Elevated Glutamatergic Compounds in Pregenual Anterior Cingulate in Pediatric Autism Spectrum Disorder Demonstrated by 1H MRS and 1H MRSI

Abstract

Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy (1H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging (1H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD.

Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: an MRS study

“…Cochran et al [33] found higher glutamine (Gln) levels and lower GABA/Cre levels in ASD, supporting the idea of an excitatory (Glu)/inhibitory (GABA) imbalance hypothesis. Anterior cingulate NAA, t-Cho, Cre, and mI signals were also found to be altered in some earlier studies [9, 10, 31, 34–37]. In the left dorsolateral prefrontal cortex (DLPFC), low NAA/Cre levels were found in the study by Fujii and colleagues [36], but no significant differences were found in two other studies [34, 38].…”

Advancing the understanding of autism disease mechanisms through genetics

“…This further highlights how early developmental abnormalities may have repercussions later on. It is also important to note that E/I imbalance studies have mainly been carried out in animal models, hence a detailed evaluation of when, where and how an E/I shift contributes to the ASD phenotypes in humans is warranted 161–163 .…”

The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment

“…Glx levels were not significantly correlated with IQ or autism symptom measures. Several other groups have reported significantly increased glutamate concentration since then in regions including the anterior cingulate gyrus (Joshi:2012ir; Bejjani et al 2012) and auditory cortex (Brown et al 2013). Others have reported reduced Glx in autism or no group differences in similar regions of interest (DeVito et al 2007; Bernardi et al 2011; Horder et al 2013).…”