Parkinson Disease: Lozano AM

Lozano AM. · No affiliation provided · Neurosurg Focus. · Pubmed #18341410 No free full text.

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Mayberg HS, Lozano AM. · No affiliation provided · Neurology. · Pubmed #12427872 No free full text.

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Lozano AM, Snyder BJ. · Division of Neurosurgery, Toronto Western Hospital, University of Toronto, UHN, 399 Bathurst Street WW 4-447, Toronto, ON, M5T2S8, Canada. · J Neurol. · Pubmed #18821083 No free full text.

Abstract: The cardinal motor manifestation of Parkinson's disease (PD) is being treated with greater and greater efficacy with both newer medications as well as both subthalamic nucleus (STN) and globus pallidus internus (GPI) deep brain stimulation (DBS). The burden of disease is shifting towards the non-dopaminergic disease manifestations including gait and posture. Based on evidence in the literature and in animal models, recent trials are underway to examine the effects of pedunculopontine nucleus DBS on the treatment of parkinsonian gait disorder. We review the rationale behind this treatment and the status of the current trials.

Hodaie M, Neimat JS, Lozano AM. · Division of Neurosurgery, Toronto Western Hospital, University Health Network and University of Toronto, Toronto, Canada. · Neurosurgery. · Pubmed #17228250 No free full text.

Abstract: For several decades, the clinical study of Parkinson's disease has driven an increasingly sophisticated understanding of the dopaminergic system and its complex role in modulating motor behavior. This article reviews salient areas of research in this field, commencing with the molecular biology of the development of the mesencephalic dopaminergic system. We then discuss events thought to be crucial in the cellular and molecular pathology of Parkinson's disease, proposed mechanisms of cell death, and relevant toxin models. These advancements are used as a template to review emerging therapeutic techniques, including neuroprotection strategies, surgical treatment of trophic factors, gene therapy, and neural transplantation.

Hamani C, Neimat J, Lozano AM. · Division of Neurosurgery, University of Toronto, Toronto Western Hospital, Toronto, Canada. · J Neural Transm Suppl. · Pubmed #17017558 No free full text.

Abstract: Approximately 30,000 patients have been treated throughout the world with deep brain stimulation for Parkinson's disease and other conditions. With accumulating experience, there has been an appreciation of the important benefits of this procedure, including the alleviation of disability and improvement in the quality of life. We have also become aware of some limitations of DBS surgery. Among the important issues that remain to be resolved are the timing of surgery, whether early or late in the course of the disease, and the best target for the individual patient, including a reassessment of the relative merits of globus pallidus versus subthalamic nucleus surgery. A better understanding of the symptoms that are resistant to both levodopa therapy and DBS surgery is also required.

Neimat JS, Hamani C, Lozano AM. · Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada. · Expert Rev Neurother. · Pubmed #16466317 No free full text.

Abstract: Neural stimulation has rapidly become an integral tool in the treatment of Parkinson's disease and other movement disorders. Today it serves as an important adjunct to medical therapy that continues to gain applicability to patients in whom the disease has progressed significantly. Studies have demonstrated efficacy in several deep-brain targets, with prolonged benefit exceeding 5-year follow-up times. Continuing study is teaching us more about the mechanism of deep-brain stimulation effect. New targets, which may treat the disease more successfully, are being examined. In this review, the history of deep-brain stimulation, the rationale for the known targets of stimulation; the clinical evidence demonstrating their benefit and, finally, future perspectives on new treatments that are being investigated and may have an impact on the field are discussed.

Voon V, Moro E, Saint-Cyr JA, Lozano AM, Lang AE. · Department of Psychiatry, Toronto Western Hospital, UHN, Toronto, Canada. · Adv Neurol. · Pubmed #16383217 No free full text.

Abstract: Bilateral subthalamic stimulation is a very effective neurosurgical treatment for advanced Parkinson's disease. Despite the range and frequency of psychiatric symptoms occurring in the postoperative state, most of these symptoms are transient and manageable. In clinical practice, preoperative psychiatric vulnerability, as with that of preoperative cognitive status, takes on an important role. Psychiatric assessment and active preoperative and postoperative intervention can potentially modify psychiatric outcomes. These psychiatric and psychological issues will take on greater importance, particularly with the rapid expansion of the number of neurosurgical sites and the need for adequate assessment and optimal management of patients. The paucity of the literature underscores the need for well-designed studies on psychiatric issues investigating both pathophysiology and clinical outcomes.

Hamani C, Richter E, Schwalb JM, Lozano AM. · Division of Neurosurgery, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada. · Neurosurgery. · Pubmed #15918948 No free full text.

