Search PubMed⌕ Search

Biomedical subjects

J A Obeso

Publications and source records attributed to J A Obeso.

At least 37 records · Page 2Linked to original sources
PubMed2000

Ineffective subthalamic nucleus stimulation in levodopa-resistant postischemic parkinsonism.

The authors report a patient with postischemic parkinsonism who responded neither to levodopa nor to bilateral subthalamic nucleus (STN) stimulation. MRI revealed bilateral lesions of the substantia nigra, the striatum, the external pallidum, and part of the internal pallidum. PET showed reduced striatal dopa-decarboxylase activity, D2 receptor binding, and glucose metabolism. Perioperative microrecording showed low-frequency activity of STN cells. This case suggests that parkinsonian patients who do not have a good response to levodopa or in whom a postsynaptic dopaminergic lesion can be shown may not be good candidates for STN surgery.

Antiparkinson Agents↗
PubMed2000

Excitatory responses in the 'direct' striatonigral pathway: effect of nigrostriatal lesion.

The existence of a striatonigral GABAergic projection that inhibits substantia nigra reticulata (SNr) cells has been well established. We report on electrophysiological evidence in the rat for a striatonigral excitatory pathway that affects 15% of all SNr cells. Using the antidromic response test to classify SNr cells in relation to their projecting nucleus, an excitatory striatonigral response was found in 57% of cells projecting to the pedunculopontine tegmental nucleus (PPTg) and 11% of cells projecting to the thalamus. SNr cells innervated by inhibitory or excitatory striatonigral inputs had a similar firing rate but a lower variation coefficient (VC) than SNr cells that did not respond to striatonigral inputs. The 6-hydroxydopamine (6-OHDA) degeneration of nigrostriatal dopaminergic cells (A9) induced an increase in the percentage of SNr cells excited from the striatum (52%) and in the VC, but no modification of the firing rate or of the number of spikes induced by each striatal stimulus. This increase in VC was found for the striatonigral inhibitory, but not for the striatonigral excitatory pathway. These data indicate that in addition to its inhibitory action, the direct striatonigral pathway has an excitatory activity that is particularly prominent for SNr cells projecting to the pedunculopontine nucleus. Because the percentage of SNr cells excited by this pathway was markedly increased by DA cell degeneration, our findings suggest that the excitatory striatonigral system could be involved in the pathophysiology of Parkinson's disease.

Action Potentials↗
PubMed2000

Metabolic effects of nigrostriatal denervation in basal ganglia.

In the past, functional changes in the circuitry of the basal ganglia that occur in Parkinson's disease were primarily analyzed with electrophysiological and 2-deoxyglucose measurements. The increased activity of the subthalamic nucleus (STN) observed has been attributed to a reduction in inhibition mediated by the external segment of the globus pallidus (GPe), secondary to the loss of dopaminergic-neuron influence on D2-receptor-bearing striato-pallidal neurons. More recently, in situ hybridization studies of cytochrome oxidase subunit I have confirmed the overactivity of the STN in the parkinsonian state. In addition, this technique has provided evidence that the change in STN activity is owing not only to decreased inhibition from the GPe but to hyperactivity of excitatory inputs from the parafascicular nucleus of the thalamus and the pedunculopontine nucleus in the brainstem.

Basal Ganglia↗
PubMed2000

Pathophysiology of the basal ganglia in Parkinson's disease.

Insight into the organization of the basal ganglia in the normal, parkinsonian and L-dopa-induced dyskinesia states is critical for the development of newer and more effective therapies for Parkinson's disease. We believe that the basal ganglia can no longer be thought of as a unidirectional linear system that transfers information based solely on a firing-rate code. Rather, we propose that the basal ganglia is a highly organized network, with operational characteristics that simulate a non-linear dynamic system.

Animals↗
PubMed2000

Continuous dopamine-receptor stimulation in advanced Parkinson's disease.

