Magnetic brain stimulation has greatly contributed to the advancement of neuroscience. However, challenges remain in the power of penetration and precision of magnetic stimulation, especially in small animals. Here, a novel combined magnetic stimulation system (c-MSS) was established for brain stimulation in mice. The c-MSS uses a mild magnetic pulse sequence and injection of superparamagnetic iron oxide (SPIO) nanodrugs to elevate local cortical susceptibility. After imaging of the SPIO nanoparticles in the left prelimbic (PrL) cortex in mice, we determined their safety and physical characteristics. Depressive-like behavior was established in mice using a chronic unpredictable mild stress (CUMS) model. SPIO nanodrugs were then delivered precisely to the left PrL cortex using in situ injection. A 0.1 T magnetic field (adjustable frequency) was used for magnetic stimulation (5 min/session, two sessions daily). Biomarkers representing therapeutic effects were measured before and after c-MSS intervention. Results showed that c-MSS rapidly improved depressive-like symptoms in CUMS mice after stimulation with a 10 Hz field for 5 d, combined with increased brain-derived neurotrophic factor (BDNF) and inactivation of hypothalamic-pituitary-adrenal (HPA) axis function, which enhanced neuronal activity due to SPIO nanoparticle-mediated effects. The c-MSS was safe and effective, representing a novel approach in the selective stimulation of arbitrary cortical targets in small animals, playing a bioelectric role in neural circuit regulation, including antidepressant effects in CUMS mice. This expands the potential applications of magnetic stimulation and progresses brain research towards clinical application.

BackgroundTMS is an effective anti-depression method commonly used in clinical practice, but it also faces the problems of low spatial resolution, treatment parameters to be optimized and limitation in mechanism research.ObjectiveTo develop a precise magnetic stimulation anti-depression method for the scientific research of magnetic stimulation, especially the mechanism research in animal experiments.MethodsThe cytotoxicity test was conducted in advance to ensure the security of intervention from SPIO nanoparticles and RMF. In animal experiments, 300nl SPIO solution was injected into the right hippocampus of the CUMS model mice, and then treated experimental group mice with rotating magnetic field for five days. The Sucrose Preference Test (SPT), the Forced Swim Test (FST) and BDNF expression levels were used to evaluate the antidepressant effect of this method.ResultsNo significant decrease of cell viability was observed when the iron concentration is between 52.2µg/ml and 208.8µg/ml. And the application of RMF with a certain frequency was considered to be safe in the cytotoxicity test. When treated with SPIO+RMF, the sucrose preference of SPIO+RMF group mice increased markedly (n=9, p<0.01 vs. CUMS), the FST immobile time reduced (n=8, P<0.05 vs. CUMS) and the BDNF level in the hippocampus was significantly up-regulated (n=5, P<0.01 vs. CUMS). However, merely SPIO intervention failed to be effective.Conclusionswhen intervened with external rotating magnetic field, the SPIO nanoparticles injected into the right hippocampus could produce rapid antidepressent effects in mice.