Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

In Parkinson's disease (PD), the oscillatory activity recorded from the basal ganglia shows dopamine-dependent changes. In the "off" parkinsonian motor state, there is prominent activity in the beta band (12-30 Hz) that is mostly attenuated after dopaminergic therapy ("on" medication state). The on state is also characterized by activity in the gamma (60 -80 Hz) and high-frequency (300 Hz) bands that is modulated by movement. We recorded local field potentials from a group of 15 PD patients (three females) treated with bilateral deep brain stimulation of the subthalamic nucleus, using a high sampling rate (2 kHz) and filters suitable to study high-frequency activity (0.3-1000 Hz). We observed high-frequency oscillations (HFOs) in both the off and on motor states. In the off state, the amplitude of the HFOs was coupled to the phase of the abnormal beta activity. The beta-coupled HFOs showed little or even negative movement-related changes in amplitude. Moreover, the degree of movement-related modulation of the HFOs correlated negatively with the rigidity/ bradykinesia scores. In the on motor state, the HFOs were liberated from this beta coupling, and they displayed marked movementrelated amplitude modulation. Cross-frequency interactions between the phase of slow activities and the amplitude of fast frequencies have been attributed an important role in information processing in cortical structures. Our findings suggest that nonlinear coupling between frequencies may not only be a physiological mechanism (as shown previously) but also that it may participate in the pathophysiology of parkinsonism.

Single-cell recording of the subthalamic nucleus (STN) was undertaken in 14 patients with Parkinson's disease submitted to surgery. Three hundred and fifty neurones were recorded and assessed for their response to passive and active movements. Thirty-two per cent were activated by passive and active movement of the limbs, oromandibular region and abdominal wall. All neurones with sensorimotor responses were in the dorsolateral region of the STN. Arm-related neurones were lateral (> or =14 mm plane) to leg-related neurones, which were found more medially (< or =12 mm). Representation of the oromandibular musculature was in the middle of the sensorimotor region (approximately 13 mm plane) and ventral to the arm and leg. Two hundred neurones were adequately isolated for 'off-line' analysis. The mean frequency of discharge was 33 +/- 17 Hz (13-117 Hz). Three types of neuronal discharges were distinguished: irregular (60.5%), tonic (24%) and oscillatory (15.5 %). They were statistically differentiated on the basis of their mean firing frequency and the coefficient of variation of the interspike interval. Neurones responding to movement were of the irregular or tonic type, and were found in the dorsolateral region of the STN. Neurones with oscillatory and low frequency activity did not respond to movement and were in the ventral one-third of the nucleus. Thirty-eight tremor-related neurones were recorded. The majority (84%) of these were sensitive to movement and were located in the dorsolateral region of the STN. Cross power analysis (n = 16) between the rhythmic neuronal activity and tremor in the limbs showed a peak frequency of 5 Hz (4-8 Hz). Neuronal activity of the substantia nigra pars reticulata was recorded 0.5-3 mm below the STN. Eighty neurones were recorded 'on-line' and 27 were isolated for 'off-line' analysis. A tonic pattern of discharge characterized by a mean firing rate of 71 +/- 28 Hz (35-122 Hz) with a mean coefficient of variation of the interspike interval of 0.85 +/- 0.29 ms was found. In only three neurones (11%) was there a response to sensorimotor stimulation. The findings of this study indicate that the somatotopic arrangement and electrophysiological features of the STN in Parkinson's disease patients are similar to those found in monkeys.

The basal ganglia (BG) are a highly organized network, where different parts are activated for specific functions and circumstances. The BG are involved in movement control, as well as associative learning, planning, working memory, and emotion. We concentrate on the "motor circuit" because it is the best understood anatomically and physiologically, and because Parkinson's disease is mainly thought to be a movement disorder. Normal function of the BG requires fine tuning of neuronal excitability within each nucleus to determine the exact degree of movement facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and postsynaptic mechanisms as well as interneuron activity, and secured by several recurrent or internal BG circuits. The motor circuit of the BG has two entry points, the striatum and the subthalamic nucleus (STN), and an output, the globus pallidus pars interna (GPi), which connects to the cortex via the motor thalamus. Neuronal afferents coding for a given movement or task project to the BG by two different systems: (1) Direct disynaptic projections to the GPi via the striatum and STN. (2) Indirect trisynaptic projections to the GPi via the globus pallidus pars externa (GPe). Corticostriatal afferents primarily act to inhibit medium spiny neurons in the "indirect circuit" and facilitate neurons in the "direct circuit." The GPe is in a pivotal position to regulate the motor output of the BG. Dopamine finely tunes striatal input as well as neuronal striatal activity, and modulates GPe, GPi, and STN activity. Dopaminergic depletion in Parkinson's disease disrupts the corticostriatal balance leading to increased activity the indirect circuit and reduced activity in the direct circuit. The precise chain of events leading to increased STN activity is not completely understood, but impaired dopaminergic regulation of the GPe, GPi, and STN may be involved. The parkinsonian state is characterized by disruption of the internal balance of the BG leading to hyperactivity in the two main entry points of the network (striatum and STN) and excessive inhibitory output from the GPi. Replacement therapy with standard levodopa creates a further imbalance, producing an abnormal pattern of neuronal discharge and synchronization of neuronal firing that sustain the "off" and "on with dyskinesia" states. The effect of levodopa is robust but short-lasting and converts the parkinsonian BG into a highly unstable system, where pharmacological and compensatory effects act in opposing directions. This creates a scenario that substantially departs from the normal physiological state of the BG.