Gray Matter and White Matter Functional Connectivity Changes induced by rTMS concurrent with Cognitive training in Alzheimer’s disease

Primarily by targeting the gray matter (GM), repetitive transcranial magnetic stimulation (rTMS) has shown promise in improving cognitive function in individuals with Alzheimer's disease (AD). However, the impact of rTMS on white matter (WM) remains poorly understood. This study aimed to investigate the functional connectivity (FC) changes in both GM and WM induced by rTMS, and explore their relationship with the clinical manifestation of the disease. Sixteen patients with mild to moderate AD were enrolled and randomly assigned to either the real rTMS group (n = 8) or the sham treatment group (n = 8). Both groups received cognitive training in combination with rTMS. The real rTMS group received 10Hz stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) followed by the left lateral temporal lobe (LTL), with each session lasting 20minutes per day for 4 weeks, while sham with the coil positioned at a 90° angle. Resting-state BOLD signals were averaged to generate mean time series for each of the 82 GM regions and 48 WM bundles, both before and after treatment for each subject. We analyzed the resting-state fMRI data by using a 2 × 2 factorial design with "time" as the within-subjects factor and "group" as the between-subjects factor. In the analysis of 82 GM regions, when using left LTL as the seed, significant time main effect was observed in right ventral Posterior cingulate cortex (vPCC) (F=9.356, p=0.009, η2=0.401) and right inferior temporal gyrus (ITG) (F=11.784, p=0.004, η2=0.457). In the analysis of 48 WM bundles, when using left DLPFC as the seed, significant time × group interactions were found in right cingulum (hippocampus part, CGH) (F=12.123, p=0.004, η2=0.464). The FC between left DLPFC and right cerebral peduncle (CBRP) demonstrated significant time main effect (F=15.569, p=0.001, η2=0.527). Moreover, the FC between left DLPFC and right CGH was significantly correlated with MMSE scores changes (r =-0.610, p=0.027), reflecting cognitive improvements after treatment. The current study suggested that rTMS, when combined with cognitive training, can concurrently modulate functional activities in both GM and WM in patients with mild to moderate AD, which are associated with cognitive improvements. Notably, the limbic system appears to play a pivotal role in facilitating this therapeutic process.