Experimental Origin of Subthalamic Stimulation
During the last decade, the subthalamic nucleus (STN) has become a target of choice for the surgical treatment of severe forms of PD. Its implication in the pathophysiology of the disease was originally determined from experimental data in animal models. Numerous experimental studies have demonstrated that the depletion of dopamine induces a disorganisation of neuronal activity in basal ganglia structures. In rodent (6-hydroxy-dopamine (6-OHDA)-lesioned rat) and non-human primate (monkeys rendered parkinsonian by systemic injections of 1-methyl-4-phenyl-^1,2,3,6-tetrahydro- pyridine (MPTP)) models of PD, abnormal activity of STN neurons has been reported. Increased firing rates and/or important changes in the firing pattern of STN neurons have also been shown. According to the generally accepted model of the functional organisation of basal ganglia,¹ these changes result in hyperactivity of the output structures of basal ganglia, the pars reticulata of the substantia nigra (SNr) and the internal part of globus pallidus (GPi). In this way, an increase in the tonic inhibitory influence exerted by these structures on the motor thalamic nuclei results in a deactivation of motor cortical areas.

At the beginning of the 1990s, the STN was identified as a potential target for neurosurgical therapy for PD. STN lesions in MPTP-treated monkeys induces an improvement in parkinsonian motor symptoms that accompanies the expression of abnormal movements.² Due to the fact that STN lesioning is irreversible, the author and his colleagues have proposed to replace this approach by electrical high-frequency stimulation (HFS). This research group has shown that HFS (100Hz frequency) of the STN alleviates parkinsonian motor symptoms in monkeys rendered parkinsonian by MPTP, without any evident side effects. Quantification of motor performance has shown that HFS of the STN induces a normalisation of both reaction and movement times as well as electro-myogram (EMG) activity of agonist/antagonist muscles.³ This beneficial effect is comparable with that obtained after the administration of L-dopa without motor fluctuations. Based on such experimental evidence, HFS of the STN has become the most promising therapy for the treatment of PD.

Clinical Effect of Subthalamic Stimulation
Since 1993, HFS of the STN has been successfully transferred to human patients and has been shown to alleviate all the major motor symptoms of PD while allowing a dramatic reduction in daily levodopa (L-dopa) requirements and dyskinesias.⁴ Bilateral STN HFS (130Hz, 0.06 millisecond (ms) pulse width at 2 to 4 volts) improves parkinsonism considerably more than unilateral STN deep brain stimulation (DBS).⁵ Krack et al.⁶ suggested that parkinsonian patients who do not respond well to L-dopa treatment or in whom a post-synaptic dopaminergic lesion are not good candidates for STN surgery. The Unified Parkinson’s Disease Rating Scale (UPDRS) motor examination scoring after STN HFS is decreased by approximately 60%. Motor fluctuations also tend to disappear and offperiod dystonia is immediately alleviated. Moreover, treated patients no longer need help in their daily activities. Bilateral STN stimulation improves most axial features that responded to Ldopa before surgery.⁷

Recent work has shown that the efficacy of STN HFS in reducing motor symptoms and L-dopainduced dyskinesia in patients with severe PD is largely maintained for five years after surgery.⁸ Daily living activity (UPDRS II) was dramatically improved by STN HFS. Parkinsonian motor disability (UPDRS III) was also improved. L-dopa daily doses were reduced by 58%. The score for speech only improved during the first year and then progressively worsened, returning to baseline levels at five years after surgery. However, with time, there is deterioration in akinesia, axial symptoms, and cognitive problems associated with the progression of the underlying disease. Stimulation of the STN also seems most useful for relatively young patients who have motor complications from Ldopa treatment and who are independent in terms of daily living activities in their best on-medication state. Examination of the long-term effects of STN HFS has shown that despite motor and cognitive decline, the marked improvement in motor performance and daily quality of life was maintained five years after surgery.