Targeting the Medial Prefrontal Cortex With Transcranial Temporal Interference Stimulation Alleviates Chronic Pain

Chronic pain involves prefrontal maladaptation, but noninvasive modulation of the medial prefrontal cortex (mPFC) remains challenging. We investigated whether transcranial temporal interference stimulation (tTIS) could alleviate chronic pain and explored neural mechanisms by systematically optimizing stimulation parameters.

In a mouse model of chronic pain, we applied tTIS to the mPFC and comprehensively evaluated key parameters-including stimulation paradigm (continuous vs. intermittent), consciousness state (awake vs. anesthetized), current intensity, duration, envelope frequency, and carrier frequency-to determine their impact on analgesic efficacy and durability.

tTIS targeting the mPFC produced robust and sustained analgesia, as measured by significantly enhanced paw withdrawal thresholds. Continuous tTIS applied in awake mice elicited superior and longer-lasting therapeutic effects compared with intermittent stimulation or application under anesthesia, suggesting state-dependent engagement of neural circuits. Systematic parameter optimization revealed that stimulation duration and envelope frequency were the most critical determinants of efficacy, accounting for 39.58% and 31.45% of the treatment effect, respectively. The optimal protocol (continuous mode, awake state, 0.05 mA, 2000/2020 Hz, 20 minutes) induced analgesia that persisted for several days following stimulation.

Our findings provide preclinical evidence that tTIS can effectively modulate prefrontal circuits to alleviate chronic pain. This work establishes a mechanistic framework for tTIS parameter selection and highlights its potential as a novel noninvasive neuromodulatory therapy for chronic pain.