Hemiballism in Parkinson's disease.
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Brain↗
Biomedical subjects
J A Obeso
Publications and source records attributed to J A Obeso.
Clinical aspects of negative myoclonus.
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Dystonia↗
Restoration of thalamocortical activity after posteroventral pallidotomy in Parkinson's disease.
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Cerebral Cortex↗
MPTP-induced parkinsonism in primates: pattern of striatal dopamine loss following acute and chronic administration.
We analyzed the effect of two different schedules of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment on dopaminergic systems in the striatum of cynomolgus monkeys. Acute MPTP treatment produced a marked dopamine (DA) depletion, more severe in the caudate nucleus than in the putamen. Chronic MPTP induced a more pronounced reduction in DA levels, the putamen being slightly more affected than the caudate nucleus, in accord with immunohistochemical findings that showed a higher loss of tyrosine-hydroxylase positive neurons in ventral subpopulations of the substantia nigra pars compacta. A striking increment in the quotient DOPAC+HVA/DA was also observed in chronically but not in acutely treated monkeys, especially in the putamen. In chronically treated animals there was a nearly complete loss of DA in all subdivisions of the putamen. In the caudate nucleus, a rostrocaudal gradient of DA depletion was found, with a greater decrease in DA concentration in the rostral parts, especially in the dorsolateral portions. The pattern of striatal DA loss characteristic of Parkinson's disease can be reproduced to a certain extent in MPTP-intoxicated primates.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
The role of pulsatile versus continuous dopamine receptor stimulation for functional recovery in Parkinson's disease.
More effective measures to control and replace the dopaminergic deficit of Parkinson's disease are being actively sought. One basic problem is how the striatal dopamine loss should be replaced in order to mimic most accurately the physiological state. Animal electrophysiology indicates that the dopaminergic nigrostriatal pathway has a dual tonic and phasic action. Intermittent dopaminergic stimulation is associated with behavioural hyposensitivity both in animal models and in patients with Parkinson's disease. Continuous dopaminergic stimulation provides a tonic background and improves some clinical problems but is also associated with tolerance. None of the available pharmacological approaches can restore the dopamine deficiency of Parkinson's disease to physiological levels. Continuous dopaminergic stimulation for < 24 h, associated with small doses of levodopa or a short-acting dopamine agonist, appears to be the best, albeit imperfect, therapeutic approach until other, more efficacious remedies are developed.
Animals↗
Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopa and GM1 ganglioside therapy.
Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein found in the remaining cells. The reduced expression of tyrosine hydroxylase may be due to either the evolving neurodegenerative process or its downregulation, possibly secondary to chronic levodopa treatment. The cellular content of tyrosine hydroxylase was determined in the mesencephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonian by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatment) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalon of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, the cellular content of tyrosine hydroxylase was reduced by 40% in the surviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosine hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expression of tyrosine hydroxylase found in nigral dopaminergic neurons after partial degeneration of the mesostriatal dopaminergic system is not influenced by levodopa treatment and is partially reversed by GM1 ganglioside administration.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Variable onset of adult inherited focal dystonia: a problem for genetic studies.
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Adult↗
The functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson's disease.
