Mol Psychiatry. 2026 Jul 31. doi: 10.1038/s41380-026-03771-5. Online ahead of print.
ABSTRACT
Objective neural markers that reflect the underlying pathophysiological mechanisms of affective disorders are needed to facilitate early identification of individuals most at risk of future affective disorders and ultimately provide neural targets to guide therapeutic interventions. Using an emotional n-back paradigm designed to examine working memory (WM) and emotional regulation (ER) capacity, we previously showed that WM-related elevated left dlPFC activity (a key node of the central executive network (CEN)) and elevated right precuneus activity (a key node of the default mode network (DMN)), as well as ER-related elevated left dlPFC activity were positively associated with future depression severity in young adults at risk for affective disorders. We now aimed to replicate and extend these previous longitudinal findings by examining relationships among right precuneus activity and left dlPFC activity during WM and ER tasks and future depression severity in a new independent young adult sample (n = 77: 50 female, age = 24.68), and a larger combined sample (n = 121: 83 female, age = 23.81) comprising the original and new samples. The Hamilton Rating Scale for Depression (HAM-D) and Young Mania Rating Scale (YMRS) were measured at 12 months post scan to assess future depression and mania/hypomania severity respectively. In the new sample, we showed patterns of left dlPFC activity and right precuneus activity during WM, and left dlPFC activity during ER that were consistent with the original sample. In both the new and combined samples, future depression severity was robustly predicted by WM-related left dlPFC activity and right precuneus activity, and ER-related left dlPFC activity (all ps < 0.05 qFDR). These findings were specific to future depression severity. The effect sizes (pseudo R-squared values) for the full models including all IVs in the new and combined samples ranged from approximately 25-43%, with left dlPFC and right precuneus activity during WM explaining 15.59% of variance in future depression severity in the new sample; and left dlPFC activity during ER explaining 14.63% of variance in future depression severity in the combined sample. These replicated, longitudinal findings provide candidate neural markers to guide risk identification and targeting of new interventions for individuals with and those at risk for future affective disorders.
PMID:42538394 | DOI:10.1038/s41380-026-03771-5
