Central medial thalamic nucleus–targeted temporal interference stimulation promotes arousal: translational evidence from optimized preclinical models to patients with disorders of consciousness

Abstract

Patients with disorders of consciousness (DoC) lack effective non-invasive neuromodulation therapies capable of targeting deep-brain arousal circuits. Temporal interference stimulation (TIS) offers potential for non-invasive deep brain targeting. However, its efficacy, optimal stimulation parameters, and underlying neural mechanisms remain to be systematically investigated. We constructed a rodent TIS electrode configuration with cathode affixed to the masseter muscle to achieve free-moving stimulation in mice, and optimized stimulation parameters in isoflurane-anesthetized C57 mice, validated using righting reflex assays. Target specificity was confirmed by comparing Central Medial Thalamic Nucleus (CM) stimulation with that of the caudate putamen. Neuronal activation was assessed via calcium imaging, c-Fos staining, and electrocorticography. Biosafety was evaluated through acute and 7-day repeated histopathological analyses and open-field testing. Preliminary feasibility was assessed in two patients with chronic DoC using Coma Recovery Scale–Revised and functional near-infrared spectroscopy. Optimal TIS parameters (60 s, 0.8 mA, 10 Hz) significantly promoted arousal, accelerated righting reflex recovery, and increased respiratory rate. CM-targeted TIS preferentially activated CM neurons, enhanced cortical beta/gamma oscillations, and suppressed delta activity. No tissue damage, neuronal loss, microglial activation, or motor deficits were observed under acute or repeated stimulation. In two patients, 10 Hz TIS transiently improved consciousness ratings and enhanced functional connectivity and right Broca’s area activation. CM-targeted TIS is a promising non-invasive deep neuromodulation strategy, supported by a translational evidence chain from preclinical optimization, mechanistic validation, and biosafety assessment to preliminary clinical feasibility. Chinese Clinical Trial Registry, ChiCTR2500114570. Registered 15 December 2025.