutamate ratios in the thalamus 1) differ between youth with and without ASD; and 2) correlate with behavioral measures of SOR within children with ASD.

Methods: Single-voxel edited ¹H-MR spectra and SOR measures were acquired from 19 youth with ASD (17 males; age (mean±SD) 16.0±2.0 years) and 8 typically developing (TD) youth (4 males; age 13.8±2.1 years). MRS GABA levels were measured in the bilateral thalamus with a midline voxel (8750mm²) using a Siemens prototype MEGA‐PRESS sequence (TE/TR 68/2000ms; 256 averages). Post-processing in MATLAB (Guo et al., 2018) consisted of spectra phase and frequency correction, difference editing, and frequency-domain peak fitting with a simulated basis-set yielding high accuracy GABA and Glutamate+Glutamine (Glx) concentrations. Child sensory responsivity questionnaires were completed by parents including the Short Sensory Profile (SSP; Dunn, 1999) and the Sensory Over-Responsivity (SenSOR) Inventory (Schoen et al., 2008).

Results: Student’s t-tests did not demonstrate significant differences between ASD and TD groups in MRS GABA measurements. Pearson’s correlations were used to characterize associations between GABA:Glx ratio and SOR measures where higher scores indicate greater severity of SOR symptoms. In the ASD group, negative correlations were found between GABA:Glx ratio and SOR scores on both the SenSOR and the SSP. (SenSOR Total r=-0.68, p<0.01; SSP Tactile Sensitivity r=-0.71, p<0.01; SSP Auditory/Visual Sensitivity r=-0.79, p<0.001).

Conclusions: These preliminary results relate lower thalamic GABA (inhibitory) to Glutamate (excitatory) ratios to greater severity of SOR symptoms within autism, suggesting that in ASD youth, SOR is associated with a deficit in thalamocortical inhibition. These correlations within the ASD group – despite the lack of significant differences between ASD and TD groups in GABA levels – may reflect the considerable phenotypic and etiologic heterogeneity of ASD. Abnormalities of the thalamic excitatory/inhibitory neurochemical balance could interfere with the role of the thalamus in integrating, relaying, and inhibiting attention to sensory information. Further analyses will correlate these spectroscopic findings with thalamocortical connectivity as measured by resting state fMRI.