A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder

Abstract

Multiple lines of research have reported thalamic abnormalities in individuals with autism spectrum disorder (ASD) that are associated with social communication impairments (SCI), restricted and repetitive behaviors (RRB), or sensory processing abnormalities (SPA). Thus, the thalamus may represent a common neurobiological structure that is shared across symptom domains in ASD. Same-sex monozygotic (MZ) and dizygotic (DZ) twin pairs with and without ASD underwent cognitive/behavioral evaluation and magnetic resonance imaging to assess the thalamus. Neurometabolites were measured with H magnetic resonance spectroscopy (MRS) utilizing a multi-voxel PRESS sequence and were referenced to creatine+phosphocreatine (tCr). N-acetyl aspartate (NAA), a marker of neuronal integrity, was reduced in twins with ASD (n=47) compared to typically-developing (TD) controls (n=33), and this finding was confirmed in a sub-sample of co-twins discordant for ASD (n=11). NAA in the thalamus was correlated to a similar extent with SCI, RRB, and SPA, such that reduced neuronal integrity was associated with greater symptom severity. Glutamate+glutamine (Glx) was also reduced in affected versus unaffected co-twins. Additionally, NAA and Glx appeared to be primarily genetically-mediated, based on comparisons between MZ and DZ twin pairs. Thus, thalamic abnormalities may be influenced by genetic susceptibility for ASD but are likely not domain-specific.

Heritability of cerebral glutamate levels and their association with schizophrenia spectrum disorders: a 1[H]-spectroscopy twin study

“…Using a 1.5 Tesla MRI scanner, Batouli et al [38] found NAA (h 2 = 72%), Cho (h 2 = 33%), Cr (h 2 = 51%), and MI (h 2 = 55%) to be heritable in the posterior cingulate cortex. In the MRS study of children with autism, contradictory to the current findings in left thalamus, Cho was not found to be heritable but NAA and MI were found heritable in the thalamus bilaterally [34]. These discrepancies with our findings could possibly be due to differences in age, although this is not currently supported.…”

“…The finding of common genetic influences on glutamate levels in the thalamus and disease in our study is supported by a report of higher glx levels in the thalamus of subjects at increased familial risk for schizophrenia [33], and a recent study linking higher glx levels to glutamate-related genes associated with risk for schizophrenia [5]. The current heritability estimates are in line with the heritability estimate of glx in the thalamus reported in a twin study in children with autism and controls [34], suggesting a generalizability of the heritability estimate across populations. The present study could not confirm exploratory findings from a MRS study of 2 MZ and 12 DZ twin pairs discordant for schizophrenia describing decreased glutamate levels in the ACC of patients and unaffected co-twins [29].…”

“…The latter result is in accordance with findings in patients and suggests a specific familial and likely genetic, influence on glutamate in this region. Genetic influences on cerebral glutamate were also detected in an MRS twin study in children with autism spectrum disorder where glx was found to be heritable in the thalamus [34]. Since schizophrenia itself is highly heritable [35], and abnormal glutamate levels appear to be influenced by genetic factors, it is possible that the same genes influence both traits.…”

Concentrations of Cortical GABA and Glutamate in Young Adults With Autism Spectrum Disorder

“…Hence, although the overall trend is for lower GABA+ in ASD, it seems that results are inconsistent, owing perhaps to differences in experimental procedures and analysis methods, regions of interest (ROIs), and sample characteristics, as summarized in several recent reviews [Ajram et al, 2019;Ford & Crewther, 2016;Schür et al, 2016]. In the case of Glx, results are even less conclusive, with studies reporting reduced [Bernardi et al, 2011;Corrigan et al, 2013;DeVito et al, 2007;Hegarty et al, 2018;Horder et al, 2013Horder et al, , 2018Kubas et al, 2012;Tebartz Van Elst et al, 2014], equivalent [Ajram et al, 2017;Aoki et al, 2012;Brix et al, 2015;Carvalho Pereira et al, 2018;Endres et al, 2017;Friedman et al, 2006;Goji et al, 2017;Hardan et al, 2008;Horder et al, 2018;Ito et al, 2017;Libero et al, 2016;Mikkelsen et al, 2017;Robertson et al, 2016], or increased [Bejjani et al, 2012;Brown, Singel, Hepburn, & Rojas, 2013;Doyle-Thomas et al, 2014;Page et al, 2006] levels in ASD. In the current study, we sought to extend previous results by measuring GABA+ and Glx simultaneously using current methodology, in a relatively large sample of well-characterized individuals with ASD, including previously unexamined ROIs, and testing the functional relevance of neurometabolite levels by correlating individual differences in MRS measures with behavior and ASD symptomatology.…”

Four Social Brain Regions, Their Dysfunctions, and Sequelae, Extensively Explain Autism Spectrum Disorder Symptomatology

“…Overall, the nature and etiology of cerebellar anomalies in ASD require further investigation. A structural meta-analysis has reported modest abnormalities of the thalamus [47], and a study of metabolites in ASD and TD twin pairs reported several significant abnormalities in ASD [374]. Further structural meta-analyses and a cellular study that examined it have not reported thalamic abnormalities [45,48,49].…”