Deep rTMS Mitigates Behavioral and Neuropathologic Anomalies in Cuprizone-Exposed Mice Through Reducing Microglial Proinflammatory Cytokines

Abstract

In comparison to conventional repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation is stronger and more effective as a brain stimulation approach within short periods. Although this deep rTMS technique is being applied in treating neuropsychiatric disorders, few animal studies have attempted to clarify the neurobiological mechanisms underlying its beneficial effects. This animal study examined the effects of deep rTMS on the cuprizone-induced neuropathologic and behavioral anomalies and explored the underlying mechanism. Adolescent male C57BL/6 mice were fed a rodent chow without or with cuprizone (CPZ; 0.2% w/w) for 5 weeks. Another two groups of mice were subjected to deep rTMS or sham rTMS once a day during weeks 2-5 of the CPZ-feeding period. The behaviors of all mice were assessed after the withdrawal of CPZ before neuropathological and immunological analyses. Compared to the CNT group, mice in CPZ and CPZ + Sham groups showed deficits in social recognition and spatial working memory as well as anxiety-like behavior, in addition to myelin breakdown and OL loss in the corpus callosum (CC), caudate putamen, cerebral cortex, and hippocampus of the brain. Deep rTMS effectively reduced behavioral anomalies and blocked myelin breakdown and OL loss in CPZ-fed mice. Besides, it also dampened microglia activation at lesion sites and rectified cytokines levels (IL-1β, IL-6, and IL-10) in CPZ-affected regions. The most significant effect was seen in the cerebral cortex where alleviated neuropathology co-existed with less microglia activation and higher IL-10 level. These data provided experimental evidence for the beneficial effects of deep rTMS in CPZ-fed mice and revealed a neurobiological mechanism of the modality.

Repetitive transcranial magnetic stimulation increases the brain’s drainage efficiency in a mouse model of Alzheimer’s disease

“…Previous findings have shown that rTMS may suppress or induce glial activation via different frequency and strength used and may be context-dependent. For example, rTMS treatment (gamma oscillations, 30-40 Hz) for 4 weeks has been reported to attenuate cuprizone-induced microglia activation and pro-inflammatory cytokine expression in the frontal cortex and hippocampus of the affected mouse brains [ 68 ]. In a rat model of spinal cord injury, high frequency (25 Hz) rTMS treatment for 8 weeks was found to suppress astrocyte activation [ 35 ].…”

Non-invasive Brain Stimulation for Central Neuropathic Pain

“…rTMS has been shown to alter IL-10 levels in a variety of situations. rTMS reduced the activation of microglia and increased the level of IL-10 in the cortex, alleviating neurological abnormalities in rats with MS-induced neurological injury ( Yang et al, 2020 ). The reduction of neurotoxic astrocyte polarization through IL-10 effects has been proposed as a mechanism by which rTMS (5-10 Hz) is effective in nerve regeneration induced by stroke in rats ( Hong et al, 2020 ).…”

Repetitive Transcranial Magnetic Stimulation: A Potential Treatment for Obesity in Patients with Schizophrenia

“…Interestingly, ziprasidone (an antipsychotic medication approved for the treatment of schizophrenia and also considered to possess the least risk of weight gain [91]) also increased the translocation of Nrf2 from the cytoplasm to the nucleus [92], suggesting that this shared mechanism with rTMS could be responsible for its relatively low liability for weight gain in patients. Theoretically, rTMS could also potentially be anti-inflammatory via its effect on glial cells, since high frequency rTMS was shown to inhibit the proliferation of astrocytes and reduced microglial activation in rodent CNS [93,94]; reactive astrocytes and activated microglia can contribute to neuroinflammation and neuronal death [95] and have been implicated in the pathophysiology of schizophrenia [96].…”