Intermittent or pulsatile dopamine-receptor stimulation is postulated to induce plastic changes in motor systems that are responsible for the development of the motor fluctuations and dyskinesia that complicate long-term L-dopa therapy of Parkinson's disease. As a corollary to this hypothesis, continuous dopamine-receptor stimulation can avoid or reverse these complications. Such continuous stimulation is unlikely to mimic completely the normal function of the dopaminergic system, but should avoid the supra-physiological swings in extracellular dopamine that accompany intermittent L-dopa dosing. The concern is that this continuous stimulation might induce tolerance rather than sensitization to some effects of L-dopa. Open clinical trials support the value of continuous dopaminergic stimulation in Parkinson's disease with established motor complications, but rigorous studies, although experimentally difficult, are needed.

Antiparkinson Agents↗
PubMed2000

Levodopa motor complications in Parkinson's disease.

Parkinson's disease (PD) is an age-related neurodegenerative disorder with an average onset age of 60 years. In the United States, approximately one million persons suffer from PD, and there are 60,000 newly diagnosed cases every year. The estimated cost of PD to society is $27 billion per year. Based on United States Census Bureau projections, it is estimated that the frequency of PD will increase fourfold by the year 2040, making it an even larger burden on patients, their families and society.

Age of Onset↗
PubMed2000

Excitotoxic ablation.

Explore the source record for details and available documents.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Pathophysiology of levodopa-induced dyskinesias in Parkinson's disease: problems with the current model.

The anatomical and physiological basis of levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease (PD) is reviewed in the light of the current model for the organization of the basal ganglia. This model, which was developed in the late 1980s, works relatively well in explaining the motor features of PD but, for example, it does not account for why tremor, rigidity, bradykinesia, gait dysfunction and postural instability present to differing degrees in different patients, and may respond differently to levodopa treatment or surgical procedures. Recent information suggests that LIDs develop as a consequence of pulsatile stimulation of dopamine receptors, with consequent dysregulation of genes and proteins in downstream neurons resulting in changes in neuronal firing patterns. A modified model of the basal ganglia in PD patients with LID is proposed, which incorporates more recent clinical and experimental data.

Basal Ganglia↗
PubMed2000

Preventing levodopa-induced dyskinesias.

The precise cause of levodopa-induced dyskinesias is unknown. Current evidence indicates that dyskinesias develop in response to pulsatile stimulation of striatal dopamine receptors. The half-life of the dopaminergic agent employed and disease severity are thought to affect the occurrence of pulsatile stimulation. Dyskinesias are not seen or are attenuated with continuous delivery of levodopa or short-acting agonists, or with the use of long-acting agonists. In advanced disease, there are fewer striatal dopamine terminals and reduced buffering capacity; fluctuations in plasma levodopa concentration are more likely to cause fluctuations in striatal dopamine concentration and pulsatile stimulation of dopamine receptors. Pulsatile stimulation is thought to induce postsynaptic gene and protein changes that result in alterations in the patterns of neuronal communication, with the emergence of dyskinetic movements. Thus, strategies preventing pulsatile stimulation may prevent the development of dyskinesias. These could include the use of dopaminergic agents with a relatively long half-life, neuroprotective therapies that prevent the loss of dopamine neurons, and transplantation strategies or trophic factors that increase the number of dopamine terminals capable of buffering fluctuations in striatal dopamine. Alternatively, approaches that interfere with or compensate for postsynaptic molecular and neurophysiologic changes that ensue in downstream neurons might provide antidyskinetic benefits.

Dopamine Agents↗
PubMed2000

The evolution and origin of motor complications in Parkinson's disease.

