Deep cerebellar stimulation reduces ataxic motor symptoms in the shaker rat

Abstract

Objective: Degenerative cerebellar ataxias (DCAs) affect up to 1 in 5,000 people worldwide, leading to incoordination, tremor, and falls. Loss of Purkinje cells, nearly universal across DCAs, dysregulates the dentatothalamocortical network. To address the paucity of treatment strategies, we developed an electrical stimulation-based therapy for DCAs targeting the dorsal dentate nucleus. Methods: We tested this therapeutic strategy in the Wistar Furth shaker rat model of Purkinje cell loss resulting in tremor and ataxia. We implanted shaker rats with stimulating electrodes targeted to the dorsal dentate nucleus and tested a spectrum of frequencies ranging from 4 to 180 Hz. Results: Stimulation at 30 Hz most effectively reduced motor symptoms. Stimulation frequencies >100 Hz, commonly used for parkinsonism and essential tremor, worsened incoordination, and frequencies within the tremor physiologic range may worsen tremor. Interpretation: Low-frequency deep cerebellar stimulation may provide a novel strategy for treating motor symptoms of degenerative cerebellar ataxias.

Little Brain, Big Expectations

“…Regarding invasive stimulation, low-frequency DBS of the dentate nucleus has been applied in a rat model of neurogenerative ataxia [4]. A frequency of 30 Hz improved motor symptoms, such as ataxia and tremor, and high-frequency stimulation worsened incoordination.…”

“…On an organizational level, the fibers from the cerebellar nuclei directly regulate movement commands in the spinal cord and brainstem, increase motor signals in the cerebral cortex, and modulate signals for adaptive learning via connections to the inferior olive. Direct stimulus to the dentate nucleus via a double-cone coil TMS (which allows for the stimulation of deep structures) [8] and DBS could be more precise, resetting abnormal firing oscillations or enhancing cerebellar output activity, depending on the parameters [4].…”

“…If this is true, one must consider the possibility that direct dentate nucleus stimulation could have variable effects, according to which specific regions are recruited [5]. Evidence suggests that the hot spot of modulation is likely located in more dorsal parts of the dentate nucleus, the presumed motor domain [4]. The study of the volume of tissue activated through DBS contacts can represent a powerful research platform to study connectomics from distributed brain networks in the "human connectome" [2].…”

“…In this scenario, the connectivity power of the cerebellum has motivated the study of its modulation among many teams worldwide, and it has been so far explored in a range of well-conducted preclinical and clinical studies [4,5]. The appeal of the cerebellum for neuromodulation strategies is easy to understand: it is a fascinating structure that boasts more neurons than all of the other brain regions combined, and it is implicated in virtually all movement disorders known to date.…”

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2

“…Current clinical studies show that some ataxia signs can be partly improved pharmacologically by treatment with 4-aminopyridine, riluzole, valproic acid, and thyrotropinreleasing hormone, whereas lithium and deferiprone have a negative effect or its absence [122]. Low-frequency deep cerebellar stimulation has been suggested as a potential strategy for treating cerebellum-related motor symptoms, but no clinical studies on SCA patients have been carried out yet [123].…”