A dopaminergic defi ciency in patients with Parkinson's disease (PD) causes abnormalities of movement, behaviour, learning, and emotions. The main motor features (ie, tremor, rigidity, and akinesia) are associated with a defi ciency of dopamine in the posterior putamen and the motor circuit. Hypokinesia and bradykinesia might have a dual anatomo-functional basis: hypokinesia mediated by brainstem mechanisms and bradykinesia by cortical mechanisms. The classic pathophysiological model for PD (ie, hyperactivity in the globus pallidus pars interna and substantia nigra pars reticulata) does not explain rigidity and tremor, which might be caused by changes in primary motor cortex activity. Executive functions (ie, planning and problem solving) are also impaired in early PD, but are usually not clinically noticed. These impairments are associated with dopamine defi ciency in the caudate nucleus and with dysfunction of the associative and other non-motor circuits. Apathy, anxiety, and depression are the main psychiatric manifestations in untreated PD, which might be caused by ventral striatum dopaminergic defi cit and depletion of serotonin and norepinephrine. In this Review we discuss the motor, cognitive, and psychiatric manifestations associated with the dopaminergic defi ciency in the early phase of the parkinsonian state and the diff erent circuits implicated, and we propose distinct mechanisms to explain the wide clinical range of PD symptoms at the time of diagnosis.

Recent imaging studies in healthy controls with a conditional stop signal reaction time (RT) task have implicated the subthalamic nucleus (STN) in response inhibition and the pre-supplementary motor area (pre-SMA) in conflict resolution. Parkinson's disease (PD) is characterized by striatal dopamine deficiency and overactivity of the STN and underactivation of the pre-SMA during movement. We used the conditional stop signal RT task to investigate whether PD produced similar or dissociable effects on response initiation, response inhibition and response initiation under conflict. In addition, we also examined inhibition of prepotent responses on three cognitive tasks: the Stroop, random number generation and Hayling sentence completion. PD patients were impaired on the conditional stop signal reaction time task, with response initiation both in situations with or without conflict and response inhibition all being significantly delayed, and had significantly greater difficulty in suppressing prepotent or habitual responses on the Stroop, Hayling and random number generation tasks relative to controls. These results demonstrate the existence of a generalized inhibitory deficit in PD, which suggest that PD is a disorder of inhibition as well as activation and that in situations of conflict, executive control over responses is compromised.

We conducted an open label pilot study of the effect of bilateral subthalamotomy in 18 patients with advanced Parkinson's disease. In seven patients, the first subthalamotomy pre-dated the second by 12-24 months ('staged surgery'). Subsequently, a second group of 11 patients received bilateral subthalamotomy on the same day ('simultaneous surgery'). Patients were assessed according to the CAPIT (Core Assessment Program for Intracerebral Transplantation) protocol, a battery of timed motor tests and neuropsychological tests. Evaluations were performed in the 'off' and 'on' drug states before surgery and at 1 and 6 months and every year thereafter for a minimum of 3 years after bilateral subthalamotomy. Compared with baseline, bilateral subthalamotomy induced a significant (P < 0.001) reduction in the 'off' (49.5%) and 'on' (35.5%) Unified Parkinson's Disease Rating Scale (UPDRS) motor scores at the last assessment. A blind rating of videotape motor exams in the 'off' and 'on' medication states preoperatively and at 2 years postoperatively also revealed a significant improvement. All of the cardinal features of Parkinson's disease as well as activities of daily living (ADL) scores significantly improved (P < 0.01). Levodopa-induced dyskinesias were reduced by 50% (P < 0.01), and the mean daily levodopa dose was reduced by 47% at the time of the last evaluation compared with baseline (P < 0.0001). Dyskinesias occurred intraoperatively or in the immediate postoperative hours in 13 patients, but were generally mild and short lasting. Three patients developed severe generalized chorea that gradually resolved within the next 3-6 months. Three patients experienced severe and persistent postoperative dysarthria. In two, this coincided with the patients exhibiting large bilateral lesions also suffering from severe dyskinesias. No patient exhibited permanent cognitive impairment. The motor benefit has persisted for a follow-up of 3-6 years. This study indicates that bilateral subthalamotomy may induce a significant and long-lasting improvement of advanced Parkinson's disease, but the clinical outcome was variable. This variability may depend in large part on the precise location and volume of the lesions. Further refinement of the surgical procedure is mandatory.

