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

Gajendra Kumar, Pallavi Asthana, Wing Ho Yung, Kin Ming Kwan, Chung Tin, Chi Him Eddie Ma*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

5 Citations (Scopus)

Abstract

Cerebellum is one of the major targets of autoimmunity and cerebellar damage that leads to ataxia characterized by the loss of fine 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 first characterized ataxia-related motor symptom of a Purkinje cell (PC)-specific 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 field 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 firing. 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 deficits in ataxia mice as detected by animal behavioral tests and EMG recording. Mechanistically, cytokine array analysis revealed that anti-inflammatory cytokines such as interleukin (IL)-13 and IL-4 were upregulated after IN-DCN-DBS, 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.

Original languageEnglish
Pages (from-to)4578-4592
Number of pages15
JournalMolecular Neurobiology
Volume59
Issue number7
Early online date17 May 2022
DOIs
Publication statusPublished - Jul 2022

Scopus Subject Areas

  • Neurology
  • Cellular and Molecular Neuroscience

User-Defined Keywords

  • Ataxia
  • Cytokines
  • Deep brain stimulation
  • Deep cerebellar nuclei
  • Interposed nucleus
  • Motor coordination

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