Abstract: OBJECTIVE: To evaluate the benefits and adverse effects of bilateral subthalamic nucleus stimulation in the treatment of Parkinson's disease (PD) by systematically reviewing the published literature. METHODS: A search of the PubMed database using the key words subthalamic, nucleus, and stimulation yielded 624 articles published between 1966 and December 2003. Only articles that included original, nonduplicated descriptions of patients with PD treated with bilateral subthalamic nucleus stimulation were selected for further analysis. RESULTS: A total of 38 studies from 34 neurosurgical centers in 13 countries were identified for critical review. The outcomes for 471 patients with PD treated with bilateral subthalamic nucleus stimulation were assessed according to the Unified Parkinson's Disease Rating Scale in both on-medication and off-medication conditions. With stimulation, Unified Parkinson's Disease Rating Scale motor scores in the off-medication condition improved by 50% after 6 months, 56% after 12 months, 51% after 2 years, and 49% after 5 years compared with preoperative off-medication scores. At 12 months of subthalamic nucleus stimulation, the mean improvement in tremor was 81%, in rigidity was 63%, in bradykinesia was 52%, in gait was 64%, and in postural instability was 69% when compared with preoperative off-medication subscores. On-medication dyskinesias were reduced by 94%, as assessed 12 months after stimulation using the Unified Parkinson's Disease Rating Scale IV complications of therapy score. There was an overall 52% reduction in the l-dopa-equivalent dose intake after 12 months of stimulation. Most adverse effects were mild to moderate. There was a 1 to 2% incidence of severe adverse effects (death or permanent neurological deficits related to intracerebral hemorrhages). Nineteen percent of the patients had adverse effects related to stimulation that could be reversed by changing stimulation parameters. There was a 9% incidence of adverse effects related to the hardware (infections, lead and pulse generator problems). CONCLUSION: Bilateral subthalamic nucleus stimulation is effective in the treatment of PD. Further refinements in patient selection and surgical technique may lessen the incidence of complications associated with this procedure.

Lozano AM, Mahant N. · Division of Neurosurgery, Department of Surgery, The Toronto Western Hospital Research Institute, 399 Bathurst Street, Toronto, Ont., Canada M5T 2S8. · Parkinsonism Relat Disord. · Pubmed #15109587 No free full text.

Abstract: Despite the introduction of new medications, motor fluctuations and dyskinesias disable a significant proportion of Parkinson's disease patients. This has lead to renewed interest in stereotactic neurosurgery. A skilled team is needed to ensure that patient assessment and selection, operative technique, intraoperative monitoring, and post-operative management are optimised. High frequency stimulation has similar effects to ablative surgery, and is generally preferred. The clinical effects and possible mechanisms of action of deep brain stimulation of the subthalamic nucleus and globus pallidus are reviewed.

Kalia SK, Nash JE, Lozano AM. · Division of Applied and Interventional Research, The Toronto Western Hospital Research Institute, Toronto ON, Canada M5T 2S8. · Exp Neurol. · Pubmed #14736500 No free full text.

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Hamani C, Saint-Cyr JA, Fraser J, Kaplitt M, Lozano AM. · Division of Neurosurgery, Toronto Western Hospital, Toronto Western Research Institute, Ontario, Canada. · Brain. · Pubmed #14607789 links to  free full text

Abstract: 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.

Lozano AM, Dostrovsky J, Chen R, Ashby P. · Toronto Western Hospital Research Institute, and Department of Surgery, University of Toronto, ON, Canada. · Lancet Neurol. · Pubmed #12849455 No free full text.

Abstract: Many people are disabled by Parkinson's disease (PD) despite the drug treatments that are currently available. For these patients, neurosurgery has the potential to help restore their function. The most effective neurosurgical procedures to date use electrical stimulation--deep brain stimulation (DBS)--of small targets in the brain by use of a pacemaker-like device to deliver constant stimulation. Although these operations can produce striking results, the mechanism by which delivery of electrical stimulation to targets deep in the brain can restore function in the motor system is not clear. This type of surgery probably works by interfering with and shutting down abnormal brain activity in areas where the current is delivered, such as the thalamus, globus pallidus, or the subthalamic nucleus. With this abnormal neuronal activity neutralised, motor areas of the brain can resume their function and normal movements are reinstated. Current research is aimed at elucidating how DBS works and using this information to develop better treatments for patients with PD and other neurological disorders.

Lozano AM. · Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. · Adv Neurol. · Pubmed #12442688 No free full text.

This publication has no abstract.

Dostrovsky JO, Hutchison WD, Lozano AM. · Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada. · Neuroscientist. · Pubmed #12061508 No free full text.