We report our experience of unilateral subthalamotomy in patients with Parkinson's disease (PD). Eleven patients were included in a pilot, open‐labeled study to assess the effect of unilateral lesion of the subthalamic nucleus (STN) with a minimum of 12 months of follow‐up. The guidelines of CAPIT (Core Assessment Program for Intracerebral Transplantation) were followed for recruitment into the study and follow‐up assessment. Levodopa equivalents daily intake (mean 967 mg) were unchanged during the first 12 months in all but one patient who stopped medication. The sensorimotor region of the STN was defined by semimicrorecording and stimulation and a thermolytic lesion was placed accordingly. There was a significant reduction in both UPDRS parts II and III in the “off” state at 1‐, 6‐, and 12‐month follow‐up. This effect was maintained in four patients up to 24 months. The dyskinesia score did not change postoperatively. Lesion‐induced dyskinesias were not a management problem except in one patient who developed a large infarction several days postsurgery. This initial study indicates that a lesion of the STN is not generally associated with hemiballismus in PD. Subthalamotomy may induce considerable motor benefit and could become another surgical option under specific circumstances. Mov. Disord. 16:72–78, 2001. © 2001 Movement Disorder Society.

Background: Stereotactic thermocoagulative lesions of the subthalamic nucleus (STN) have been shown to induce significant motor improvement in patients with Parkinson's disease (PD). Patients and methods: 89 patients with PD were treated with unilateral subthalamotomy. 68 patients were available for evaluations after 12 months, 36 at 24 months and 25 at 36 months.

The subthalamic nucleus (STN) is hypothesized to play a central role in the rapid stopping of movement in reaction to a stop signal. Single-unit recording evidence for such a role is sparse, however, and it remains uncertain how that role relates to the disparate functions described for anatomic subdivisions of the STN. Here we address that gap in knowledge using non-human primates and a task that distinguishes reactive and proactive action inhibition, switching and skeletomotor functions. We found that specific subsets of STN neurons have activity consistent with causal roles in reactive action stopping or switching. Importantly, these neurons were strictly segregated to a ventromedial region of STN. Neurons in other subdivisions encoded task dimensions such as movement per se and proactive control. We propose that the involvement of STN in reactive control is restricted to its ventromedial portion, further implicating this STN subdivision in impulse control disorders.

No abstract

Summary:The role of the subthalamic nucleus (STN) in the origin of parkinsonian tremor is discussed. Previous studies in monkeys madc parkinsonian by MPTP ( I -methyl-4-phenyl-1.~.3.6-trtrahydropyridine) administration suggested a direct participation of the STN in the pathophysiology of tremor. We recorded tremor-related activity in the STN in 12 patients with Parkinson's disease (PD) and found that microstimulation of the sensorimotor region of the nucleus, where these neurons are present. stopped the tremor with a very short latency. Longterm treatment by means of bilateral deep-brain stimulation (DBS) in the same I ? patients led to a significant reduction of tremor a s well as other cardinal features of PD. This effect wasThe origin of tremor in Parkinson's disease (PD) is still a matter of debate. Until recently, the ventralis intermedialis nucleus (Vim) of the thalamus was the only structure closely associated with tremor in PD.' The development of the I -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in monkeys allowed us to ~.carry out new physiologic observations in animals showing resting and postural tremors (see Bergmann et al. in this supplement, pp. 29-34). These studies indicate that fairly selective dopamine deficiency, as induced by longterm MPTP administration, may provoke tremor in monkeys that share the characteristics present in PD. ' In such animals, it was shown that tremor in the limbs is associated with oscillatory neuronal discharges in the external globus pallidum (GPe), internal globus pallidum (GPi), and subthalamic nucleus (STN) rhythmically firing in phase with the tremor in the limbs3 Neurons with oscillatory discharges in the STN and GPi were found in - 111Address correspondence and reprint requests to J. A. Obeso at Neurology and Neurosurgery. HOSPITEN Rambla 1 15. Tenerife. Spain. blindly assessed at 3 months after implantation. In another group of seven patients, a unilateral lesion of the STN was performed. Both postural and resting tremor were significantly improved on the limbs contralateral to the lesion side. In three patients, tremor disappeared completely after I2 months of follow up. The electrophysiologic data and therapeutic effect of inactivating the STN strongly indicated that this structure is directly involved in the origin of parkinsonian tremor. normal monkeys, but their presence increased dramatically (-90%) in parkinsonian animals.3 The degree of synchrony between the electromyographic (EMG) activity underlying the tremor and the neuronal discharges was high, but the analysis could not determine whether the tremor-related neuronal activity in the STN was induced (peripherally driven) by the tremor or causally provoking it. Tremor cells were found mainly in the dorsolateral two thirds of the STN, but precise data about their somatotopic organization was not provided. Lesion of the STN reduced4 or even abolished"' the tremor in MPTP monkeys, although there was no effect on the 4-to 8-Hz oscillatory neuronal activity recorded in the GPL4 In our ...