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J A Obeso

Publications and source records attributed to J A Obeso.

At least 55 records · Page 3Linked to original sources
PubMed2000

Pathophysiologic basis of surgery for Parkinson's disease.

Dopamine depletion induces a series of changes in the basal ganglia motor circuit that underlie the origin of the cardinal features of Parkinson's disease. It has now been established that hyperactivity of the subthalamic nucleus (STN) is an essential feature of the parkinsonian state. This leads to increased excitatory driving onto the globus pallidum internum (GPi) and substantia nigra reticulata (SNr) which, in turn, overinhibits the motor projections to the thalamus and brainstem. The STN and GPi have become the preferred targets for surgery to treat PD. In keeping with the classic pathophysiologic model, physiologic and neuroimaging studies in patients have shown that lesioning or functional blockades (by deep brain stimulation, or DBS) of these nuclei increased cortical activation, in parallel with clinical improvements of bradykinesia. Neuronal recording during surgery has also shown tremor-related activity in both the STN and GPi. However, the pathophysiologic model of the basal ganglia needs further refinement to provide a more detailed explanation of the origin of both tremor and rigidity in Parkinson's disease and to explain the antidyskinetic effect of surgery of the GPi and STN.

Basal Ganglia↗
PubMed1999

The effects of posteroventral pallidotomy on the preparation and execution of voluntary hand and arm movements in Parkinson's disease.

We studied the effect of posteroventral pallidotomy on movement preparation and execution in 27 parkinsonian patients using various motor tasks. Patients were evaluated after overnight withdrawal of medication before and 3 months after unilateral pallidotomy. Surgery had no effect on initiation time in unwarned simple and choice reaction time tasks, whereas movement time measured during the same tasks was improved for the contralesional hand. Movement times also improved for isometric and isotonic ballistic movements. In contrast, repetitive, distal and fine movements measured in finger-tapping and pegboard tasks were not improved after pallidotomy. Preparatory processes were investigated using both behavioural and electrophysiological measures. A precued choice reaction time task suggested an enhancement of motor preparation for the contralesional hand. Similarly, movement-related cortical potentials showed an increase in the slope of the late component (NS2) when the patients performed joystick movements with the contralesional hand. However, no significant change was found for the early component (NS1) or when the patient moved the ipsilesional hand. The amplitude of the long-latency stretch reflex of the contralesional hand decreased after surgery. In summary, the data suggest that pallidotomy improved mainly the later stages of movement preparation and the execution of proximal movements with the contralesional limb. These results provide detailed quantitative data on the impact of posteroventral pallidotomy on previously described measures of upper limb akinesia in Parkinson's disease.

Electroencephalography↗
PubMed1999

Stereotactic targeting of the globus pallidus internus in Parkinson's disease: imaging versus electrophysiological mapping.

OBJECTIVE: The reintroduction of pallidotomy for the treatment of Parkinson's disease (PD) has generated various opinions regarding the ideal anatomic or physiological location of the target within the globus pallidus. The role of microelectrode recording guidance in pallidotomy for the treatment of advanced PD is presently under debate. The purpose of this study was twofold. The first goal was to determine the degree of accuracy in the targeting of the globus pallidus internus (GPi) with magnetic resonance imaging (MRI), by comparing these results with the final placement of the thermolytic lesions (as defined by electrophysiological assessment). The second goal was to ascertain the somatotopic arrangement of the GPi in PD. METHODS: The analysis involved 50 patients with PD who underwent microrecording-guided pallidotomy. The theoretical coordinates for lesioning were calculated after definition of the intercommissural line by MRI. The actual placement of the lesions was determined after mapping of the GPi by microrecording, using stimulation to identify the sensorimotor region and its somatotopic organization. RESULTS: In most cases, the lesions were placed posterior and lateral to the targets chosen by MRI. Mapping by microrecording revealed differences of 2.3 +/- 1.55 mm and 3 +/- 1.9 mm in the mediolateral and anteroposterior coordinates, respectively. The actual lesion overlapped the theoretical target for only 45% of the patients. The somatotopic organization of the GPi was analyzed. Most of the units with sensorimotor activity or tremor-related activity were in the lateral portion of the nucleus. Upper limb and axial units were in the most lateral region and mainly in the ventral one-third of the nucleus. Lower limb responses were recorded mainly in the dorsal one-third of the nucleus. Tremor-related cells were found throughout the sensorimotor region of the nucleus. CONCLUSION: These results indicate that lesion targeting based on MRI alone is not sufficiently accurate to guarantee placement of the lesion in the sensorimotor region of the GPi.

