Age‐related parietal GABA alterations in children with autism spectrum disorder

Abstract

GABA is the primary inhibitory neurotransmitter in the brain, and is essential to the balance of cortical excitation and inhibition. Reductions in GABA are proposed to result in an overly excitatory cortex that may cause, or contribute to, symptoms of autism spectrum disorder (ASD). This study employed a cross‐sectional design to explore GABA+ differences in ASD and the impact of age, comparing 4–12 year olds with ASD (N = 24) to typically developing children (N = 35). GABA+ concentration was measured using edited magnetic resonance spectroscopy in the left parietal lobe. This study used a mixed model to investigate group differences between children with ASD and typically developing children. There was a significant difference in GABA+ levels between the groups, a significant effect of age and interaction between age and diagnostic group. The ASD group showed an association between GABA+ and age, with GABA+ levels gradually increasing with age (r = 0.59, p = 0.003). Typically developing children did not show age‐related change in GABA+ concentration (r = 0.09, p = 0.60). By the age of 9, children with ASD showed GABA+ levels that were comparable to their typically developing peers. This study suggests that children with ASD have initially lower levels of GABA+ in the left parietal lobe compared to typically developing children, and that these initially lower levels of GABA+ increase with age in ASD within this region. It is suggested that this developmental shift of GABA+ levels within the left parietal lobe provides a possible explanation for the previously found reductions in childhood that does not persist in adults. Lay Summary This study measured levels of GABA in the left parietal lobe using magnetic resonance spectroscopy in children with ASD and typically developing children. GABA levels were initially lower in the ASD group, and increased with age, while GABA did not change with age in the typically developing group. This suggests that alterations in GABA signaling may be associated with ASD in childhood. Autism Res 2021, 14: 859–872. © 2021 International Society for Autism Research, Wiley Periodicals LLC.

Cerebellar gamma‐aminobutyric acid: Investigation of group effects in neurodevelopmental disorders

“…We found no significant group effects in cerebellar GABA+ and no differences between the three NDDs and the typically developing group. We had expected to see reduced GABA+, as there are a number of reports of reduced cortical GABA+, particularly in ASD (e.g., DeMayo et al, 2021; Ito et al, 2017). The lack of this finding could be due to the heterogeneity of the NDDs, the use of a cerebellar voxel, or that this metric of brain function is not sensitive to cerebellar GABA+ differences in the NDD versus TD groups.…”

“…Reduced GABA+ has been reported frequently in children with ASD in sensorimotor (Puts et al, 2017), frontal (Cochran et al, 2015; Ito et al, 2017), parietal (DeMayo et al, 2021), occipital (Drenthen et al, 2016) or motor and auditory areas (Gaetz et al, 2014; Rojas et al, 2014). Other studies, however, did not find a reduction in GABA+ in ASD in occipital (Gaetz et al, 2014; Puts et al, 2017) and sensorimotor regions and thalamus (He et al, 2021), suggesting ROI‐related variability in these findings.…”

“…The levels of key inhibitory (gamma‐amino butyric acid [GABA]) and excitatory (glutamate) neurotransmitters can be quantified with magnetic resonance spectroscopy (MRS) protocols to assess E/I balance (e.g., Ajram et al, 2017; Drenthen et al, 2016; Gonçalves et al, 2017; He et al, 2021; Horder et al, 2018; Kahl et al, 2022; Maier et al, 2022; Rideaux et al, 2022). MRS studies in ASD have found reduced GABA in children with ASD (e.g., Cochran et al, 2015; DeMayo et al, 2021; Drenthen et al, 2016; Gaetz et al, 2014; Puts et al, 2017), but either no differences (Horder et al, 2018; Kolodny et al, 2020) or increased cortical GABA (Maier et al, 2022) in adults with ASD. Some of the developmental studies (DeMayo et al, 2021; Gaetz et al, 2014) showed greater changes in parietal GABA with age in ASD than in typical development, suggesting that the reported GABA deficit may decrease with age.…”

“…MRS studies in ASD have found reduced GABA in children with ASD (e.g., Cochran et al, 2015; DeMayo et al, 2021; Drenthen et al, 2016; Gaetz et al, 2014; Puts et al, 2017), but either no differences (Horder et al, 2018; Kolodny et al, 2020) or increased cortical GABA (Maier et al, 2022) in adults with ASD. Some of the developmental studies (DeMayo et al, 2021; Gaetz et al, 2014) showed greater changes in parietal GABA with age in ASD than in typical development, suggesting that the reported GABA deficit may decrease with age. Thus, while the consensus is that there is a disruption in E/I balance in autism, the nature of the imbalance is still unresolved (Dickson et al, 2016; Port et al, 2019; Zhao et al, 2022).…”

“…To this end, we conducted a prospective MRS study in a large group of children through to young adults with ASD, ADHD, OCD and typical development to test whether GABA+ concentration levels in the cerebellum would differentiate the NDDs from controls and differentiate between the NDD groups. We hypothesized that there would be reduced GABA+, as the bulk of studies found reduced cortical GABA in the NDDs (Cochran et al, 2015; DeMayo et al, 2021; Drenthen et al, 2016; Edden et al, 2012; Gaetz et al, 2014; Li et al, 2019; Puts et al, 2017; 2020) and that this could be more pronounced in ASD, as abnormalities are more routinely seen in those with ASD (Schür et al, 2016, but see Naaijen et al, 2015).…”