<b>Background:</b> As a central component of the brain's reward system, nucleus accumbens (NAcc) plays a crucial role in reward salience and substance use behaviors. Changes in the NAcc are also relevant to higher rates of substance use of youth and adults from low-income backgrounds. Although resting-state functional connectivity (rsFC) of the NAcc provides valuable insights into the neural mechanisms underlying reward processing and the propensity for self-reported reward salience and substance use, research exploring the association between NAcc rsFC and brain networks beyond the default mode network (DMN) and prefrontal cortex (PFC) is limited. <b>Objective:</b> To investigate the role of the resting-state functional connectivity of the NAcc with the cingulo-opercular network, sensorimotor mouth network, and sensorimotor hand network in the association between socioeconomic status, self-reported reward salience, and future substance use. <b>Methods:</b> Data were obtained from the Adolescent Brain Cognitive Development (ABCD) study. NAcc rsFC with the cingulo-opercular network, sensorimotor mouth network, and sensorimotor hand network was assessed at baseline. Socioeconomic status was measured using family income. Self-reported reward salience was assessed using validated psychometric scales. Substance use outcomes were tracked longitudinally over the study period. Structural Equation Modeling was employed to examine the covariances between family income, NAcc rsFC, reward salience, and subsequent substance use. <b>Results:</b> Higher baseline family income was positively associated with baseline NAcc rsFC (B = 0.092, p < 0.001) and negatively associated with baseline reward salience (B = -0.040, p = 0.036) and future substance use (B = -0.081, p < 0.001). Baseline NAcc rsFC was strongly and positively associated with reward salience (B = 0.734, p < 0.001) and future substance use up to age 13 (B = 0.124, p < 0.001). Additionally, baseline reward salience was positively associated with future substance use (Covariance = 0.176, p < 0.001). <b>Conclusion:</b> The findings suggest that NAcc rsFC with brain networks beyond the DMN or PFC may contribute to the links between low parental socioeconomic status, reward salience, and substance use risk. Expanding the understanding of NAcc rsFC provides new insights into the neural mechanisms underlying these associations. These results have important implications for developing targeted interventions aimed at preventing substance use, particularly among low-income youth with heightened reward salience. Further research is needed to explore causal pathways and moderating factors influencing these relationships.
