Associations between striatal neurochemical changes and resting-state functional connectivity following transcranial temporal interference stimulation

Background Non-invasive modulation of deep brain structures remains a major challenge in human neuroscience and neurorehabilitation. Transcranial temporal interference stimulation (tTIS) has emerged as a promising approach for engaging subcortical regions, but its effects on striatal neurochemical markers and functional connectivity remain unclear. Objective To investigate whether 20-Hz tTIS designed to target the right striatum modulates GABA+ and glutamate-glutamine complex (Glx) levels and whether neurochemical changes are associated with changes in resting-state functional connectivity. Methods Thirty-four healthy right-handed participants were randomly assigned to the tTIS group (20-Hz beat frequency) or sham group (0-Hz frequency difference). Participants underwent proton magnetic resonance spectroscopy (1H-MRS) and resting-state fMRI before and after 30 min of stimulation. One participant in the tTIS group was excluded from the 1H-MRS analyses because of data corruption. Results The direct between-group difference in Glx change did not reach statistical significance, although the tTIS group showed a numerically greater reduction than the sham group (p = 0.066). Exploratory within-group analyses showed a significant decrease in striatal Glx in the tTIS group (p < 0.001), whereas the decrease in the sham group was not significant. No significant GABA+ changes were observed within or between groups. The association between striatal Glx change and functional connectivity change differed between groups in the sensorimotor cortex, right parahippocampal gyrus, and bilateral fusiform gyri. Conclusion These exploratory findings suggest that 20-Hz tTIS may be associated with striatal Glx modulation and group-dependent coupling between neurochemical and cortico-subcortical network changes.