Abstract: Parkinson's disease (PD) is caused by the degeneration of the dopaminergic neurons in the substantia nigra. Loss of dopaminergic innervation leads to hyperactivity in the internal segment of the globus pallidus (GPi), the main output nucleus of the basal ganglia and to a profound disturbance in the function of motor circuits. Lesions of the GPi (or in its upstream modulator, the subthalamic nucleus) can greatly improve the motor symptoms of PD presumably by reducing this pathological activity. Paradoxically, high-frequency electrical stimulation of the GPi (deep brain stimulation, DBS) mimics the effects of pallidotomy and has become an accepted therapeutic technique. The mechanisms underlying the beneficial effects of pallidal DBS are not known. Various mechanisms that might account for inhibiting or disrupting the pathological pallidal outflow by high-frequency DBS have been proposed ranging from depolarization block to stimulation-evoked release of GABA, and these are discussed.

Lozano AM, Lang AE. · Division of Neurosurgery, Movement Disorders Centre, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada. · Adv Neurol. · Pubmed #11554004 No free full text.

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Lozano AM. · Division of Neurosurgery, University of Toronto, The Toronto Hospital, Western Division, Toronto, Ontario, Canada. · Arch Med Res. · Pubmed #11036177 No free full text.

Abstract: Chronic stimulation of the ventral intermediate nucleus (Vim) of the thalamus is highly effective for the treatment of tremor. Patients with tremor associated with Parkinson's disease and essential tremor appear to respond best. Patients with cerebellar tremors may also respond but to a lesser extent. Although tremor is improved, Vim DBS does not substantially improve the daily living activities of patients with Parkinson's disease. This is related to the lack of effect on rigidity, bradykinesia, and gait and postural disturbances associated with Parkinson's. For this reason, the majority of patients with Parkinson's disease who require surgery are better treated with interventions in the globus pallidus or subthalamic nucleus, targets that allow improvement in all cardinal features of Parkinson's disease. In contrast, Vim DBS has unequivocal functional benefit in patients with essential tremor, this is likely to remain the major indication of this form of therapy. The mechanism of action of thalamic DBS is not understood and remains a research priority.

Pahapill PA, Lozano AM. · Department of Surgery, University of Toronto, Ontario, Canada. · Brain. · Pubmed #10960043 links to  free full text

Abstract: Akinesia and gait disturbances are particularly incapacitating for patients with Parkinson's disease. The anatomical and physiological substrates for these disturbances are poorly understood. The pedunculopontine nucleus (PPN) is thought to be involved in the initiation and modulation of gait and other stereotyped movements, because electrical stimulation and the application of neuroactive substances in the PPN can elicit locomotor activity in experimental animals. Glutamatergic neurones of the PPNd (pars dissipatus) are thought to be important regulators of the basal ganglia and spinal cord. The other component of the PPN, the cholinergic pars compacta (PPNc), is a principal component in a feedback loop from the spinal cord and limbic system back into the basal ganglia and thalamus. Electrophysiological studies suggest that 'bursting' glutamatergic PPNd neurones are related to the initiation of programmed movements while non-bursting cholinergic PPNc neurones are related to the maintenance of steady-state locomotion. Furthermore, since patients with Parkinson's disease have significant loss of PPN neurones and experimental lesions in the PPN of normal monkeys result in akinesia, the degeneration of PPN neurones or their dysfunction may be important in the pathophysiology of locomotor and postural disturbances of parkinsonism. The goal of this review is (i) to highlight the anatomical connections and physiological attributes of the PPN, (ii) to discuss how the function of these connections may be altered in the parkinsonian state, and (iii) to speculate how present and potential future therapy directed to the PPN might improve akinesia and gait difficulties in parkinsonian patients.

Gross RE, Lozano AM. · Department of Neurosurgery, University of Utah Health Sciences Center, Salt Lake City 84132, USA. · Neurol Res. · Pubmed #10769817 No free full text.

Abstract: In just 12 years since its introduction, deep brain stimulation (DBS) has become well established as a safe and effective therapy in the treatment of medically refractory movement disorders. Ventralis intermedius (Vim) DBS has virtually replaced thalamotomy in the routine clinical treatment of essential tremor, affording relief to thousands of patients who previously would not have undergone surgery, and there is increasing usage of Vim DBS in other tremors of intention (e.g., multiple sclerosis). Subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS have revolutionized the treatment of advanced stage Parkinson's disease, improving all cardinal disease features and increasing 'on' time without dyskinesias. Finally, DBS of various sub-cortical structures is being developed and tested in other less prevalent movement disorders such as dystonia. Future developments in this rapidly advancing area will no doubt include widening indications for this relatively safe surgical procedure, elucidation of the mechanisms of action of electrical stimulation, and technological advancements improving effectiveness and convenience.

