Dose-response relationship between iTBS and prefrontal activation during executive functioning: A fNIRS study

INTRODUCTION: Intermittent theta-burst stimulation (iTBS) is a non-invasive brain stimulation paradigm that has demonstrated promising therapeutic benefits for a variety of neuropsychiatric disorders. It has recently garnered widespread favor among researchers and clinicians, owing to its comparable potentiation effects as conventional high-frequency repetitive transcranial magnetic stimulation (rTMS), but administered in a much shorter time frame. However, there is still a lack of agreement over the optimal stimulation intensity, particularly when targeting the prefrontal regions. The objective of this study was to systematically investigate the influence of different stimulation intensities of iTBS, applied over the left dorsolateral prefrontal cortex (DLPFC), on brain activity and executive function in healthy adults. METHODS: Twenty young healthy adults were enrolled in this randomized cross-over experiment. All participants received a single session iTBS over the left DLPFC at intensities of 50, 70, or 100% of their individual resting motor threshold (RMT), each on separate visits. Functional near-infrared spectroscopy (fNIRS) was used to measure changes of hemoglobin concentrations in prefrontal areas during the verbal fluency task (VFT) before and after stimulation. RESULTS: After stimulation, iTBS to the left DLPFC with 70% RMT maintained the concentration change of oxyhemoglobin (HbO) in the target area during the VFT. In contrast, 50% [t((17)) = 2.203, P = 0.042, d = 0.523] and 100% iTBS [t((17)) = 2.947, P = 0.009, d = 0.547] significantly decreased change of HbO concentration, indicating an inverse U-shape relationship between stimulation intensity and prefrontal hemodynamic response in healthy young adults. Notably, improved VFT performance was only observed after 70% RMT stimulation [t((17)) = 2.511, P = 0.022, d = 0.592]. Moreover, a significant positive correlation was observed between task performance and the difference in HbO concentration change in the targeted area after 70% RMT stimulation (r = 0.496, P = 0.036) but not after 50 or 100% RMT stimulation. CONCLUSION: The linear relationship between stimulation intensity and behavioral outcomes reported in previous conventional rTMS studies may not be translated to iTBS. Instead, iTBS at 70% RMT may be more efficacious than 100% RMT.