The basal ganglia play a role in controlling movement. The motor circuits within the striato-pallidal complex are thought to facilitate desired movement and inhibit unwanted movement through their influence via thalamus, mainly on precentral motor cortical regions. Lesions in the motor thalamus, or in the globus pallidus, therefore might be expected to impair voluntary movement. But stereotaxic lesions in patients with Parkinson's disease directed at the motor thalamus verified at autopsy, and lesions in the globus pallidus, which improve rigidity and tremor, apparently do not worsen parkinsonian hypokinesia and bradykinesia; nor do they regularly cause dyskinesias. Reasons for this discrepancy are reviewed. It is concluded that the motor circuits of the basal ganglia are part of a distributed motor system which can operate, albeit imperfectly, in the absence of striato-pallido-thalamo-cortical feedback. There may, however, be subtle defects in motor performance after thalamic and pallidal lesions which have escaped attention. Further consideration leads to two hypotheses concerning normal basal ganglia motor function. First, it seems most likely that it is a pause in firing of medial pallidal and substantia nigra reticulata neurons that, by disinhibition of thalamic targets, permits movements generated by cortical motor areas. An increase in firing of medial pallidal neurons, which so far has been the major focus of attention, may be more concerned with inhibition of unwanted movement. Secondly, we suggest that the basal ganglia play a particular role in motor control. A change in firing of medial pallidal neurons appears to occur too late to initiate a new movement. However, the motor circuit within the striato-pallidal system routinely receives a continuous delayed read-out of cortical motor activity and issues an output directed via thalamus mainly to premotor cortical regions. This may permit the routine automatic execution of sequences of movements generated in cortical motor areas. There is evidence that other regions of the striatum respond to significant external or internal cues as dictated by their cortical inputs, the significance being determined by memory, novelty, emotional and other contexts. We suggest that such events capture the attention of the non-motor striatum, which then interrupts the routine operation of the motor circuit, perhaps at the level of the medial pallidum and substantia nigra pars reticulata, to permit new cortical motor action.
Animals↗
Dystonic storms: a practical management problem.
On rare occasions, torsion dystonia can rapidly worsen and produce life-threatening symptoms. We present reports on two children who had generalized dystonia and who demonstrate the management difficulties of "dystonic storms."
Child↗
Reflex myoclonus in olivopontocerebellar atrophy.
The presence of reflex myoclonus in response to touching and pin-pricking the wrist or stretching the fingers and to photic stimulation was assessed in 24 patients with a presumed diagnosis of olivopontocerebellar atrophy (OPCA) and in 30 age matched control subjects. Reflex myoclonus to soma-esthetic stimulation was found in 23 patients and in none of the controls. Photic myoclonus was present in 12 patients and in none of the controls. Electrophysiological study of the reflex myoclonus showed enhanced (> 10 microV) somatosensory evoked potentials and an associated reflex electromyographic discharge (C-wave) in 15 patients. These findings indicate that reflex myoclonus is common in OPCA and probably of cortical origin.
Atrophy↗
Motor response to apomorphine and levodopa in asymmetric Parkinson's disease.
The motor responses of 14 patients with Parkinson's disease (six previously untreated and eight chronically receiving levodopa) with pronounced asymmetry in the severity of motor signs between the left and right sides of the body were studied. The effects of a short (60 minutes) and a long (16-22 hours) intravenous levodopa infusion as well as of subcutaneous apomorphine (1-6 mg bolus) were assessed. Four different tapping tests were used to measure motor function. For all pharmacological tests, the more affected side showed a shorter response duration, increased latency, and greater response magnitude than the less affected side. These differences were more pronounced in those patients receiving chronic levodopa treatment. As apomorphine is not dependent on dopamine storage capacity, these findings suggest that postsynaptic mechanisms play an important part in the origin of motor fluctuations in Parkinson's disease.
Apomorphine↗
Subthalamotomy improves MPTP-induced parkinsonism in monkeys.
Hyperactivity of the subthalamic nucleus (STN) is major characteristic of parkinsonism secondary to substantia nigra lesions. Interruption of the STN-internal pallidum (GPi) pathway is a new stereotactic target for Parkinson's disease. We have studied the antiparkinsonian efficacy of STN lesions in MPTP-treated monkeys. Four rhesus monkeys were made parkinsonian by MPTP (i.v. 0.15 +/- 1 mg/kg) administration over 3 months. Unilateral subthalamotomy (kainic acid) was performed by a standard stereotactic method. Severity was rated from 0 (normal) to V by fine manual motor tests. Three monkeys (severity state III/IV) showed marked improvement in spontaneous activity, facial expression and manual dexterity bilaterally but significantly greater in the limb contralateral to the lesion. Mild hemichorea was present in 2 and hemiballism in one. L-Dopa treatment (50 mg b.i.d.) enhanced the hemidyskinesias moderately. The therapeutic effect has persisted for over 8 months postsurgery. Monkey No.4 (severity stage V) showed chorea in the lower limb contralateral to the lesion but no improvement and died a few days later. Subthalamotomy improves parkinsonism in moderately severe parkinsonian monkeys. Dyskinesia might be a persistent complication.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
[Olivopontocerebellar atrophy and Parkinson's disease: diagnostic problems].
