Increased Glutamate Concentration in the Auditory Cortex of Persons With Autism and First‐Degree Relatives: A ¹H‐MRS Study

Abstract

Lay Abstract We investigated brain chemistry of the primary region of the brain involved in auditory processing in adults with autism spectrum disorder (ASD). Due to the highly heritable nature of ASD and the lack of prior brain chemistry data on unaffected first-degree relatives, we also enrolled parents of children with ASD (pASD), comparing both groups to a healthy adult control group. The technique used to quantify chemical signals was magnetic resonance spectroscopy (MRS), which we used to assess the concentration of auditory glutamate, the primary excitatory brain neurotransmitter, as well as other metabolites that assess neuronal integrity and metabolism. We found significantly higher levels of auditory glutamate in persons with ASD. In addition, increases in two other metabolites, n-acetyl-aspartate (NAA), and creatine (Cr), were observed in the ASD group. No differences were observed in the pASD group in any MRS measurement. We interpret the glutamate finding as suggestive of an increase in brain excitability, and the NAA and Cr findings as indicative of a change in brain energy metabolism in ASD. Scientific Abstract Increased glutamate levels have been reported in the hippocampal and frontal regions of persons with autism using proton magnetic resonance spectroscopy (1H-MRS). Although autism spectrum disorders (ASD) are highly heritable, MRS studies have not included relatives of persons with ASD. We therefore conducted a study to determine if glutamate levels are elevated in people with autism and parents of children with autism. Single-voxel, point resolved spectroscopy (PRESS) data were acquired at 3T for left and right hemisphere auditory cortical voxels in 13 adults with autism, 15 parents of children with autism, and 15 adult control subjects. The primary measure was Glx. Additional measures included n-acetyl-aspartate (NAA), choline (Cho), myoinositol (mI) and creatine (Cr). The autism group had significantly higher Glx, NAA and Cr concentrations than the control subjects. Parents did not differ from control subjects on any measures. No significant differences in Cho or mI levels were seen among groups. No reliable correlations between autism symptom measures and MRS variables were seen after Bonferroni correction for multiple comparisons. The elevation in Glx in autism is consistent with prior MRS data in the hippocampus and frontal lobe and may suggest increased cortical excitability. Increased NAA and Cr may indicate brain metabolism disturbances in autism. In the current study, we found no reliable evidence of a familial effect for any spectroscopy measure. This may indicate that these metabolites have no heritable component in autism, the presence of a compensatory factor in parents, or sample specific limitations such the participation of singleton families.

Neuroimages in Autism

“…MRS data from children cohorts indicate that autism groups exhibit reduced Glx levels in cortical gray matter (DeVito et al 2007), anterior cingulate cortex (Bernardi et al 2011), frontal and occipital cortex, and cerebellum (DeVito et al 2007). Recent research have suggested elevated Glx levels in ASD in the anterior cingulate cortex (Bejjani et al 2012) and putamen (Doyle-Thomas et al 2014) of children, and the auditory cortex of adults (Brown et al 2013). These results are consistent with the hyperglutamatergic theories of ASD, supporting an excitation/inhibition imbalance underlying the pathophysiology of ASD.…”

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).…”

“…In two studies reporting either negative effects or reductions in glutamate, subjects were sedated using drugs that are known to interact with GABA and glutamate transmission (DeVito et al 2007; Corrigan et al 2013), but such sedation is typically also used with lower functioning and/or younger children. Four studies to date have reported Glu levels separately or in addition to Glx (Harada et al 2010; Joshi et al 2012; Brown et al 2013; Hassan et al 2013). Of those, 3 reported increases in autism (Joshi et al 2012; Brown et al 2013; Hassan et al 2013) and one reported no significant differences (Harada et al 2010).…”

“…Four studies to date have reported Glu levels separately or in addition to Glx (Harada et al 2010; Joshi et al 2012; Brown et al 2013; Hassan et al 2013). Of those, 3 reported increases in autism (Joshi et al 2012; Brown et al 2013; Hassan et al 2013) and one reported no significant differences (Harada et al 2010). Hassan et al (2013) are the only group to date that have acquired both plasma and 1H-MRS measures of glutamate in the same sample, reporting significant increases in autism relative to controls with both measures, which were highly correlated.…”

The Role of Thiamine in Autism

“…Glutamic acid decarboxylase (GAD) was reduced by 48%-61% in the parietal and cerebellar areas of the brains of people with autism compared with controls [84]. Increased glutamate concentration was demonstrated in the auditory cortex of persons with autism and first-degree relatives [85]. Proton magnetic resonance spectroscopy revealed lower Nacetylaspartate/creatine (NAA/Cr), γ-aminobutyric acid/creatine (GABA/Cr) and glutamate/creatine (Glx/Cr) in the frontal lobes of an autistic group compared with normal controls [86].…”