Adult↗
PubMed1999

[Pallidotomy in the treatment of complicated Parkinson's disease: clinical results at two years and analysis of prognostic factors].

BACKGROUND: There is a renewed interest in pallidotomy as a treatment for complicated Parkinson's disease (PD). AIM: To present the clinical results as well as the analysis of prognostic factors obtained in 28 patients with PD and motor complications submitted to pallidotomy and followed by one year (n = 28) and 2 years (n = 12). RESULTS: The total motor score (Unified Parkinson's Disease Rating Scale [UPDRS]) in the off state improved by 33 and 23% at one and two years, respectively (p < 0.01). All the cardinal signs of the disease were significantly improved (p < 0.01): tremor (92%), rigidity (67%), bradykinesia (46%) and axial symptoms (21%). A slight tendency to worsening in axial symptoms was observed. Dyskinesias disappeared in all but one patient. The Schawb & England Scale in off was improved by 21%. No improvement in the non-operated side was observed. The subgroup of patients with an improvement of less than 30% in the UPDRS was older than the one with larger clinical benefit. The observed tendency to worsening in the total motor score was related mainly to the progression of the symptoms in the non-operated side. Complications were mild and transient. CONCLUSIONS: Pallidotomy is a relatively safe and effective therapeutic option for complicated PD patients. An adequate selection of patients is necessary, since efficacy is partial and limited to one hemibody.

Adult↗
PubMed1999

[Pathophysiological bases, clinical results and indications for surgical treatment in Parkinson disease].

We review the present status of surgery for Parkinson's disease. Surgical options for Parkinson's disease are rapidly spanding. The main objectives of surgical techniques are to restore the dopaminergic deficit in the striatum (transplantation) and to normalize the neuronal activity of the subthalamic-pallidal circuit (pallidotomy and deep brain stimulation). Whereas cell transplantation is still considered an experimental procedure, ablative procedures and deep brain stimulation are widely used. Both types of surgical procedures are supported by strong scientific data. However, much work remains to be done in order to understand several aspects not clearly elucidated at present. The results and current indications for pallidotomy and deep brain stimulation are analyzed.

Brain↗
PubMed1998

Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection.

Dopamine deficiency causes disinhibition and overactivity of the subthalamic nucleus (STN). Output neurons from the STN are excitatory and use glutamate as a neurotransmitter. They project to the external and internal segments of the globus pallidum (GPe and GPi), the substantia nigra pars reticulata (SNr), and the pedunculopontine nucleus (PPN). In addition, STN neurons provide excitatory innervation to dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that contain glutamate receptors. Stimulation of the STN induces bursting activity in SNc dopaminergic neurons. This raises the possibility that the disinhibition of STN neurons that occurs as a result of a dopamine lesion might induce excitotoxic damage in target structures, including the SNc. In addition, the reduction in complex I activity found in the nigra in Parkinson's disease (PD) may cause mitochondrial dysfunction and make SNc dopaminergic neurons vulnerable to even physiologic concentrations of glutamate. We postulate that the dopamine loss that occurs in PD produces augmented STN activity which, in turn, causes further damage to vulnerable dopaminergic neurons, thereby creating a scenario for an increasing cycle of neuronal loss in the SNc. In addition, STN overactivity could, in theory, cause damage to the GPi, SNr, and PPN and thereby account for the development of parkinsonian features that do not respond to levodopa in patients with advanced disease. This hypothesis suggests that pharmacologic or surgical therapies that reduce STN neuronal overactivity or block glutamate receptors in the SNc and other target structures might be neuroprotective and might slow or halt the progression of neurodegeneration in PD.

Cell Death↗
PubMed1998

The offset cortical potential: an electrical correlate of movement inhibition in man.

