Transcranial High-Frequency Terahertz Stimulation Alleviates Anxiety-like Behavior in Mice via a Noninvasive Approach

Terahertz waves, positioned between infrared and microwave frequencies, have important potential in various fields, but their potential for in vivo biomedical applications has mostly remained untapped. In the present study, we focused on testing the potential of noninvasive high-frequency terahertz stimulation (HFTS) as a treatment for anxiety in mice. Mice were subjected to acute restraint stress to induce anxiety and then clustered into anxiety-susceptible and anxiety-resilient groups using the <i>K</i>-means algorithm. We developed an anxiety phenotype prediction classifier utilizing the naïve Bayes algorithm to accurately categorize mice. Noninvasive HFTS was targeted at the anterior cingulate cortex across the skulls of anxiety-susceptible mice, resulting in a marked anxiolytic effect. The underlying mechanism of HFTS's anxiolytic effect was subsequently elucidated through in vivo and in vitro electrophysiological and morphological methods, revealing that HFTS decreases the excitability of pyramidal neurons in the anterior cingulate cortex by enhancing voltage-gated K⁺ channel and leak K⁺ channel conductance. The study not only expands the potential applications of HFTS, particularly its noninvasive use, in the regulation of anxiety-like disorders but also introduces innovative methodologies and insights that have the potential to lay the groundwork for future research in the field of physical biomedicine.