Striatal temporal interference stimulation alleviates motor deficits and confers neuroprotection in an MPTP-induced mouse model of Parkinson's disease with associated improvements in mitochondrial homeostasis.

Temporal interference (TI) stimulation is an emerging noninvasive neuromodulation approach capable of selectively targeting deep brain structures, but its therapeutic effects and underlying mechanisms in Parkinson's disease (PD) remain unclear. Here, we evaluated striatal TI stimulation in an MPTP-induced mouse model of PD. TI stimulation using 2 and 2.02 kHz carrier frequencies, a 20 Hz offset, and a current of 150 μA was delivered for 10 min/day, with 30 s ramp-up and ramp-down, for 7 or 14 consecutive days. We found that TI stimulation significantly reduced motor deficits, with greater behavioral benefit observed after 14 days of stimulation, and attenuated dopaminergic neurodegeneration and α-synuclein accumulation. Meanwhile, TI stimulation improved multiple aspects of mitochondrial homeostasis, including mitochondrial morphology and dynamics, PINK1/Parkin-mediated mitophagy, complex I activity, and mitochondria-dependent apoptotic signaling. Importantly, pharmacological inhibition with Mdivi-1 largely attenuated the behavioral, neuropathological, and mitochondrial effects of TI stimulation, suggesting that mitochondrial quality-control pathways may contribute to TI-associated neuroprotection. Together, these findings indicate that striatal TI stimulation ameliorates motor impairment and exerts neuroprotective effects in parkinsonian mice, with associated improvements in mitochondrial homeostasis, and support TI stimulation as a promising noninvasive therapeutic strategy for PD.