Nine normal subjects were asked to make either a brisk isometric pinch of a force transducer held between the forefinger and thumb, or to hold a pinch for approximately 15 s and then release the force suddenly without any overt antagonist contraction. EEG activity was averaged about the onset or offset of EMG activity, and movements were made in the subjects' own time. All subjects found the task simple. The EEG activity preceding offset of contraction (offset cortical potential) was significantly smaller in lateral leads than that seen before onset of contraction. Midline activation was similar in both tasks. We suggest that in the onset task, motor cortex activity related to the act to be performed contributes substantially to the EEG potentials in lateral leads. This activity is absent in the offset task which requires only withdrawal of tonic input to motor cortex. Midline activity, common to both onset and offset tasks, could reflect timing, attentional, or other processes. The results are discussed in relation to previous data from an isotonic relaxation task.

Adult↗
PubMed1998

The subthalamic nucleus and tremor in Parkinson's disease.

The role of the subthalamic nucleus (STN) in the origin of parkinsonian tremor is discussed. Previous studies in monkeys made parkinsonian by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) 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. Long-term treatment by means of bilateral deep-brain stimulation (DBS) in the same 12 patients led to a significant reduction of tremor as well as other cardinal features of PD. This effect was 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 12 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, as suggested by the MPTP model.

Adult↗
PubMed1998

[125I]EGF binding in basal ganglia of patients with Parkinson's disease and progressive supranuclear palsy and in MPTP-treated monkeys.

Since EGF is known to protect and stimulate the activity of dopaminergic neurons, an autoradiographic study of [125I]EGF binding sites was performed in the striatum and pallidal complex in parkinsonian syndromes. The analysis was performed on postmortem brain tissues of three control subjects, three patients with Parkinson's disease, and three patients with progressive supranuclear palsy, another parkinsonian syndrome in which dopaminergic neurons also degenerate. Since all six patients had been treated with L-Dopa, we also analyzed the effects of this drug in an animal model of Parkinson's disease. Quantitative analysis of [125I]EGF binding was performed on the brains of three control monkeys, nine monkeys rendered parkinsonian by MPTP intoxication, three of which were treated with L-Dopa. An increased density of [125I]EGF binding was observed at anterior levels in the dorsal striatum, but not in the pallidum, of patients with Parkinson's disease and progressive supranuclear palsy. [125I]EGF binding was unchanged in parkinsonian monkeys whether or not they had been treated with L-Dopa. The data suggest an increased expression of EGFRs in the striatum in chronic parkinsonian syndromes but not in acute models of the disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Consequences of nigrostriatal denervation on the functioning of the basal ganglia in human and nonhuman primates: an in situ hybridization study of cytochrome oxidase subunit I mRNA.

To examine the consequences of nigrostriatal denervation and chronic levodopa (L-DOPA) treatment on functional activity of the basal ganglia, we analyzed, using in situ hybridization, the cellular expression of the mRNA encoding for cytochrome oxidase subunit I (COI mRNA), a molecular marker for functional neuronal activity, in the basal ganglia. This analysis was performed in monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Intoxication, some of which had been receiving L-DOPA, and in patients with Parkinson's disease (PD). In MPTP-intoxicated monkeys compared with control animals, COI mRNA expression was increased in the subthalamic nucleus (STN) and in the output nuclei of the basal ganglia, i.e., the internal segment of the globus pallidus and the substantia nigra pars reticulata. This increase was partially reversed by L-DOPA treatment. COI mRNA expression remained unchanged in the external segment of the globus pallidus (GPe). In PD patients, all of whom had been treated chronically by L-DOPA, COI mRNA expression in the analyzed basal ganglia structures was similar to that in control subjects. These results are in agreement with the accepted model of basal ganglia organization, to the extent that the output nuclei of the basal ganglia are considered to be overactive after nigrostriatal denervation, partly because of increased activity of excitatory afferents from the STN. Yet, our results would also seem to contradict this model, because the overactivity of the STN does not seem to be attributable to a hypoactivation of the GPe.

Aged↗
PubMed1997

Step initiation in Parkinson's disease: influence of levodopa and external sensory triggers.

