Deep brain stimulation of the ventroanterior and ventrolateral thalamus improves motor function in a rat model of Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disease with affected individuals exhibiting motor symptoms of bradykinesia, muscle rigidity, tremor, postural instability and gait dysfunction. The current gold standard treatment is pharmacotherapy with levodopa, but long-term use is associated with motor response fluctuations and can cause abnormal movements called dyskinesias. An alternative treatment option is deep brain stimulation (DBS) with the two FDA-approved brain targets for PD situated in the basal ganglia; specifically, in the subthalamic nucleus (STN) and globus pallidus pars interna (GPi). Both improve quality of life and motor scores by ~50–70% in well-selected patients but can also elicit adverse effects on cognition and other non-motor symptoms. Therefore, identifying a novel DBS target that is efficacious for patients not optimally responsive to current DBS targets with fewer side-effects has clear clinical merit. Here, we investigate whether the ventroanterior (VA) and ventrolateral (VL) motor nuclei of the thalamus can serve as novel and effective DBS targets for PD. In the limb-use asymmetry test (LAT), hemiparkinsonian rats showcased left forelimb akinesia and touched only 6.5 ± 1.3% with that paw. However, these animals touched equally with both forepaws with DBS at 10 Hz, 100 μsec pulse width and 100 uA cathodic stimulation in the VA (n = 7), VL (n = 8) or at the interface between the two thalamic nuclei which we refer to as the VA|VL (n = 12). With whole-cell patch-clamp recordings, we noted that VA|VL stimulation in vitro increased the number of induced action potentials in proximal neurons in both areas albeit VL neurons transitioned from bursting to non-bursting action potentials (APs) with large excitatory postsynaptic potentials time-locked to stimulation. In contrast, VA neurons were excited with VA|VL electrical stimulation but with little change in spiking phenotype. Overall, our findings show that DBS in the VA, VL or VA|VL improved motor function in a rat model of PD; plausibly via increased excitation of residing neurons.