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

Abstract

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.

Keywords: Dorsolateral Prefrontal Cortex; Rumination; Stress; Theta Burst Stimulation; Trier Social Stress Test.

Fig. 1

The allocation of experimental groups (A) and overview of the experimental procedure (B). Above the line, the respective tasks and experimental phases are shown. Below the line, the time points of questionnaire assessments are displayed in bold, with the names of the corresponding questionnaires highlighted in blue. RRS = Ruminative Response Scale; TBS = Theta Burst Stimulation; BDI-II = Beck's Depression Inventory II; PANAS = Positive and Negative Affect Schedule; SRSRQ = Stress-Reactive State Rumination Questionnaire; stress = subjective stress assessed via a Visual Analogue Scale (0–100%); *Only assessed at the first appointment (AP1)

Fig. 2

Line plot of the contrasts of subjective stress ratings dependent on order of conditions (A = sham stimulation at the first appointment, active stimulation at the second appointment; B = active stimulation at the first appointment, sham stimulation at the second appointment), and line plot of raw data of subjective stress ratings dependent on the appointment (C = first appointment; D = second appointment). rest = resting-state measurement; ctl1 = control task 1; ctl2 = control task 2; TSST = Trier Social Stress Test; sTBS = sham Theta Burst Stimulation; cTBS = continuous Theta Burst Stimulation; iTBS = intermittent Theta Burst Stimulation; 15 min = 15 min after the TSST; RRS = Ruminative Response Scale. Please note that the effect of the order of stimulation conditions is visually depicted within the plots of the different appointments (first appointment: sTBS = participants with order of stimulation conditions sham → active; iTBS and cTBS = participants with order of stimulation conditions active → sham; second appointment: vice versa). Error bars indicate 1 standard error of the mean

Fig. 3

Line plot of the contrasts of state rumination ratings dependent on order of conditions (A = sham stimulation at the first appointment, active stimulation at the second appointment; B = active stimulation at the first appointment, sham stimulation at the second appointment), and line plot of raw data of state rumination ratings dependent on order of conditions and appointment (C = first appointment sham stimulation; D = first appointment active stimulation; E = second appointment active stimulation; F = second appointment sham stimulation). rest = resting-state measurement; 60 min post TSST = 60 min after the Trier Social Stress Test; RRS = Ruminative Response Scale. Error bars indicate 1 standard error of the mean

Fig. 4

Line plot of the contrasts of negative affect ratings dependent on order of conditions (A = sham stimulation at the first appointment, active stimulation at the second appointment; B = active stimulation at the first appointment, sham stimulation at the second appointment) and line plot of raw data of negative affect ratings dependent on the appointment (C = first appointment; D = second appointment). rest = resting-state measurement; sTBS = sham Theta Burst Stimulation; cTBS = continuous Theta Burst Stimulation; iTBS = intermittent Theta Burst Stimulation; 0 min post TSST = 0 min after the Trier Social Stress Test; RRS = Ruminative Response Scale. Please note that the effect of the order of stimulation conditions is visually depicted within the plots of the different appointments (first appointment: sTBS = participants with order of stimulation conditions sham → active; iTBS and cTBS = participants with order of stimulation conditions active → sham; second appointment: vice versa). Error bars indicate 1 standard error of the mean

Fig. 5

Plots of the t-values of the paired t-tests in each channel testing the active stimulation condition against the sham stimulation in each channel dependent on the stimulation condition A = cTBS, B = iTBS, TSST = arithmetic task of the TSST. The figure legend was scaled so that channels showing a significant t-value are displayed in blue ($\le$−1.66) or red ($\ge$ 1.66). Significant channels in the cTBS condition are channel 9 (left VLPFC), 22, 34, 36 (SAC), 41, and 42. Significant channels in the iTBS condition are channel 7 (left VLPFC), 33, and 34

Fig. 6

The z-standardized hemodynamic responses during the arithmetic task of the TSST in the left DLPFC in low and high ruminators depending on the TBS-condition at the first appointment (A) and the second appointment (B). A.1, A.2, B.1, and B.2 illustrate the raw data. A.3, A.4, B.3, and B.4 illustrate the contrasts (cTBS minus sTBS and iTBS minus sTBS). The light shading marks the 40 s trial and the dark shading the 20 s pause to allow the hemodynamic response to recover. Shadings around the hemodynamic curves reflect standard errors of the mean. The baseline includes the 5 s before each trial; 0 s on the x-axis marks the beginning of the trial. See supplementary material S11 for the time series of the other ROIs