Depression is a debilitating disorder with high prevalence and socioeconomic cost, but the central processes that are altered during depressive states remain largely elusive. Here, we build on recent findings in macaques that indicate a direct causal relationship between pupil dilation and anterior cingulate cortex mediated arousal during anticipation of reward. Using pupillometry and concurrent fMRI in a sample of unmedicated participants diagnosed with major depression and healthy controls, we observed reduced pupil dilation during reward anticipation in depressed participants with acute symptomatology. We further observed that individual differences in arousal during reward anticipation track the load and impact of depressive symptoms, a correlation that we replicated in a second sample of unmedicated depressed participants. Moreover, these group differences and correlations were mirrored at the neural level. The upregulation and maintenance of arousal during reward anticipation is a translational and well-traceable process that could prove a promising gateway to a physiologically informed patient stratification.

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