Lateralization of Brain Networks and Clinical Severity in Toddlers with Autism Spectrum Disorder: A HARDI Diffusion MRI Study

Abstract

Recent diffusion tensor imaging studies in adolescents and children with Autism Spectrum Disorder (ASD) have reported a loss or an inversion of the typical left-right lateralization in fronto-temporal regions crucial for sociocommunicative skills. No studies explored atypical lateralization in toddlers and its correlation with clinical severity of ASD. We recruited a cohort of 20 subjects aged 36 months or younger receiving a first clinical diagnosis of ASD (15 males; age range 20-36 months). Patients underwent diffusion MRI (High-Angular-Resolution Diffusion Imaging protocol). Data from cortical parcellation were combined with tractography to obtain a connection matrix and diffusion indexes (DI ) including mean fractional anisotropy (DFA ), number of tracts (DNUM ), and total tract length (DTTL ). A laterality index was generated for each measure, and then correlated with the Autism Diagnostic Observation Schedule-Generic (ADOS-G) total score. Laterality indexes of DFA were significantly correlated with ADOS-G total scores only in two intrafrontal connected areas (correlation was positive in one case and negative in the other). Laterality indexes of DTTL and DNUM showed significant negative correlations (P < 0.05) in six connected areas, mainly fronto-temporal. This study provides first evidence of a significant correlation between brain lateralization of diffusion indexes and clinical severity in toddlers with a first diagnosis of ASD. Significant correlations mainly involved regions within the fronto-temporal circuits, known to be crucial for sociocommunicative skills. It is of interest that all correlations but one were negative, suggesting an inversion of the typical left-right asymmetry in subjects with most severe clinical impairment.

White Matter Integrity and Treatment-Based Change in Speech Performance in Minimally Verbal Children with Autism Spectrum Disorder

“…This suggests that integrity of the right-hemisphere FAT may contribute more to the synthetic fluency-related independent variable than does left-hemisphere tract integrity in MV children with ASD. This is consistent with work showing atypical lateralization of the AF (meaning that the typical leftward dominance in volume of the AF is altered) in MV children with ASD (Wan et al, 2012), in older verbal participants with ASD (Fletcher et al, 2010; Moseley et al, 2016), and with younger children with ASD (Fletcher et al, 2010; Joseph et al, 2014; Conti et al, 2016; Vogan et al, 2016). …”

“…The nature of the synthetic variables in CCA analysis is not always straightforward to interpret, however; and the synthetic independent variable includes a component of laterality. Again, this result would be consistent with the finding of altered laterality of AF in participants with ASD (Fletcher et al, 2010; Wan et al, 2012; Joseph et al, 2014; Conti et al, 2016; Moseley et al, 2016; Vogan et al, 2016). …”

Sex-specific gene–environment interactions underlying ASD-like behaviors

“…Prolonged activation of CRHR1 in the hippocampus as a result of early stress affects the structure, synaptic function, and cognition (30,31), but we are not aware of any studies that have investigated the sex-specific effect of prenatal (immunological) stress on CRH or its receptors in the hippocampus. Because ASD is associated with changes in lateralization [behavioral study (32), MRI studies (33,34), magnetoencephalography study (35), and references in these studies], and many genes are asymmetrically expressed in the rodent hippocampus (36), we performed Crh, Crhr1, Crhr2, and Crhbp (corticotropin-releasing factor-binding protein) mRNA geneexpression assays on the two hemispheres separately. Because we found the strongest effects on Crhr1 mRNA expression in the left hippocampus, we then continued to investigate histone modifications on the promoter area of the Crhr1 gene in the left hippocampus.…”

Autism spectrum disorder: Trends in research exploring etiopathogenesis

“…The laterality indices of mean fractional anisotropy in the two intra-frontal connected areas were significantly correlated with the total scores on the Autism Diagnostic Observation Schedule -Generic. 104 The laterality indices of the number of tracts and total tract length showed significant negative correlations with the Autism Diagnostic Observation Schedule -Generic in various areas, including the languagerelated frontotemporal region. Thus, the possibility of a relationship between clinical severity of ASD and brain lateralization of diffusion indexes needs to be considered in future studies.…”

“…This hypothesis was tested in a cohort of 20 subjects with ASD who were aged 36 months or younger. The laterality indices of mean fractional anisotropy in the two intra‐frontal connected areas were significantly correlated with the total scores on the Autism Diagnostic Observation Schedule – Generic . The laterality indices of the number of tracts and total tract length showed significant negative correlations with the Autism Diagnostic Observation Schedule – Generic in various areas, including the language‐related frontotemporal region.…”