Evidence for Brainstem Contributions to Autism Spectrum Disorders

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects one in 59 children in the United States. Although there is a mounting body of knowledge of cortical and cerebellar contributions to ASD, our knowledge about the early developing brainstem in ASD is only beginning to accumulate. Understanding how brainstem neurotransmission is implicated in ASD is important because many of this condition’s sensory and motor symptoms are consistent with brainstem pathology. Therefore, the purpose of this review was to integrate epidemiological, behavioral, histological, neuroimaging, and animal evidence of brainstem contributions to ASD. Because ASD is a neurodevelopmental condition, we examined the available data through a lens of hierarchical brain development. The review of the literature suggests that developmental alterations of the brainstem could have potential cascading effects on cortical and cerebellar formation, ultimately leading to ASD symptoms. This view is supported by human epidemiology findings and data from animal models of ASD, showing that perturbed development of the brainstem substructures, particularly during the peak formation of the brainstem’s monoaminergic centers, may relate to ASD or ASD-like behaviors. Furthermore, we review evidence from human histology, psychophysiology, and neuroimaging suggesting that brainstem development and maturation may be atypical in ASD and may be related to key ASD symptoms, such as atypical sensorimotor features and social responsiveness. From this review there emerges the need of future research to validate early detection of the brainstem-based somatosensory and psychophysiological behaviors that emerge in infancy, and to examine the brainstem across the life span, while accounting for age. In all, there is preliminary evidence for brainstem involvement in ASD, but a better understanding of the brainstem’s role would likely pave the way for earlier diagnosis and treatment of ASD.

Quantitative cellular-resolution map of the oxytocin receptor in postnatally developing mouse brains

“…Developmental expression in subcortical brain regions. Kinetics of neural circuit maturation vary significantly between different brain regions 32 . Since OTR is also widely expressed in different brain regions outside of the cortex, we sought to find whether these brain regions undergo similar expression trajectory to the isocortex in postnatally developing brains.…”

Quantitative Cellular-Resolution Map of the Oxytocin Receptor in Postnatally Developing Mouse Brains

“…Kinetics of neural circuit maturation vary significantly between different brain regions 32 . Since OTR is widely expressed in different brain regions outside of the cortex, we sought to find whether these brain regions undergo similar expression trajectory to the isocortex in postnatally developing brains.…”

Pre-emptive Intervention for Autism Spectrum Disorder: Theoretical Foundations and Clinical Translation

“…This paper draws on the hypotheses concerning the primacy of either in utero , intra-partum, or very early life motor lesions in ASD etiology, as detailed in ground-breaking syntheses by Torres et al (2013), Trevarthen and Delafield-Butt (2013), Delafield-Butt and Trevarthan (2017), Dadalko and Travers (2018), and Delafield-Butt et al (2018). These researchers propose that a structural (genetic or injury) or functional (monoaminergic) motor lesion is sustained in the brainstem systems or cortical subplate in the critically neuroplastic window in utero , intra-partum, or in very early life, which impairs prospective, affect-driven movement.…”

“…Reduced movement complexity and variability, that is, reduced movement repertoire, associated with decreased affect-driven prospective movement from birth, impairs sensory feedback and parent response, limiting capacity to process sensory information (Delafield-Butt et al, 2018). In the phase of secondary variability of general movements, these infants have further difficulty selecting an appropriately adapted strategy from of their repertoire, due to limited variability (Hadders-Algra, 2010; Dadalko and Travers, 2018; Delafield-Butt et al, 2018; Hadders-Algra, 2018b). Shafer et al (2017) propose that motor stereotypy is a downstream manifestation of low motor complexity.…”

“…See Torres et al (2013), Trevarthen and Delafield-Butt (2013), Delafield-Butt and Trevarthan (2017), Dadalko and Travers (2018), Delafield-Butt et al (2018) for comprehensive reviews.…”