Microelectrode recording was performed in the basal ganglia of 3 patients with generalized dystonia and 1 patient with hemiballismus secondary to a brainstem hemorrhage. Neuronal activity was recorded from the internal and external segments of the globus pallidus and assessed for mean discharge rate and pattern of spontaneous activity. The responses of neurons in the internal segment of the globus pallidus to passive and active movements were also evaluated. Mean discharge rates of neurons in both segments of the pallidum in patients with dystonia and the patient with hemiballismus were considerably lower than those reported for patients with idiopathic Parkinson's disease. In addition, the pattern of spontaneous neuronal activity was highly irregular, occurring in intermittent grouped discharges separated by periods of pauses. Although receptive fields in the dystonia patients were widened and less specific than those reported in normal monkeys, neuronal responses to movement were uncommon in the hemiballismus patient. Before surgery, patients with dystonia experienced abnormal posturing and involuntary movements. Coactivation of agonist–antagonist muscle groups was observed both at rest and during the performance of simple movements. After pallidotomy there was a significant reduction in the involuntary movement associated with these disorders and a more normal pattern of electromyographic activity during rest and movement. Given the improvement in dystonic and hemiballistic movements in these patients after ablation of the sensorimotor portion of the internal segment of the globus pallidus, we suggest that pallidotomy can be an effective treatment for patients with dystonia and also for patients with medically intractable hemiballismus. Based on the finding of decreased neuronal discharge rates in pallidal neurons, we propose that physiologically dystonia most closely resembles a hyperkinetic movement disorder. A model for dystonia is proposed that incorporates the observed changes in the rate and pattern of neuronal activity in the pallidum with data from neuroimaging with positron emission tomography and 2‐deoxyglucose studies. Ann Neurol 1999;46:22–35

Intrinsic, striatal tyrosine hydroxylase-immunoreactive (TH-i) cells have received little consideration. In this study we have characterized these neurons and their regulatory response to nigrostriatal dopaminergic deafferentation. TH-i cells were observed in the striatum of both control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys; TH-i cell counts, however, were 3.5-fold higher in the striatum of MPTPlesioned monkeys. To establish the dopaminergic nature of the TH-i cells, sections were double-labeled with antibodies to dopamine transporter (DAT). Immunofluorescence studies demonstrated that nearly all TH-i cells were double-labeled with DAT, suggesting that they contain the machinery to be functional dopaminergic neurons. Two types of TH-i cells were identified in the striatum: small, aspiny, bipolar cells with varicose dendrites and larger spiny, multipolar cells. The aspiny cells, which were more prevalent, corresponded morphologically to the GABAergic interneurons of the striatum. Doublelabel immunofluorescence studies using antibodies to TH and glutamate decarboxylase (GAD 67 ), the synthetic enzyme for GABA, showed that 99% of the TH-i cells were GAD 67 -positive. Very few (Ͻ1%) of the TH-i cells, however, were immunoreactive for the calcium-binding proteins calbindin and parvalbumin. In summary, these results demonstrate that the dopaminergic cell population of the striatum responds to dopamine denervation by increasing in number, apparently to compensate for loss of extrinsic dopaminergic innervation. Moreover, this population of cells corresponds largely with the intrinsic GABAergic cells of the striatum. This study also suggests that the adult primate striatum does retain some intrinsic capacity to compensate for dopaminergic cell loss.

Thirty-six patients with Parkinson's disease (PD) were randomized to either medical therapy (N ‫؍‬ 18) or unilateral GPi pallidotomy (N ‫؍‬ 18). The primary outcome variable was the change in total Unified Parkinson's Disease Rating Scale (UPDRS) score at 6 months. Secondary outcome variables included subscores and individual parkinsonian symptoms as determined from the UPDRS. At the six month follow-up, patients receiving pallidotomy had a statistically significant reduction (32% decrease) in the total UPDRS score compared to those randomized to medical therapy (5% increase). Following surgery, patients' showed improvement in all the cardinal motor signs of PD including tremor, rigidity, bradykinesia, gait and balance. Drug-induced dyskinesias were also markedly improved. Although the greatest improvement occurred on the side contralateral to the lesion, significant ipsilateral improvement was also observed for bradykinesia, rigidity and drug-induced dyskinesias. A total of twenty patients have been followed for 2 years to assess the effect of time on clinical outcome. These patients have shown sustained improvement in the total UPDRS ( p < 0.0001), "off" motor ( p < 0.0001) and complications of therapy subscores ( p < 0.0001). Sustained improvement was also seen for tremor, rigidity, bradykinesia, percent on time and drug-induced dyskinesias. Neurol 2003;53:558 -569 Over the past decade, there has been a marked resurgence of interest in surgery for Parkinson's disease (PD). Several factors have contributed to this: (1) the need for better therapies to treat the continued worsening of parkinsonian motor symptomatology and the development of drug-induced dyskinesias and motor fluctuations, (2) advances in our understanding of the physiological basis of parkinsonism and the rationale for surgery, 1,2,4 and (3) the report by Laitinen and colleagues of improvement in parkinsonian motor signs after pallidotomy. 3 Although there are now numerous reports on the benefits of pallidotomy for PD, 5-15 there has been only one randomized clinical trial comparing the effects of pallidotomy to best medical therapy. 16 In some of the previous studies, nontremulous 7 or predominately asymmetric 6 patients were selected, whereas in others nonstandardized methods of clinical evaluation were used. 10,12,13 Therefore, it is difficult to compare the results of pallidotomy across studies and to assess the effect of pallidotomy for patients regardless of symptom profile. AnnWe present here the results of a randomized, prospective clinical trial comparing the effectiveness of pallidotomy to best medical management in patients followed up for 6 months. In addition, we present data for the first 20 patients who have been followed up for 2 years. Patients and Methods Patient Recruitment and AssessmentPatients were recruited from the Movement Disorders Center at Emory and Grady Memorial Hospital Clinics. To limit patient attrition, we limited the geographical location for patient recruitment to a 500-mile radius from the City of Atlanta...