Conductivity-driven electric field disparities at gray–white matter interfaces during transcranial magnetic stimulation in Alzheimer’s disease

Transcranial magnetic stimulation (TMS) has shown potential in enhancing cognitive function in patients with Alzheimer’s disease (AD). While TMS modeling is crucial for optimizing therapy, uncertainties in tissue conductivity values require systematic investigation into how these parameters affect electric field (E-field) distribution between gray matter (GM) and white matter (WM). This study aims to determine how AD-related changes in GM and WM conductivity alter TMS-induced E-field distribution, particularly at GM–WM interfaces. Using MRI data from 35 AD patients and 35 healthy controls, we analyzed TMS induced intracerebral E-field distributions in four target sites (left dorsolateral prefrontal cortex, left angular gyrus, left primary motor cortex, and precuneus) and their GM–WM interfaces across varying conductivity configurations, with systematic 30° coil rotations around each target. Under default conductivity settings, both healthy controls and AD patients exhibited stronger WM E-field (EWM) than GM E-field (EGM) across all four brain regions (P < 0.001), while coil orientation did not alter this pattern. Although this EWM dominance gradually diminished with increasing WM conductivity, the predominance of EWM persisted with conductivity values reported from the literature. Furthermore, AD patients exhibited significantly lower coefficients of variation (CV) than healthy controls in both EWM (P = 0.025) and EGM (P = 0.014). EWM consistently demonstrated greater CV values compared to EGM across both groups. This study identifies WM conductivity as a key determinant of E-field strength in AD. These insights advance the understanding of TMS mechanisms in AD and underscore the importance of refining conductivity parameters to optimize therapeutic targeting of GM–WM interactions.