The effects of intermittent theta burst stimulation (iTBS) on resting-state brain entropy (BEN)

Intermittent theta burst stimulation (iTBS), a novel protocol within repetitive transcranial magnetic stimulation (rTMS), has shown superior therapeutic effects for depression compared to conventional high-frequency rTMS (HF-rTMS). However, the neural mechanisms underlying iTBS remain poorly understood. Brain entropy (BEN), a measure of the irregularity of brain activity, has recently emerged as a promising marker for regional brain function and has demonstrated sensitivity to depression and HF-rTMS. Given its potential, BEN may help elucidate the mechanisms of iTBS. In this study, we computed BEN using resting-state fMRI data from sixteen healthy participants obtained from OpenNeuro. Participants underwent iTBS over the left dorsolateral prefrontal cortex (L-DLPFC) at two different intensities (90 ​% and 120 ​% of resting motor threshold (rMT)) on separate days. We used a 2 ​× ​2 repeated measures analysis of variance (ANOVA) to analyze the interaction between iTBS stimulation intensity and the pre- vs. post-stimulation effects on BEN and paired sample t-tests to examine the specific BEN effects of iTBS at different intensities. Additionally, spatial correlation analysis was conducted to determine whether iTBS altered the baseline coupling between BEN and neurotransmitter receptors/transporters, to investigate potential neurotransmitter changes induced by iTBS. Our results indicate that subthreshold iTBS (90 ​% rMT) reduced striatal BEN, while suprathreshold iTBS (120 ​% rMT) increased it. Subthreshold iTBS led to changes in the baseline coupling between BEN and several neurotransmitter receptor/transporter maps, primarily involving serotonin (5-HT), cannabinoid (CB), acetylcholine (ACh), and glutamate (Glu). Our findings suggest that BEN is sensitive to the effects of iTBS, with different stimulation intensities having distinct effects on neural activity. Notably, subthreshold iTBS may offer more effective stimulation. This research highlights the crucial role of stimulation intensity in modulating brain activity and lays the groundwork for future clinical studies focused on optimizing therapeutic outcomes through precise stimulation intensity.