A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning–based predictive tests examined cerebellar–frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar–default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity–based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities

Correlation Between Ventral Striatal Catecholamine Content and Nociceptive Thresholds in Neuropathic Mice

Neuropathic pain is characterized by persistent, intractable pain following damage or dysfunction of the nervous system. Analgesics that include central, rather than purely peripheral, targets are more effective when treating neuropathic pain, highlighting the spinal and/or supraspinal mechanisms that contribute to this aberrant pain condition. The striatum represents one of the brain regions that have been implicated in pain processing. Release of dopamine in the ventral striatum is normally associated with analgesia. Clinical and human imaging studies suggest dopamine is disrupted in neuropathic pain patients, although the conclusions drawn from these studies are limited by their non-invasive imaging or pharmacological approaches. In this study, we used a C57Bl/6 mouse model of neuropathic pain to describe the changes in neurotransmitter content in the striatum and their relationship to evoked pain thresholds. Striatal dopamine content negatively correlated with mechanical thresholds in sham animals. Neuropathic pain animals had reduced dopamine content that was not correlated with mechanical thresholds. In contrast, norepinephrine content was significantly increased and correlated with mechanical thresholds in neuropathic, but not sham animals. These results describe changes in striatal signaling in neuropathic pain animals, and contribute to the literature defining the role of dopamine and norepinephrine in mediating sensory thresholds in healthy and neuropathic pain states