Phase-Synchronized TECS Integrating TI-tACS and rTMS: Modeling, Hardware Implementation, and In Vivo Neurophysiological Validation.

OBJECTIVE: Conventional noninvasive neuromodulation is constrained by trade-offs among field strength, focality, and penetration. We propose a phase-synchronized transcranial electromagnetic combined stimulation (TECS) approach that concurrently combines temporal interference transcranial alternating current stimulation (TI-tACS) with repetitive transcranial magnetic stimulation (rTMS) to improve the local intensity-focality trade-off in the motor cortex. To our knowledge, this is the first study to investigate a phase-synchronized concurrent TI-tACS + rTMS paradigm. METHODS: Finite-element simulations quantified the peak magnitude-based stimulation metric in the target M1 region, together with the equivalent focal area and effective penetration depth under a half-maximum criterion. A phase-synchronized TECS system was implemented and evaluated in rats using rotarod performance, c-Fos immunofluorescence, and histology, with comparisons to TI-tACS alone, rTMS alone, and a sham-like control condition. RESULTS: TECS produced the highest peak target-region electric-field value (178.0 V/m) while maintaining a much smaller focal area than rTMS alone (8.3 vs. 76.0 mm²) and greater penetration than TI-tACS alone (2.1 vs. 1.2 mm). In vivo, TECS produced the longest rotarod latency on Day 7 (288.5 ± 16.4 s; n = 6 rats/group; daily values averaged over three trials/rat), exceeding the control, TI-tACS, and rTMS groups by 75.3%, 15.3%, and 19.4%, respectively. TECS also induced the highest c-Fos activation, with corresponding increases of 50.1%, 9.4%, and 12.8%, respectively. Histology revealed no overt abnormalities across conditions. CONCLUSION: Phase-synchronized TECS enhances focal electric-field intensity and neuronal activation, translating to improved motor performance. SIGNIFICANCE: The proposed TECS platform provides a promising neuroengineering approach for targeted noninvasive brain stimulation, supported by simulation-defined field metrics and in vivo feasibility and safety validation.