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Exploring Anxiety in ASD Using Cross-Species Neuroimaging Analytics
Children and adolescents with Autism Spectrum Disorder (ASD) often present with a wide variety of comorbidities (Pasciuto et al, 2015). Among these, anxiety is the most common psychiatric comorbidity, with rates as high as 84% (Kerns et al, 2015). ASD patients who also suffer from anxiety experience an increased burden of disease. In spite of this, there are no established clinical pathways for the treatment of anxiety in ASD (Vasa et al, 2016). Moreover existing pharmacological treatments that are effective in the general population result in adverse effects when used to treat patients with ASD (Vasa et al, 2016). A greater understanding of the neuroscience underlying anxiety in ASD will facilitate the development of novel treatments for this vulnerable population.
Objectives:
Using structural magnetic resonance imaging (sMRI) data from patients with ASD and from a variety of mouse models for ASD, we examine which neuroanatomical regions are associated with anxiety as a comorbidity.
Methods:
Three data sets were used from the Province of Ontario Neurodevelopmental Disorders (POND) network: 1. Ex-vivo sMRI scans of 2084 mice from 61 genetic mouse models of ASD with literature-based annotations for anxiety, 2. Ex-vivo sMRI scans and anxiety-related behavioural assays of 822 mice from inbred strains related to ASD, and 3. 571 sMRI scans and anxiety assessments of child and adolescent patients with neurodevelopmental disorders. Volumetric measures were computed from the MRI scans using an image registration pipeline and deformation-based morphometry (Lerch et al, 2011). Statistical analyses using multiple linear and mixed-effects regressions were performed on a structure-wise basis for each of the three data sets to examine the association between neuroanatomical volume and anxiety. Appropriate statistical models were selected to account for the effects due to sex and age. Results were corrected for multiple comparisons using the false discovery rate (FDR) method.
Results:
A number of brain regions were found to be significantly associated with anxiety within each of the data sets, at a FDR level of 0.05. Convergence of results across all three data sets implicates the amygdala, the cerebellum and the cingulate cortex. Structures displaying convergence only between the mouse studies additionally included the midbrain, the pons, the basal forebrain and the anterior commissure.
Conclusions:
Anxiety is not well understood in ASD despite being the most common psychiatric comorbidity. Neuroimaging studies are an indispensable tool when it comes to understanding which regions of the brain are associated with a given condition. Using an approach relying on convergence across multiple mouse and human studies, we have identified the amygdala, the cerebellum, and the cingulate cortex as being implicated in anxiety within ASD. It is well known that the amygdala plays a role in emotional regulation and a recent study has demonstrated that it is associated with anxiety in ASD (Herrington et al, 2017), so these results are in line with the existing literature. While the cerebellum is known to be involved in ASD, our results suggest that it may also play a role in anxiety, perhaps through a pathway that is unique to ASD.