Deep Brain Stimulation of the Interposed Nucleus Reverses Motor Deficits and Stimulates Production of Anti-inflammatory Cytokines in Ataxia Mice

Cerebellum is one of the major targets of autoimmunity and cerebellar damage that leads to ataxia characterized by the lossof fne motor coordination and balance, with no treatment available. Deep brain stimulation (DBS) could be a promisingtreatment for ataxia but has not been extensively investigated. Here, our study aims to investigate the use of interposednucleus of deep cerebellar nuclei (IN-DCN) for ataxia. We frst characterized ataxia-related motor symptom of a Purkinjecell (PC)-specifc LIM homeobox (Lhx)1 and Lhx5 conditional double knockout mice by motor coordination tests, andspontaneous electromyogram (EMG) recording. To validate IN-DCN as a target for DBS, in vivo local feld potential (LFP)multielectrode array recording of IN-DCN revealed abnormal LFP amplitude surges in PCs. By synchronizing the EMGand IN-DCN recordings (neurospike and LFP) with high-speed video recordings, ataxia mice showed poorly coordinatedmovements associated with low EMG amplitude and aberrant IN-DCN neural fring. To optimize IN-DCN-DBS for ataxia,we tested DBS parameters from low (30 Hz) to high stimulation frequency (130 or 150 Hz), and systematically varied pulsewidth values (60 or 80 µs) to maximize motor symptom control in ataxia mice. The optimal IN-DCN-DBS parameter reversedmotor defcits in ataxia mice as detected by animal behavioral tests and EMG recording. Mechanistically, cytokine arrayanalysis revealed that anti-infammatory cytokines such as interleukin (IL)-13 and IL-4 were upregulated after IN-DCNDBS, which play key roles in neural excitability. As such, we show that IN-DCN-DBS is a promising treatment for ataxiaand possibly other movement disorders alike. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022