Prefrontal Circuitry Abnormalities and Cognitive Impairment in Adolescents with Early- Onset Psychosis

Early-onset psychosis (EOP) is associated with marked cognitive impairment and poorer health-related and psychosocial outcomes compared to adult-onset illness, yet the neural mechanisms underlying these deficits during adolescence remain incompletely understood. Despite evidence implicating dorsolateral prefrontal cortex (dlPFC) dysfunction, the region’s functional and structural correlates in youth with EOP are not well characterized. Adolescents with EOP (N=31) and healthy controls (HC; N=20) completed NIH Toolbox cognitive assessments and PROMIS self-reports. Prefrontal function was assessed using functional near-infrared spectroscopy (fNIRS) during a Stroop task and at rest. Multimodal MRI, including resting-state fMRI, diffusion tensor imaging, and structural imaging, was used to examine connectivity and morphology of prefrontal and fronto-cerebellar circuits. Adolescents with EOP exhibited poorer cognitive performance across executive functioning domains compared to HC. fNIRS revealed reduced right dlPFC activation on a cognitive control paradigm (p=0.007) and increased resting-state connectivity between right dlPFC and ventrolateral PFC (p=0.02). Furthermore, resting-state fMRI showed increased dlPFC-striatal connectivity and reduced connectivity with cerebellar Crus I/II (p-FDR<0.05). White matter integrity of the superior longitudinal fasciculus correlated with dlPFC activation during task performance. Structural analyses identified reduced frontal cortical thickness and decreased cerebellar Crus II volumes (p-FWE<0.05) in patients with EOP, with frontal morphology associating with cognitive measures. In summary, cognitive impairment in adolescents with EOP is associated with convergent abnormalities in dlPFC function, fronto-striatal connectivity, and fronto-cerebellar structure. These findings support a model of disrupted prefrontal circuit maturation in EOP and highlight multimodal imaging markers with potential relevance for early identification and targeted intervention.