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Midbrain hypoactivation and mesocortical hypoconnectivity in inhibitory control learning in autism
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DOI：10.1093/braincomms/fcag265.png)
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Abstract
En 中文
Repetitive behaviour, resulting from impaired inhibitory control and error monitoring, represents a core manifestation of autism, with a poorly understood neural basis. Our primary hypothesis was that a striatum-midbrain framework could provide a theoretical basis for understanding neural changes underlying response inhibition in autism. This conceptual approach considered two critical neurobehavioural factors: (a) inhibition as a dynamic process requiring trial-and-error learning, and (b) efficient error learning relying on the striatum receiving dopaminergic signals from the midbrain—a framework analogous to an ‘actor-critic’ architecture. Eighteen adults with a diagnosis of autism spectrum disorder and 21 age-matched healthy controls performed a stop-signal task adjusted for functional MRI (fMRI). To dissect domain-dependent correlates of neural inhibition, we measured brain activation and connectivity as a function of task phases in the dorsal striatum and dopaminergic midbrain nuclei. Repetitive behaviour severity was assessed using the observer-reported Repetitive Behaviours Scale—Revised. A striking hypoactivation in the midbrain during failed inhibition events was observed in relation with the severity of repetitive behaviours. We also identified, in the autism group, reduced functional connectivity between the midbrain-striatum hubs and regions involved in cognitive control (prefrontal cortex) and error monitoring (bilateral insula), during response preparation periods. Finally, although both groups achieved similar final performance levels, neurodivergent subjects learned slower and displayed delayed striatal engagement when behavioural adjustment was required. These results reveal a novel autism profile characterized by midbrain hypoactivation mediating repetitive behaviour manifestations and reduced long-range mesocortical hypoconnectivity during inhibitory response preparation phases. Accordingly, we suggest that individuals with autism exhibit midbrain-dependent reduced motivational arousal, limiting their ability to develop proactive strategies for trial-and-error learning and regulate out-of-context behaviours. By highlighting the key role of dopaminergic midbrain structures and related long-range pathways, we challenge the view autism as solely a cortical dysfunction condition and provide evidence for promising targets for neurobiologically-driven interventions based on dopaminergic mechanisms.
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