Lang AE, Duff J, Saint-Cyr JA, Trepanier L, Gross RE, Lombardi W, Montgomery E, Hutchinson W, Lozano AM. · The Division of Neurology, Dept. of Medicine, The Toronto Western Hospital, 399 Bathurst St., MP-11, Toronto, Ontario, M5T 2S8, Canada. · J Neurol. · Pubmed #10526000 No free full text.

Abstract: There has been a resurgence in the use of functional neurosurgery for Parkinson's disease. An important factor that has played a role in this development is the recent understanding of the functional anatomy of the basal ganglia including a knowledge of the changes in the activities of neurons in the internal segment of the globus pallidus (Gpi) and the subthalamic nucleus (STN) in Parkinson's disease as well as the knowledge of the presence of segregated functional loops within the basal ganglia which include a sensory-motor loop that involves the posteromedial globus pallidus rather than the anterior GPi where earlier pallidotomy lesions had been made. Laitinen reintroduced the modern posteroventral medial pallidotomy (PVMP) in 1992. Since then it has become clear that this treatment has major effects on levodopa-induced dyskinesias and, unlike Vim thalamotomy, improves bradykinesia and rigidity as well as tremor. In this report, we review a number of topics related to PVMP including the clinical results of pallidotomy available in the literature as well as an update of our own 2 year follow-up data, studies evaluating factors that might predict the subsequent response to pallidotomy, the neuropsychological effects of the procedure, results of imaging studies including the correlation of clinical effects with lesion location, the question of bilateral pallidotomy and pallidotomy combined with deep brain stimulation and finally whether PVMP is effective in other parkinsonian disorders.

Honey C, Gross RE, Lozano AM. · Department of Surgery, University of British Columbia, Canada. · Can J Neurol Sci. · Pubmed #10451760 No free full text.

Abstract: Despite optimization of medical therapy, a large number of patients with Parkinson's disease continue to be disabled. For this group, alternate treatment strategies such as neurosurgical intervention can be considered. Recent advances in neurosurgical techniques and in understanding the pathophysiology of motor disturbances in PD have made surgery safer and more effective. Functional neurosurgical procedures to lesion or electrically modulate dysfunctional basal ganglia circuits or to protect or restore dopaminergic transmission are being increasingly used. These procedures are having a profound impact on the motor disturbances of PD and are producing important improvements in quality of life of patients.

Strafella AP, Lozano AM, Lang AE, Ko JH, Poon YY, Moro E. · Movement Disorders Center, Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. · Mov Disord. · Pubmed #17894326 No free full text.

Abstract: There has been some evidence that electrical stimulation of the primary motor cortex (MCS) may relieve motor symptoms of Parkinson's disease (PD). This surgical technique is being studied as alternative for PD patients who are considered poor candidates for deep brain stimulation (DBS) of subthalamic nucleus (STN). In 4 PD patients with unilateral MCS, we used [(15)O] H(2)O positron emission tomography to measure changes in regional cerebral blood flow (rCBF) while testing motor performance with a joystick motor task during different stimulation frequencies, OFF-condition, 50 and 130 Hz. We found that different stimulation settings did neither improve performance on joystick task nor modify the pattern of movement-related rCBF. Similarly, no changes were observed in UPDRS motor score between Off and On stimulation while off medication. We conclude that while MCS may be a simpler and safer surgical procedure than DBS of STN, it failed to provide evidence of clear effect on motor performance and movement-related activation pattern in patients with advanced PD.

Piboolnurak P, Lang AE, Lozano AM, Miyasaki JM, Saint-Cyr JA, Poon YY, Hutchison WD, Dostrovsky JO, Moro E. · Movement Disorders Center, Division of Neurology, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada. · Mov Disord. · Pubmed #17443692 No free full text.

Abstract: Subthalamic nucleus deep brain stimulation (STN-DBS) is effective in advanced Parkinson's disease (PD), but its effects on the levodopa response are unclear. We studied the levodopa response after long-term STN-DBS, STN-DBS efficacy and predictive value of preoperative levodopa response to long-term DBS benefit in 33 PD patients with bilateral STN-DBS. Patients were assessed using the Unified Parkinson's Disease Rating Scale preoperatively (with and without medications) and postoperatively (without medications or stimulation, with only medications or stimulation, and with both medications and stimulation). Levodopa response significantly decreased postoperatively by 31.1% at 3 years and 32.3% at 5 years, possibly related to the reduction in medication requirement, direct STN stimulation effect or PD progression. STN-DBS alone significantly improved motor scores (37.2% at 3 years and 35.1% at 5 years) and activities of daily living scores (27.1% at 3 years and 19.2% at 5 years). Anti-PD drugs were significantly reduced by 47.9% at 3 years and 39.8% at 5 years. However, the magnitude of the preoperative response to levodopa did not predict DBS benefit at 3 and 5 years.

