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 loss of fne motor coordination and balance, with no treatment available. Deep brain stimulation (DBS) could be a promising treatment for ataxia but has not been extensively investigated. Here, our study aims to investigate the use of interposed nucleus of deep cerebellar nuclei (IN-DCN) for ataxia. We frst characterized ataxia-related motor symptom of a Purkinje cell (PC)-specifc LIM homeobox (Lhx)1 and Lhx5 conditional double knockout mice by motor coordination tests, and spontaneous 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 EMG and IN-DCN recordings (neurospike and LFP) with high-speed video recordings, ataxia mice showed poorly coordinated movements 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 pulse width values (60 or 80 µs) to maximize motor symptom control in ataxia mice. The optimal IN-DCN-DBS parameter reversed motor defcits in ataxia mice as detected by animal behavioral tests and EMG recording. Mechanistically, cytokine array analysis 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 ataxia and possibly other movement disorders alike.