Pupil size-resting state network coupling in major depressive disorder: a longitudinal iTBS study

Altered central-peripheral autonomic nervous system communication plays a key role in major depressive disorder (MDD). In this context, pupillary dynamics may be considered a non-invasive peripheral proxy of treatment-related changes during intermittent theta-burst stimulation (iTBS) in MDD. However, the relationship between spontaneous pupillary fluctuations and the resting-state functional networks (RSNs) involved in MDD is still underexplored. Here, we investigated longitudinal changes in pupil-RSN coupling in patients with MDD undergoing an iTBS intervention. Resting-state functional magnetic resonance imaging with concurrent pupillometry was acquired at four study visits. Group independent component analysis was used to estimate tonic pupil coupling with predefined RSNs of interest, along with a linear mixed-effects model to assess longitudinal changes in pupil size-RSN coupling and, exploratively, the effect of potential clinical and behavioral moderators. Among the examined RSNs, the left executive control network (lECN), including the left dorsolateral prefrontal cortex as the cortical target of stimulation, exhibited a sustained reduction in positive pupil size coupling relative to baseline, irrespective of treatment order (active-sham). To determine whether this longitudinal change was accompanied by a more general change in pupil diameter, we additionally examined pupil size independently of RSNs. Pupil diameter decreased significantly from baseline, with greater decreases being positively associated with greater reductions in anxiety scores. Notably, reduction in anxiety symptoms were also positively correlated with reduction in depressive symptoms. Together, these findings suggest that longitudinal reductions in pupil-IECN coupling occur alongside reductions in pupil diameter that are associated with reductions in anxiety symptoms.