Motor Thalamic Deep Brain Stimulation Alters Cortical Activity and Shows Therapeutic Utility for Treatment of Parkinson's Disease Symptoms in a Rat Model.

Deep brain stimulation (DBS) in Parkinson's disease (PD) alters neuronal function and network communication to improve motor symptoms. The subthalamic nucleus (STN) is the most common DBS target for PD, but some patients experience adverse effects on memory and cognition. Previously, we reported that DBS of the ventral anterior (VA) and ventrolateral (VL) nuclei of the thalamus and at the interface between the two (VA|VL), collectively VA-VL, relieved forelimb akinesia in the hemiparkinsonian 6-hydroxydopamine (6-OHDA) rat model. To determine the mechanism(s) underlying VA-VL DBS efficacy, we examined how motor cortical neurons respond to VA-VL DBS using single-unit recording electrodes in anesthetized 6-OHDA lesioned rats. VA-VL DBS increased spike frequencies of primary (M1) and secondary (M2) motor cortical pyramidal cells and M2, but not M1, interneurons. To explore the translational merits of VA-VL DBS, we compared the therapeutic window, rate of stimulation-induced dyskinesia onset, and effects on memory between VA-VL and STN DBS. VA-VL and STN DBS had comparable therapeutic windows, induced dyskinesia at similar rates in hemiparkinsonian rats, and adversely affected performance in the novel object recognition (NOR) test in cognitively normal and mildly impaired sham animals. Interestingly, a subset of sham rats with VA-VL implants showed severe cognitive deficits with DBS off. VA-VL DBS improved NOR test performance in these animals. We conclude that VA-VL DBS may exert its therapeutic effects by increasing pyramidal cell activity in the motor cortex and interneuron activity in the M2, with plausible potential to improve memory in PD.

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

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 ±â€¯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.