Reduced GABA Levels Predict Altered Sensory Function in Children with Autism Spectrum Disorder

Thursday, May 12, 2016: 1:57 PM
Room 307 (Baltimore Convention Center)
N. A. Puts1,2, E. L. Wodka3, A. D. Harris4, D. Crocetti3, M. Tommerdahl5, R. A. Edden6 and S. H. Mostofsky7, (1)Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, (2)FM Kirby Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, (3)Kennedy Krieger Institute, Baltimore, MD, (4)Department of Radiology, University of Calgary, Calgary, AB, Canada, (5)University of North Carolina, Chapel Hill, NC, (6)Johns Hopkins University School of Medicine, Baltimore, MD, (7)Johns Hopkins School of Medicine, Baltimore, MD
Background:  Difficulties with sensory stimuli have been increasingly recognized and are now included as a diagnostic feature of ASD. Multiple lines of evidence suggest that GABA, the main inhibitory neurotransmitter in the brain, plays a role in the pathophysiology of ASD. It is well known that GABA plays a key role in regulating tactile processing. However, the link between GABA and autism-associated impairments in vibrotactile processing remains unclear.

Objectives: GABA can be measured using edited Magnetic Resonance Spectroscopy (MRS) and we developed a technique to measure tactile sensitivity in children objectively, in tasks linked to inhibition6. In this study, in a large cohort, we aimed to investigate whether 1) children with ASD have reduced GABA levels, 2) children with ASD show altered vibrotactile processing, and 3) whether altered GABA levels are associated with abnormal tactile processing in ASD.

Methods: Subject and parental consent were obtained under local IRB approval. Data were acquired in 37 children with ASD (10.69 ± 1.4 years, 6F) and 35 TDC (10.09 ± 1.25 years; 8F). Children had normal IQ. GABA-edited MR spectra were acquired from (3 cm)3 voxels over right primary sensorimotor (Fig 1A&B) and occipital cortices. GABA levels were calculated against the unsuppressed water signal from the same voxel and tissue corrected. Behavioral: Children performed: 1) Static and Dynamic detection tasks (DT; where the increasing (dynamic) sub-threshold stimulus is thought to act through feed-forward inhibition); 2) Amplitude discrimination with- and without an adapting stimulus (AD; linked to lateral inhibition); and 3) Frequency discrimination (FD; encoded through GABAergic inhibition). 


Sensorimotor GABA levels were significantly reduced in children with ASD compared to TDC (2.20 ± 0.44 i.u. and 2.40 ± 0.25 i.u. respectively, p = 0.016). There were no group differences in occipital GABA levels. For children with ASD, sensorimotor GABA levels correlated positively with dynamic DT, with higher GABA levels indicating a higher DT (Fig 1C). The difference between a static and dynamic DT (Figure 1D) were significantly correlated with GABA levels within the entire cohort; this finding was driven by children with ASD, such that those with lower GABA levels showed a reduced effect of sub-threshold stimulation. AD performance after single-site adaptation correlated with GABA levels in TDC but not in ASD (Fig 1E) adaptation was absent in ASD. Tactile FD is correlated with GABA in TDC, which has been previously reported (Fig 1F); this association was not observed in ASD.

Conclusions: Sensorimotor GABA levels were reduced in children with ASD compared to TDC, while occipital levels are normal, consistent with previous work. Tactile abnormalities in ASD were consistent with previous work, and consistent with reduced GABA-mediated inhibition. Our correlative results are consistent with the prediction for children with ASD; reduced GABA level was associated with stronger effect of modulating stimuli. Children with ASD show reduced GABA levels, and are associated with abnormalities in tactile performance. Altered in vivo GABA levels might explain abnormal tactile information processing in ASD. The GABA system may be a future and novel target for therapies in ASD.