J. A. Obeso

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 Parkinsons 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 Parkinsons 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.

Effects of l-DOPA on preproenkephalin and preprotachykinin gene expression in the MPTP-treated monkey striatum

The cellular expression of the genes encoding the neuropeptides enkephalin and substance P were examined in the caudate nucleus and putamen of parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys by in situ hybridization using radioactive antisense oligonucleotides coupled with computer-assisted image analysis. Behavioural evaluation of the animals revealed two levels of motor impairment; one group moderately impaired and the other severely disabled. A marked increase in the cellular content of preproenkephalin A messenger RNA was observed in medium-sized (106 +/- 9 microns2) cells in the caudate-putamen of all MPTP animals when compared with controls, the increase being greatest in the most severely impaired animals. By contrast, a marked reduction in the cellular abundance of preprotachykinin gene expression was detected in striatal cells (101 +/- 16 microns2) of these same MPTP animals. These changes in neuropeptide gene expression were not associated with a change in the density (approximately 10 cells per mm2) of messenger RNA-expressing cells. L-DOPA treatment of two of the severely-impaired MPTP monkeys resulted in a dissociation of expression of these two genes: the cellular abundance of preproenkephalin A remained elevated whilst preprotachykinin levels were normalized and comparable with controls. No change in the cellular abundance of preprotachykinin messenger RNA was observed in cells of the insular cortex or a small discrete population of large cells (208 +/- 27 microns2) in the ventral putamen. These results demonstrate that MPTP treatment of primates results in a marked potentiation in preproenkephalin messenger RNA coupled with a attenuation in preprotachykinin messenger RNA in the dopamine-denervated caudate-putamen. L-DOPA therapy given on an intermittent schedule reverses the decrease in preprotachykinin messenger RNA, but fails to reverse the increase in preproenkephalin messenger RNA in the same animal. These observations suggest that a dissociation of the activity of these two neuropeptide systems may underlie the improvement in motor skill that accompanies dopamine replacement therapy and that this dissociation may be instrumental in the long-term complications associated with L-DOPA therapy.

Movement-related changes in oscillatory activity in the human subthalamic nucleus : ipsilateral vs. contralateral movements

A voluntary movement is accompanied by a series of changes in neuronal oscillatory activity in the subthalamic nucleus (STN). These changes can be recorded through electrodes implanted for deep brain stimulation to treat Parkinsons disease in the time interval between the surgery and the internalization of the connections to the batteries. Both baseline activity and movement‐related changes are different in the ‘on’ and ‘off’ medication motor states. In the ‘off’ state a low frequency activity in the alpha–beta range (8–25 Hz) that dominates the spectrum is interrupted during the movement, while in the ‘on’ state baseline frequencies are higher and a peri‐movement gamma increase (70–80 Hz) is usually observed. Similar changes have been described with electrocorticographic recordings over the primary motor cortex but the gamma increase was only present during contralateral movements. We compared ipsi‐ and contralateral movement‐related changes in STN activity, using a time–frequency analysis of the recordings obtained simultaneously in both STN and the scalp (electroencephalography) during right and left hand movements. The movement‐related changes observed in the STN in the ‘on’ and the ‘off’ states were similar to those described previously in terms of predominant frequency bands, but we found bilateral changes in the STN during movements of either hand. A contralateral earlier start of the beta STN changes was mostly observed when the moving hand corresponded to the less‐affected side, irrespective of hand dominance. These results suggest that movement‐related activity in the STN has, by and large, a bilateral representation and probably reflects cortical input.

Metabolic activity of the basal ganglia in parkinsonian syndromes in human and non-human primates: A cytochrome oxidase histochemistry study

In order to examine the consequences of nigrostriatal denervation on metabolic and functional activity of the basal ganglia, we analysed the distribution of cytochrome oxidase, a metabolic marker for neuronal functional activity, throughout the different basal ganglia structures in parkinsonian syndromes. The study was performed using enzyme histochemistry and densitometric measurements in patients with Parkinsons disease and in monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrydine (MPTP) intoxication. In MPTP-intoxicated monkeys compared to control animals, enzyme activity was significantly increased in the subthalamic nucleus and in the output nuclei of the basal ganglia, e.g. the internal segment of the globus pallidus and the substantia nigra pars reticulata, but remained unchanged in the external segment of the globus pallidus and the striatum. L-DOPA treatment reversed the increased enzyme activity in all of the affected structures studied. In contrast, in parkinsonian patients, who had all been chronically treated with L-DOPA, no changes in enzyme activity were detected compared to control subjects. The results in MPTP-intoxicated monkeys are in agreement with the accepted model of basal ganglia organization, in which the output nuclei of the basal ganglia are considered to be overactive after nigrostriatal denervation, partly due to increased activity of excitatory afferents from the subthalamic nucleus. Since the increased enzyme activity in MPTP-intoxicated monkeys was reversed by L-DOPA therapy, the unchanged cytochrome oxidase activity observed in parkinsonian patients might result from L-DOPA treatment, combined with the chronicity of nigrostriatal denervation.

