Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for the motor symptoms of Parkinson’s disease (PD). The effects of DBS depend strongly on stimulation frequency: high frequencies (>90Hz) improve motor symptoms, while low frequencies (<50Hz) are either ineffective or exacerbate symptoms. The neuronal basis for these frequency-dependent effects of DBS is unclear. The effects of different frequencies of STN-DBS on behavior and single-unit neuronal activity in the basal ganglia were studied in the unilateral 6-hydroxydopamine lesioned rat model of PD. Only high frequency DBS reversed motor symptoms and the effectiveness of DBS depended strongly on stimulation frequency in a manner reminiscent of its clinical effects in persons with PD. Quantification of single-unit activity in the globus pallidus externa (GPe) and substantia nigra reticulata (SNr) revealed that high frequency DBS, but not low frequency DBS, reduced pathological low frequency oscillations (~9Hz) and entrained neurons to fire at the stimulation frequency. Similarly, the coherence between simultaneously recorded pairs of neurons within and across GPe and SNr shifted from the pathological low frequency band to the stimulation frequency during high frequency DBS, but not during low frequency DBS. The changes in firing patterns in basal ganglia neurons were not correlated with changes in firing rate. These results indicate that high frequency DBS is more effective than low frequency DBS, not as a result of changes in firing rate, but rather due to its ability to replace pathological low frequency network oscillations with a regularized pattern of neuronal firing.

Deep brain stimulation (DBS) and lesioning are two surgical techniques used in the treatment of advanced Parkinson’s disease (PD) in patients whose symptoms are not well controlled by drugs, or who experience dyskinesias as a side effect of medications. Although these treatments have been widely practiced, the mechanisms behind DBS and lesioning are still not well understood. The subthalamic nucleus (STN) and globus pallidus pars interna (GPi) are two common targets for both DBS and lesioning. Previous studies have indicated that DBS not only affects local cells within the target, but also passing axons within neighboring regions. Using a computational model of the basal ganglia-thalamic network, we studied the relative contributions of activation and silencing of local cells (LCs) and fibers of passage (FOPs) to changes in the accuracy of information transmission through the thalamus (thalamic fidelity), which is correlated with the effectiveness of DBS. Activation of both LCs and FOPs during STN and GPi-DBS were beneficial to the outcome of stimulation. During STN and GPi lesioning, effects of silencing LCs and FOPs were different between the two types of lesioning. For STN lesioning, silencing GPi FOPs mainly contributed to its effectiveness, while silencing only STN LCs did not improve thalamic fidelity. In contrast, silencing both GPi LCs and GPe FOPs during GPi lesioning contributed to improvements in thalamic fidelity. Thus, two distinct mechanisms produced comparable improvements in thalamic function: driving the output of the basal ganglia to produce tonic inhibition and silencing the output of the basal ganglia to produce tonic disinhibition. These results show the importance of considering effects of activating or silencing fibers passing close to the nucleus when deciding upon a target location for DBS or lesioning.

Brain stimulation is a promising therapy for several neurological disorders, including Parkinson’s disease. Stimulation parameters are selected empirically and are limited to the frequency and intensity of stimulation. We used the temporal pattern of stimulation as a novel parameter of deep brain stimulation to ameliorate symptoms in a parkinsonian animal model and in humans with Parkinson’s disease. We used model-based computational evolution to optimize the stimulation pattern. The optimized pattern produced symptom relief comparable to that from standard high-frequency stimulation (a constant rate of 130 or 185 Hz) and outperformed frequency-matched standard stimulation in the parkinsonian rat and in patients. Both optimized and standard stimulation suppressed abnormal oscillatory activity in the basal ganglia of rats and humans. The results illustrate the utility of model-based computational evolution to design temporal pattern of stimulation to increase the efficiency of brain stimulation in Parkinson’s disease, thereby requiring substantially less energy than traditional brain stimulation.

Individuals with tetraplegia lack independent mobility, making them highly dependent on others to move from one place to another. Here, we describe how two macaques were able to use a wireless integrated system to control a robotic platform, over which they were sitting, to achieve independent mobility using the neuronal activity in their motor cortices. The activity of populations of single neurons was recorded using multiple electrode arrays implanted in the arm region of primary motor cortex, and decoded to achieve brain control of the platform. We found that free-running brain control of the platform (which was not equipped with any machine intelligence) was fast and accurate, resembling the performance achieved using joystick control. The decoding algorithms can be trained in the absence of joystick movements, as would be required for use by tetraplegic individuals, demonstrating that the non-human primate model is a good pre-clinical model for developing such a cortically-controlled movement prosthetic. Interestingly, we found that the response properties of some neurons differed greatly depending on the mode of control (joystick or brain control), suggesting different roles for these neurons in encoding movement intention and movement execution. These results demonstrate that independent mobility can be achieved without first training on prescribed motor movements, opening the door for the implementation of this technology in persons with tetraplegia.