Deep cerebellar stimulation to treat degenerative cerebellar ataxias

University Of Utah, Salt Lake City UT

Investigators

Linked publications & trials

Abstract

! Degenerative cerebellar ataxias affect as many as 1 in 5,000 people worldwide, commonly leading to severe incoordination of gait, tremor, and falls. Current treatment options are not widely effective, and most patients are unable to experience substantial symptom relief. Additionally, the underlying electrophysiological changes that drive symptoms are not fully understood. We aim to develop a novel therapeutic strategy in the context of a genetic rat model of degenerative cerebellar ataxia and use it as a research tool to clarify the network changes that directly encode motor symptoms. Although etiologies vary, ranging from dozens of hereditary forms to sporadic ataxias, most, if not all, feature widespread, progressive Purkinje cell loss, resulting in modified inputs relevant to motor control in the dentate nucleus. As the dorsal dentate nucleus represents the major motor cerebellar output, we propose to develop a deep brain stimulation-like therapeutic strategy aimed at re-modulating dentate nucleus activity to reduce ataxic symptoms. We will carry out a pre- clinical test of deep cerebellar stimulation using the Wistar Furth shaker rat, which features progressive Purkinje cell loss, cerebellar tremor, profound incoordination of gait, and frequent falls. We have developed novel methodologies and software to automate the direct quantification of tremor, incoordination of gait, and fall rates in rats, and we have used them to rigorously quantify the progression of motor symptoms in our model. We have additionally collected preliminary data to strongly support the efficacy of deep cerebellar stimulation in reducing each of tremor, incoordination, and frequency of falls. Further, the ability to quickly and effectively modulate motor symptom severity will be a highly useful tool for electrophysiological study. Thus, we will carry out two specific aims. First, we will optimize deep cerebellar stimulation of the dorsal dentate nucleus to treat tremor, incoordination, and falls in the Wistar Furth shaker rat model of degenerative cerebellar ataxia. Second, we will quantify the network properties that directly underlie motor symptoms in the shaker rat. Given that the loss of Purkinje cells disinhibits the dentate nucleus, one might expect their loss to result in increased motor drive, given the excitatory nature of the dentatothalmocortical pathway. However, involuntary motor symptoms are not typically observed in ataxias, indicating that the study of patterning within dentate signaling is warranted. Indeed, we will expand on recent work that showed that irregularity in cerebellar signaling is linked, and that deep cerebellar oscillations at frequencies specific to tremors cohere strongly with motor acceleration during tremor. Using deep cerebellar stimulation as a research tool, we will test whether irregularity and increased oscillatory power not only covary with motor symptoms, but directly encode them, using electrical stimulation to encode electrophysiological signals in wild type rats, testing the hypothesis that modifying patterning with high specificity can directly lead to ataxic symptoms.