Levodopa is the major symptomatic therapy for Parkinson's disease (PD), having revolutionized the treatment of PD and provided benefit to virtually all patients. However, after 5-10 years of treatment, levodopa therapy is complicated by the development of motor complications, which include dyskinesia and motor fluctuations. The initial long duration response to a dose of levodopa becomes progressively shorter, and periods in which the patient responds to the drug become complicated by involuntary dyskinetic movements. Thus, patients may cycle between "on" periods that are complicated by dyskinesia and "off" periods in which they are severely parkinsonian. As a consequence they may experience profound disability despite the fact that levodopa remains an effective anti-parkinson agent throughout the course of the disease. In this article we review the various motor complications associated with the treatment of PD and present current concepts on the origin of these problems.

Humans↗
PubMed2000

The place of COMT inhibitors in the armamentarium of drugs for the treatment of Parkinson's disease.

Catechol-O-methyl transferase (COMT) inhibitors block the peripheral metabolism of levodopa, increase its plasma half-life, and enhance its brain availability. Two COMT inhibitors, tolcapone and entacapone, have recently been made available as adjunctive agents to levodopa. In PD patients with motor fluctuations, they have been shown to increase "on" time and reduce "off" time. In patients with more advanced disease, they provide similar benefits, but patients tend to experience less overall benefit and a greater likelihood of developing dopaminergic adverse events. Accordingly, closer monitoring is required. In stable patients who have not yet developed motor complications, there are preliminary data suggesting that they experience improvements in motor function and in activities of daily living. Finally, there are theoretical reasons to consider administering a COMT inhibitor to patients from the onset of levodopa therapy in order to reduce the likelihood that motor complications will develop. COMT inhibitors are easy to administer, do not require titration, and are generally well tolerated particularly in patients with relatively mild disease. Adverse events are primarily dopaminergic and can usually be controlled by levodopa dose adjustments. COMT inhibitors have thus proven to be a useful addition to the therapeutic armamentarium of PD.

Benzophenones↗
PubMed2000

Pulsatile stimulation of dopamine receptors and levodopa-induced motor complications in Parkinson's disease: implications for the early use of COMT inhibitors.

Increasing laboratory and clinical evidence indicates that pulsatile stimulation of dopamine receptors contributes to the development of levodopa-related motor complications in PD. In keeping with this concept, clinical trials have demonstrated that initiating therapy with a long-acting dopamine agonist reduces the risk of inducing motor complications in comparison to levodopa. However, the introduction of levodopa is associated with the development of motor complications even in the presence of a long-acting dopamine agonist in both PD patients or MPTP treated monkeys. Administration of levodopa with a catechol-O-methyl transferase (COMT) inhibitor increases its plasma half-life, smoothes out peaks and troughs, and delivers levodopa to the brain in a more continuous fashion. We hypothesize that the risk of developing motor complications in PD patients when levodopa is introduced can be reduced if the levodopa is coupled with a COMT inhibitor so as to provide more continuous dopaminergic stimulation of dopamine receptors. A proposed algorithm for the treatment of the early PD patient is to initiate therapy with a dopamine agonist, and supplement with levodopa coupled with a COMT inhibitor when the dopamine agonist cannot provide satisfactory clinical benefits.

Catechol O-Methyltransferase Inhibitors↗
PubMed2000

Targeting the basal ganglia for deep brain stimulation in Parkinson's disease.

The revitalization of surgery for Parkinson's disease (PD) has fueled discussion about the best methodology to define the target. Placement of electrodes for deep brain stimulation (DBS) requires the usual stereotactic technique but the argument is mainly centered on whether or not microrecording neuronal activity is necessary. We compared the accuracy of calculating the coordinates X (medio-lateral) and Y (rostro-caudal) considered by the classic stereotactic method, i.e., definition of the AC-PC intercomissural line by MRI and a digitized version of the Schaltenbrand's atlas, with final electrode placement according with microrecording and microstimulation in 21 patients. For both the globus pallidum internum (GPi) (n = 21) and the subthalamic nucleus (STN) (n = 36) there was, respectively, a 43% and 45% mismatching of more than 3 mm between the theoretic coordinates and the final site of electrode location. This applies to both the X and Y planes. Accuracy was not improved in patients (n = 11) in whom the bilateral procedure was undertaken in a single day. We conclude that proper electrode positioning of the STN and GPi requires fine electrophysiologic assessment.

