The subthalamic nucleus (STN) has been regarded as an important modulator of basal ganglia output. It receives its major afferents from the cerebral cortex, thalamus, globus pallidus externus and brainstem, and projects mainly to both segments of the globus pallidus, substantia nigra, striatum and brainstem. The STN is essentially composed of projection glutamatergic neurons. Lesions of the STN induce choreiform abnormal movements and ballism on the contralateral side of the body. In animal models of Parkinson’s disease this nucleus may be dysfunctional and neurons may fire in oscillatory patterns that can be closely related to tremor. Both STN lesions and high frequency stimulation ameliorate the major motor symptoms of parkinsonism in humans and animal models of Parkinson’s disease and reverse certain electrophysiological and metabolic consequences of dopamine depletion. These new findings have led to a renewed interest in the STN. The aim of the present article is to review briefly the major anatomical, pharmacological and physiological aspects of the STN, as well as its involvement in the pathophysiology and treatment of Parkinson’s disease.

Over the last decades, extensive basic and clinical knowledge has been acquired on the use of subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson’s disease (PD). It is now clear that mechanisms involved in the effects of this therapy are far more complex than previously anticipated. At frequencies commonly used in clinical practice, neural elements may be excited or inhibited and novel dynamic states of equilibrium are reached. Electrode contacts used for chronic DBS in PD are placed near the dorsal border of the nucleus, a highly cellular region. DBS may thus exert its effects by modulating these cells, hyperdirect projections from motor cortical areas, afferent and efferent fibers to the motor STN. Advancements in neuroimaging techniques may allow us to identify these structures optimizing surgical targeting. In this review, we provide an update on mechanisms and the neural elements modulated by STN DBS.

QUESTION 1: Is bilateral subthalamic nucleus deep brain stimulation (STN DBS) more, less, or as effective as bilateral globus pallidus internus deep brain stimulation (GPi DBS) in treating motor symptoms of Parkinson's disease, as measured by improvements in Unified Parkinson's Disease Rating Scale, part III (UPDRS-III) scores? RECOMMENDATION: Given that bilateral STN DBS is at least as effective as bilateral GPi DBS in treating motor symptoms of Parkinson's disease (as measured by improvements in UPDRS-III scores), consideration can be given to the selection of either target in patients undergoing surgery to treat motor symptoms. (Level I) QUESTION 2: Is bilateral STN DBS more, less, or as effective as bilateral GPi DBS in allowing reduction of dopaminergic medication in Parkinson's disease? RECOMMENDATION: When the main goal of surgery is reduction of dopaminergic medications in a patient with Parkinson's disease, then bilateral STN DBS should be performed instead of GPi DBS. (Level I) QUESTION 3: Is bilateral STN DBS more, less, or as effective as bilateral GPi DBS in treating dyskinesias associated with Parkinson's disease? RECOMMENDATION: There is insufficient evidence to make a generalizable recommendation regarding the target selection for reduction of dyskinesias. However, when the reduction of medication is not anticipated and there is a goal to reduce the severity of “on” medication dyskinesias, the GPi should be targeted. (Level I) QUESTION 4: Is bilateral STN DBS more, less, or as effective as bilateral GPi DBS in improving quality of life measures in Parkinson's disease? RECOMMENDATION: When considering improvements in quality of life in a patient undergoing DBS for Parkinson's disease, there is no basis to recommend bilateral DBS in 1 target over the other. (Level I) QUESTION 5: Is bilateral STN DBS associated with greater, lesser, or a similar impact on neurocognitive function than bilateral GPi DBS in Parkinson disease? RECOMMENDATION: If there is significant concern about cognitive decline, particularly in regards to processing speed and working memory in a patient undergoing DBS, then the clinician should consider using GPi DBS rather than STN DBS, while taking into consideration other goals of surgery. (Level I) QUESTION 6: Is bilateral STN DBS associated with a higher, lower, or similar risk of mood disturbance than GPi DBS in Parkinson's disease? RECOMMENDATION: If there is significant concern about the risk of depression in a patient undergoing DBS, then the clinician should consider using pallidal rather than STN stimulation, while taking into consideration other goals of surgery. (Level I) QUESTION 7: Is bilateral STN DBS associated with a higher, lower, or similar risk of adverse events compared to GPi DBS in Parkinson's disease? RECOMMENDATION: There is insufficient evidence to recommend bilateral DBS in 1 target over the other in order to minimize the risk of surgical adverse events. The full guideline can be found at: https://www.cns.org/guidelines/deep-brain-stimulation-parkinsons-disease.

Motor cortex stimulation via surgically implanted electrodes has been used as an off-label treatment for chronic neuropathic pain, but its efficacy has not been fully established. We aimed to objectively study the efficacy of motor cortex stimulation and characterize potential predictors of response. In this randomized, double-blind, sham-controlled, single centre trial, we recruited 18 patients with chronic neuropathic pain who did not adequately respond to conventional treatment and had a numerical pain rating scale (NRS) score ≥6. Patients were initially assigned to receive 3 months of active (‘on’) or sham (‘off’) stimulation in a double-blind cross-over phase. This was followed by a 3-month single-blind phase, and 6 months of open-label follow-up. A meaningful response in our trial was defined as a ≥30% or 2-point reduction in NRS scores during active stimulation. Using Bayesian statistics, we found a 41.4% probability of response towards on versus off motor cortex stimulation. The probability of improvement during active stimulation (double-blind, single-blind and open-label phases) compared to baseline was 47.2–68.5%. Thirty nine per cent of the patients were considered long-term responders, 71.4% of whom had facial pain, phantom limb pain or complex regional pain syndrome. In contrast, 72.7% of non-responders had either post-stroke pain or pain associated with brachial plexus avulsion. Thirty-nine per cent of patients had a substantial postoperative analgesic effect after electrode insertion in the absence of stimulation. Individuals with diagnoses associated with a good postoperative outcome or those who developed an insertional effect had a near 100% probability of response to motor cortex stimulation. In summary, we found that ∼40% of patients responded to motor cortex stimulation, particularly those who developed an insertional effect or had specific clinical conditions that seemed to predict an appropriate postoperative response.