Investigating the effects of subthalamic nucleus stimulation on gait and pedunculopontine nucleus activity in a preclinical animal model of Parkinson’s disease

Abstract

Dopamine-replacement therapy and deep brain stimulation therapy can reliably manage several cardinal motor signs of Parkinson’s disease including tremor, rigidity, and bradykinesia. The efficacy of these treatments on gait and postural dysfunction, however, are often variable and wane over time. This doctoral dissertation advanced our understanding of parkinsonian gait dysfunction by (1) defining spatiotemporal progression of gait changes with increasing parkinsonian severity in the MPTP non-human primate model of Parkinson’s disease, (2) characterizing changes in gait parameters with targeted subthalamic deep brain stimulation, and (3) defining how targeted subthalamic deep brain stimulation differentially affects neuronal spike rate and pattern changes in the pedunculopontine nucleus, which is a key structure in the mesencephalic locomotor region. The major findings were that the MPTP non-human primate model displays progressive bradykinetic gait that align with severity of other cardinal motor signs; however, asymmetric and disordered gait patterns only appeared in the more advanced parkinsonian state. Deep brain stimulation of the subthalamic nucleus showed a spatial map in of improving and worsening bradykinetic gait, and this map aligned with a differential effect on pedunculopontine nucleus modulation. These results suggest that deep brain stimulation can impart therapeutic effects on gait symptoms, but the effects depend on how one modulates pathways involved in locomotion. Such findings will be useful for future efforts to optimize deep brain stimulation for individuals with Parkinson’s disease.