We studied anticipatory postural adjustments contributing to gait initiation deficits in patients with Parkinson's disease (PD) to determine if these deficits could be improved by administration of levodopa or by external stimuli. Ground reaction forces and body kinematics were recorded for self-generated and cutaneous cue-triggered step initiation in normal subjects and in PD subjects when OFF and when ON. The effects of assisting anticipatory postural sway with a surface translation coupled with a cutaneous cue were also examined. Decreased force production, decreased velocity of movement, and slowed execution of the anticipatory postural adjustments for self-generated step characterized step initiation in PD subjects when OFF. These impairments were significantly less evident when the PD subjects were ON. Both PD and normal subjects increased force and velocity of movement when a cutaneous cue was used as a go signal. When subjects voluntarily initiated a step in response to the surface translation, both PD and normal subjects executed the anticipatory postural adjustments for step more rapidly, but the PD subjects, both ON and OFF, failed to increase force to execute push-off more rapidly. In conclusion, dopaminergic therapy and an external stimulus similarly improve the deficient force production for the anticipatory postural adjustments associated with step initiation in PD. The findings also suggest that force production during the postural adjustment phase of self-generated, but not externally triggered, step initiation is influenced by dopaminergic pathways.

Aged↗
PubMed1997

Re-evaluation of the functional anatomy of the basal ganglia in normal and Parkinsonian states.

In the late 1980s, a functional and anatomical model of basal ganglia organization was proposed in order to explain the clinical syndrome of Parkinson's disease. According to this model, the pathological overactivity observed in the subthalamic nucleus and the output station of the basal ganglia plays a crucial role in the pathophysiology of the motor signs of Parkinson's disease. The hyperactivity of subthalamic neurons in Parkinsonism is viewed as a direct consequence of a pathological hypoactivity of the external segment of the pallidum. This article reviews recent data from different experimental approaches that challenge the established model of basal ganglia organization by reinterpreting the functional interaction between the external segment of the pallidum and the subthalamic nucleus in both the normal and pathological state. Indeed, recent neurobiochemical studies have rather unexpectedly shown that the GABAergic and metabolic activities of the external pallidum are not decreased in human and non-human primates with Parkinsonism. This absence of any decrease in activity might be explained by the functionally antagonistic influences of the striatal and subthalamic afferences within the external pallidum, as suggested by several anatomical studies. In addition, there are clues from electrophysiological studies to suggest that the hyperactivity found in the subthalamic neurons in Parkinsonism may not depend solely on the level of activity in the external pallidum. In such a framework, the hyperactivity of the subthalamic neurons would have to be explained, at least in part, by other sources of excitation or disinhibition. However, any explanation for the origin of the subthalamic overactivity in Parkinsonism remains speculative.

Animals↗
PubMed1997

Pallidotomy in Parkinson's disease increases supplementary motor area and prefrontal activation during performance of volitional movements an H2(15)O PET study.

Supplementary motor area and right dorsal prefrontal cortex activation in Parkinson's disease is selectively impaired during volitional limb movements. Since posteroventral pallidotomy improves motor performance in Parkinson's disease patients 'off' medication (i.e. off medication for 9-12 h), we hypothesized that it would also concomitantly increase supplementary motor area and dorsal prefrontal cortex activation. Six Parkinson's disease patients with a median total motor Unified Parkinson's Disease Rating Scale (UPDRS) of 52.5 (range 34-66) 'off' medication underwent unilateral right posteroventral pallidotomy. The patients had H2(15)O PET when 'off' medication before and 3-4 months after surgery. Each PET study comprised four to six measurements of regional cerebral blood flow either at rest or while performing regularly paced joystick movements in freely selected directions (forward, backward, left or right) using the left hand. Pre- and postoperative scans were performed in an identical manner and the associated levels of activation were compared using statistical parametric mapping. After pallidotomy, the median total motor UPDRS score 'off' medication decreased by 34.7% (P = 0.03) and mean response times of joystick movements following the pacing tones improved by 13.8% (P = 0.08). Relative increases in activation of the supplementary motor area and right dorsal prefrontal cortex were observed during joystick movements (P < 0.001). Decreased activation was seen in the region of the right pallidum (P = 0.001). We conclude that pallidotomy reduces pallidal inhibition of thalamocortical circuits and reverses, at least partially, the impairment of supplementary motor area and dorsal prefrontal cortex activation associated with Parkinson's disease.

Adult↗
PubMed1997

[Bilateral asymmetric degeneration of the striatum as a cause of senile hemiballism].

We report the case of an 82-years old woman with sporadic acute hemiballism associated with bilateral striatal degeneration of non vascular origin which was most severe in the side contralateral to the hemiballism. The patient's neuropathological lesions resembled those of patients with senile chorea. Although hemiballism has never been described as an isolated manifestation of primary degeneration of the striatum, it may so occur in elderly patients with hemiballism.

Aged↗