Low Intensity Transcranial Magnetic Stimulation (LI-rTMS) effects on pathological cerebellar development

Overview & Synopsis

Neurodevelopmental disorders (NDDs) are complex conditions with poorly understood causes, leaving no curative treatments, especially as they have early-onset. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation method, shows promise in correcting neurological disorders. While high-intensity rTMS is used clinically, low-intensity stimulation (LI-rTMS) is effective in repairing neuronal networks and restoring behavior, making it potentially suitable for developing systems, that are particularly sensitive to external stimuli. Before clinical application, its safety must be ensured, verifying that it does not disrupt normally functioning networks. The cause and symptomatology of NDDs has been linked to the cerebellum, which has a prolonged development that extends after birth. Thus, we chose to study the RORα haploinsufficient mouse as RORα is involved in key processes impaired in NDDs including cerebellar development, circadian clock regulation and inflammation. We analyzed cerebellar molecular, cellular and behavioral development between 2 and 30 days postnatal (P2-P30). We evaluated the effects of LI-rTMS with two patterns, continuous and intermittent theta burst (cTBS and iTBS) delivered between P2 and P15 in RORα+/- as well as in RORα+/+ (wild type, WT) pups to assess the effects of stimulation in a model of physiological and pathological development. We found that RORα+/- shared cerebellar developmental abnormalities with other NDD models, including Purkinje cell loss, which persisted at P30, and social deficits in young and juvenile stages. As for LI-rTMS, cTBS and iTBS showed opposing results: first in WT, we saw that cTBS might impair correct development while iTBS did not induce dramatic changes. These effects were seen locally in the cerebellum but also at distance in the prefrontal cortex (PFC) and maintained even at P30. Second, in RORα+/- mice, we saw that iTBS was able to partly rescue cellular and behavioral deficits, while cTBS did not, even exacerbating some impairments. Overall, these findings suggest that RORα+/- is a promising target for exploring cerebellar involvement in NDDs, and highlight the importance of the rTMS protocol, particularly in immature neural systems, showing beneficial effects with iTBS that make it a promising avenue for NDD treatment.