Clinical diagnoses of Parkinson's disease (PD) is highly inaccurate. Olivopontocerebellar atrophy (OPCA) is a major source of diagnostic confusion. We have studied the clinical characteristics of 50 patients with PD, 24 patients with OPCA judged by the presence of selective atrophy of the cerebellum and brainstem (diagnosed by CT brain scan) and 30 normal controls of similar age. The typical triad of PD, tremor, rigidity and akinesia, did not distinguish among patients from either group. The presence of severe postural imbalance and reflex myoclonus (in OPCA but not in PD) were the 2 most highly discriminative clinical features.
Aged↗
Differential vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine of dopaminergic and cholinergic neurons in the monkey mesopontine tegmentum.
Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra and, in the most severe cases, by degeneration of mesopontine cholinergic neurons. In a monkey model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine we report that, despite a severe loss of dopaminergic neurons, in the mesopontine tegmentum cholinergic neurons are preserved in the same region. This suggests that the loss of mesopontine cholinergic neurons in parkinsonian patients may represent an end-stage degenerative process, the cause of which may be independent of the mechanism of dopaminergic cell death.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
In situ hybridization of GAD mRNA in monkey and human brain: quantification at both regional and cellular levels.
GAD mRNA was detected in human and monkey brain postmortem by in situ hybridization with an [35S]-labelled copy RNA corresponding to a 2.7-kb fragment of the coding region of human GAD mRNA. A characteristic and reproducible pattern of hybridization was obtained with the anti-sense, but not the sense probe in both monkey and human brain. Microscopic examination of tissue sections showed that only neuronal perikarya, not glial cells, were labelled. The data confirm the heterogeneity of GAD mRNA distribution reported in rodent brain and non-human primate brain.
Aged↗
The AMPA receptor antagonist NBQX does not alter the motor response induced by selective dopamine agonists in MPTP-treated monkeys.
We studied the motor response induced by the administration of the AMPA receptor antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline(1H,4H)dione sodium salt), in two parkinsonian monkeys and its interaction with the selective D-2 dopamine receptor agonist, (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine], and the partial dopamine D-1 receptor agonist, CY 208-243 [(-)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3a-b]phen anthyxidine]. NBQX treatment did not reverse the parkinsonism or change the responses previously induced by dopamine agonists. These results do not support an antiparkinsonian effect of the AMPA receptor antagonist, NBQX. In addition they indicate that there is no functional interaction between AMPA and dopamine receptors in monkeys with a substantia nigra lesion.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
The pathophysiology and pharmacology of photic cortical reflex myoclonus.
We studied 6 patients with myoclonus elicited by flash stimulation (1-15 Hz). Multichannel electromyographic recording showed a rostrocaudal recruitment order for the generalized myoclonic jerk. In all patients, each flash induced a large (36.9 +/- 5.7 microV) frontal biphasic wave with an onset latency of 42 msec that preceded the earliest muscle response in the face by at least 4 msec (range, 4-7 msec), the activity in the biceps by 11 to 14 msec, and the activity in tibialis anterior by 26 to 34 msec. Occipital potentials evoked by the same flash stimulation had a latency of 33.7 msec and were of normal amplitude (2.1 +/- 1.2 microV). Brain-mapping analysis indicated that the frontal activity correlated with the myoclonus originated in the premotor and motor cortices. These findings provide evidence for a cortical origin of this form of stimulus-sensitive myoclonus in humans. Administration of apomorphine and lisuride (intravenously) and levodopa-carbidopa (orally) abolished the photic myoclonus. Intravenous 5-hydroxytryptophan plus carbidopa (orally) and piracetam (orally) were also effective against photic myoclonus. The wide range of drugs active against photic cortical myoclonus suggests the participation of several biochemical mechanisms in its origin.
5-Hydroxytryptophan↗