Adult↗
PubMed2000

Deep brain stimulation of the globus pallidus pars interna in advanced Parkinson's disease.

Pallidotomy is now widely performed for the treatment of advanced Parkinson's disease (PD). Preliminary reports of the effect of globus pallidus pars interna deep brain stimulation (GPi DBS) have also been promising. We have analyzed a cohort of 22 consecutive patients enrolled in a multicenter study. Surgery was bilateral in 17 and unilateral in five patients. At 6-month follow-up, the bilaterally GPi-implanted patients demonstrated a marked improvement when examined after drug withdrawal ("off") and under optimal medication ("on") using the Unified Parkinson's Disease Rating Scale (UPDRS). The benefit induced by the stimulation in the "off" medication condition in the total motor score was 31% and in the activities of daily living (ADL) scores was 39%. During the "on" medication period, the reduction in the total "on" dyskinesias score was 66% and in the ADL score was 32%. A similar pattern of improvement was seen in the group of patients with unilateral GPi stimulation, although a second cohort of 12 patients not included in the multicenter study showed greater improvements in "on" motor functioning. Although the effect of DBS is predominantly reversible, electrode insertion alone resulted in measurable clinical effects in the absence of stimulation. Thus, at 6-month follow-up, the benefit observed without stimulation was up to 44% in the "on" dyskinesias score and 29% in timed tapping scores undertaken in the "off" medication state. Complications among 34 patients from all centers included perioperative infection (n=3), hardware fracture (n=2), and premature battery failure (n=3). These results show a positive antiparkinsonian effect of pallidal DBS. No specific complications were observed with bilateral procedures.

Adult↗
PubMed2000

Bilateral deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is rapidly becoming the preferred surgical choice for the treatment of advanced Parkinson's disease (PD). We report initial results in 15 patients after 12 months and in nine patients evaluated between 30 and 36 months postoperatively. Our experience confirms the robust antiparkinsonian effect of DBS of the STN in advanced PD. The severity of "off" episodes, as assessed by the Unified Parkinson Disease Rating Scale (UPDRS), was drastically reduced by 74% at 12 months, and dyskinesia scores (Dyskinesia Rating Scale) decreased. The levodopa daily dose was reduced by 55% at 12 months. A double-blind assessment to determine the effect of stimulation performed in nine patients at 3 months in the "off" medication condition was very significant (p<0.05). Nine patients have been followed for 3 years with maintained efficacy in the UPDRS "off" score and the dyskinesia score. The experience of other groups using a similar technique is reviewed. The overall assessment indicates a high antiparkinsonian effect of DBS of the STN even in advanced patients. The existence of a learning curve for this procedure should be taken into account when initial results are evaluated.

Electric Stimulation Therapy↗
PubMed2000

The role of deep brain stimulation as a surgical treatment for Parkinson's disease.

Patients with advanced Parkinson's disease (PD) frequently suffer disabling motor complications that cannot be satisfactorily controlled with medical therapy. Deep brain stimulation (DBS) has recently been introduced by Benabid and his colleagues in Grenoble, France, as a new surgical procedure for the treatment of PD patients. DBS simulates the effects of a lesion without the need to make a destructive brain lesion. In this procedure, an electrode is implanted in the brain target and connected to a subcutaneous pacemaker. DBS of the ventro-intermediate (Vim) nucleus of the thalamus has been shown to ameliorate tremor in patients with tremor-dominant PD. DBS of the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) have been shown to improve all of the cardinal features of PD and to markedly reduce dyskinesia and motor fluctuations. Adverse events are associated with the surgical procedure, the device, and stimulation, but the procedure is usually well tolerated. On the basis of these findings, the FDA has recently approved unilateral DBS of the Vim for treatment of tremor in PD and is currently considering approval of DBS for STN and GPi. This article reviews existing information with respect to DBS.

Brain↗