Investigating the neural and behavioral correlates of the stress-rumination link in healthy humans by modulating the left Dorsolateral Prefrontal Cortex using Theta Burst Stimulation

Theta Burst Stimulation (TBS) offers a noninvasive way to modulate neural activation patterns, helping to explore the causal role of brain regions in psychiatric symptoms. Prefrontal hypoactivation is commonly observed in high ruminators and patients with depression during stress. However, the impact of modulating Dorsolateral Prefrontal Cortex (DLPFC) activity via excitatory and inhibitory TBS during stress remains unexplored. We studied 88 healthy participants (44 low, 44 high ruminators), each attending two appointments that included stress induction using the Trier Social Stress Test (TSST) and cortical oxygenation assessment with functional Near-Infrared Spectroscopy (fNIRS). Participants received either intermittent TBS (iTBS) or continuous TBS (cTBS) applied to the left DLPFC, with sessions randomized between active and sham stimulation. While TBS had no impact on positive affect, TSST performance, or heart rate, we observed effects on stress, state rumination, negative affect, and cortical oxygenation. We observed higher stress and higher negative affect during and after the TSST in high ruminators receiving iTBS compared with sham TBS (sTBS). Low ruminators showed reduced state rumination increases after iTBS compared with sTBS at their second appointment. fNIRS data revealed cortical oxygenation differences during the TSST, although only without multiple comparison corrections. Descriptively, we observed higher activation in the left Ventrolateral Prefrontal Cortex (VLPFC) following cTBS compared with sTBS in high ruminators but lower cortical oxygenation following cTBS compared with sTBS in low ruminators but only when participants received active stimulation first. This suggests stimulation sequence affects repeated-measures TMS studies in stress contexts. Findings highlight expectancy effects and suggest a potential reduction in TBS impact due to strong hemodynamic responses during stress. HIGHLIGHTS: • High ruminators showed increased stress and negative affect after iTBS during the TSST. • Neural data showed increased cortical oxygenation in the left Ventrolateral Prefrontal Cortex (VLPFC) following cTBS to the left Dorsolateral Prefrontal Cortex (DLPFC) in high ruminators. • In low ruminators, cTBS led to decreased activation, but only when active stimulation was administered first, highlighting the role of stimulation order in TBS outcomes. • Expectancy effects and habituation are important aspects to be considered in repeated measures designs involving TBS and stress-reactive rumination.