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Background Changes in neural circuitry function may be associated with longitudinal changes in psychiatric symptom severity. Identification of these relationships may aid in elucidating the neural basis of psychiatric symptom evolution over time. We aimed to distinguish these relationships using data from the Longitudinal Assessment of Manic Symptoms cohort. Methods Forty-one youth completed two study visits (interscan mean = 21.3 months). Elastic net regression (multiple-response Gaussian family) identified emotional regulation neural circuitry that changed in association with changes in depression, mania, anxiety, affect lability, and positive mood and energy dysregulation, accounting for clinical and demographic variables. Results Nonzero coefficients between change in the previously mentioned symptom measures and change in activity over the interscan interval were identified in right amygdala and left ventrolateral prefrontal cortex. Differing patterns of neural activity change were associated with changes in each of the previously mentioned symptoms over time. Specifically, from scan 1 to scan 2, worsening affective lability and depression severity were associated with increased right amygdala and left ventrolateral prefrontal cortical activity. Worsening anxiety and positive mood and energy dysregulation were associated with decreased right amygdala and increased left ventrolateral prefrontal cortical activity. Worsening mania was associated with increased right amygdala and decreased left ventrolateral prefrontal cortical activity. These changes in neural activity between scans accounted for 13.6% of the variance; that is, 25% of the total explained variance (39.6%) in these measures. Conclusions Distinct neural mechanisms underlie changes in different mood and anxiety symptoms over time.