Fawcett AP, Cunic D, Hamani C, Hodaie M, Lozano AM, Chen R, Hutchison WD. · Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ont., Canada. · Clin Neurophysiol. · Pubmed #17097341 No free full text.

Abstract: OBJECTIVE: To investigate an ocular motor role for the STN in Parkinson's disease (PD) patients. METHODS: Potentials were recorded from deep brain stimulation (DBS) electrodes implanted in the vicinity of STN in five PD patients, while patients simultaneously performed visually cued saccades, self-paced saccades and in two patients self-paced wrist extensions. RESULTS: Premovement potentials related to visually cued saccades were found in 4/5 patients and 56% (5/9) of potentials showed phase reversal indicating a local generator. Onsets of these potentials began closer to saccade initiation from STN contacts (0.88+/-0.30s) than thalamic ones (1.39+/-0.28 s). Self-paced saccade-related potentials were found in 4/4 patients. Self-paced saccade potential onsets (1.82+/-0.88 s) were not different from self-paced wrist extension onsets (1.27+/-0.98 s), suggesting a non-specific mechanism could be responsible for both potentials. 50% (3/6) of potentials to self-paced saccades and 66% (2/3) of potentials to self-paced wrist extensions showed phase reversal. Potentials could be found either ipsilaterally or contralaterally with respect to saccade direction. CONCLUSIONS: These subcortical premovement potentials to saccades are similar to Bereitschaftspotentials and contingent negative variations to limb movements recorded in cortical and subcortical regions. SIGNIFICANCE: These studies further support a role of STN in ocular motor control and suggest a common mechanism of motor preparation for both eye and limb movements in the basal ganglia.

Moro E, Poon YY, Lozano AM, Saint-Cyr JA, Lang AE. · Movement Disorders Center and Department of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, Ontario. · Arch Neurol. · Pubmed #16831958 links to  free full text

Abstract: BACKGROUND: Deep brain stimulation (DBS) is currently the most effective surgical treatment for advanced Parkinson disease (PD). Even when the electrode is well positioned in the target, the optimization of clinical results depends on careful programming of electrical parameters and changes in antiparkinsonian drug dosages. OBJECTIVE: To determine whether stable outcomes from subthalamic nucleus DBS for PD can be improved by revising stimulation parameters and drug dosages through "hands-on" involvement of a neurologist expert in both movement disorders and DBS programming. METHODS: In 44 consecutive patients with PD with long-term stable response to subthalamic nucleus DBS (mean +/- SD, 3.5 +/- 1.7 years), we compared scores from the Unified Parkinson's Disease Rating Scale parts II through IV obtained immediately before and following a formal reprogramming of their stimulation. The reprogramming was performed by a neurologist expert in both PD and DBS and accompanied by further medication adjustments. The patients were subsequently followed up for as long as 14 months. RESULTS: In 24 patients (54.6%), the scores on the Unified Parkinson's Disease Rating Scale parts II and III significantly improved by 15.0% and 25.9%, respectively. Anti-PD drugs were significantly reduced (by 25.9%). No improvement was observed in 16 patients (36.4%), and the conditions of 4 patients (9.1%) worsened. CONCLUSIONS: Further improvement of parkinsonian signs can be achieved in the majority of patients even after long-term stable stimulation. Improved patient outcomes from subthalamic nucleus DBS are obtained when postoperative care is personally managed by a neurologist expert in movement disorders and DBS who is directly responsible for stimulation programming and simultaneous drug adjustments based on observed clinical responses to changing stimulation parameters.

Rodriguez-Oroz MC, Obeso JA, Lang AE, Houeto JL, Pollak P, Rehncrona S, Kulisevsky J, Albanese A, Volkmann J, Hariz MI, Quinn NP, Speelman JD, Guridi J, Zamarbide I, Gironell A, Molet J, Pascual-Sedano B, Pidoux B, Bonnet AM, Agid Y, Xie J, Benabid AL, Lozano AM, Saint-Cyr J, Romito L, Contarino MF, Scerrati M, Fraix V, Van Blercom N. · Department of Neurology and Neurosurgery, Clinica Universitaria and Medical School, University of Navarra and CIMA, Pamplona, Spain. · Brain. · Pubmed #15975946 links to  free full text

Abstract: 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.