40-Hz Temporally Interfering Electrical Stimulation Over the Temporal Lobe Induced Antidepressant-Like Effects in Chronic Unpredictable Mild Stress Rats

Temporally interfering (TI) electrical stimulation provides a promising noninvasive and focused stimulation for neuropsychiatric disorders. However, the feasible stimulation strategy and potential effects require further study. Our previous studies have identified gamma oscillatory abnormalities of temporal regions in depressed patients and rats. We accordingly aim to develop an effective TI antidepressant strategy. The stimulation strategy was firstly determined by modeling and simulation, and verified by c-Fos immunofluorescence staining. 32 rats were randomized into control (n = 8) and depression (n = 24) groups induced by chronic unpredictable mild stress (CUS), which were exposed to stimulation for 5 days, 20 mins per day. The behavioral and electrophysiology experiments were performed to examine the antidepressant-like effects of TI, using transcranial alternating current stimulation (tACS) as a positive control. In the electrophysiology experiment, local field potential (LFP) signals were recorded from bilateral primary auditory cortex (A1) before and after stimulation. We found that TI activated more c-Fos-positive cells in A1 target than tACS, exhibiting better stimulation focality. Both TI and tACS significantly ameliorated depression-like behaviors compared to sham group, and TI made more improvements. Furthermore, TI largely restored the gamma deficits by increasing gamma power and phase locking value (PLV) compared with tACS. And the gamma-band deficits were found remarkably correlated with depression-like behaviors. Overall, TI ameliorated depression-like behaviors in CUS rats, which may be associated with the restoration of aberrant gamma oscillations. With the advantages of both spatial targeting and noninvasive character, TI holds great promise for the clinical application of depression.