Extensive loss of brain dopamine and serotonin induced by chronic administration of MPTP in the marmoset

Common marmosets were given a subcutaneous injection of MPTP (1.25-2.5 mg/kg twice a week) for 5 or 10 consecutive months and were sacrificed after a survival time of 6 months or 15 days, respectively. The parkinsonian symptoms were not very marked at the time of sacrifice but there was a strong decrease of dopamine and, to a lesser extent, of its metabolites in the striatum and in some extrastriatal regions. There was also a profound loss of serotonin in the striatum and in all of the extrastriatal regions analyzed, which was still highly significant 6 months after discontinuation of MPTP treatment. The results suggest that the selected dosage schedule produces a widespread and lasting neuronal degeneration closely resembling the neurochemical pathology of Parkinsons disease.

Consequence of nigrostriatal denervation and L-dopa therapy on the expression of glutamic acid decarboxylase messenger RNA in the pallidum

To examine the consequences of nigrostriatal denervation and L-dopa treatment on the basal ganglia output system, we analyzed, by quantitative in situ hybridization, the messenger RNA coding for glutamic acid decarboxylase (Mr 67,000) (GAD67 mRNA) in pallidal cells from patients with Parkinsons disease (PD), monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) receiving or not receiving L-dopa, and their respective control subjects. In MPTP-treated monkeys, the expression of GAD67 mRNA was increased in cells from the internal pallidum, and this effect was abolished by L-dopa treatment. There were no differences in the levels of GAD67 mRNA between patients with PD, who were all treated with L-dopa, and control subjects. These results indicate that the level of GAD67 mRNA is increased in the cells of the internal pallidum after nigrostriatal dopaminergic denervation and that this increase can be reversed by L-dopa therapy. NEUROLOGY 1996;47: 219-224

Consequences of nigrostriatal denervation on the gamma-aminobutyric acidic neurons of substantia nigra pars reticulata and superior colliculus in parkinsonian syndromes

To examine the effects of nigrostriatal denervation on the substantia nigra pars reticulata (SNpr), one of the main outputs of the basal ganglia, we used quantitative in situ hybridization to analyze the messenger RNA coding for Mr 67,000 glutamic acid decarboxylase (GAD67 mRNA) in the SNpr neurons from patients with Parkinsons disease (PD), monkeys rendered parkinsonian by 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), and their respective controls. In MPTP-intoxicated monkeys, the expression of GAD67 mRNA was increased in the SNpr neurons, and the increase was reversed by L-dopa treatment. There were no differences in the level of GAD67 mRNA between PD patients who had been treated with L-dopa and control subjects. Combined with the previously reported increased expression of GAD67 mRNA in the internal segment of the pallidum of MPTP-intoxicated monkeys, these data suggest that the gamma-aminobutyric acid (GABAergic) activity of the output system of the basal ganglia is globally increased by nigrostriatal denervation. We also analyzed the level of GAD67 mRNA expression in the superior colliculus, a structure that receives the inhibitory influence of the GABAergic neurons of the SNpr and that is involved in eye movement control. GAD67 mRNA expression was reduced in both MPTP-intoxicated monkeys, whether or not they received L-dopa therapy, and PD patients, compared to their respective controls. This decrease may result from the hyperactivity of the inhibitory nigrotectal pathway, but also from other influences since it was not corrected by L-dopa therapy. These changes may account for the slight ocular motor and visuospatial cognitive impairment occurring in PD, even after L-dopa therapy.

Effects of Nigrostriatal Denervation and L‐Dopa Therapy on the GABAergic Neurons of the Striatum in MPTP‐treated Monkeys and Parkinson's Disease: An In Situ Hybridization Study of GAD67 mRNA

The effects of nigrostriatal denervation and L‐dopa therapy on GABAergic neurons were analysed in patients with Parkinsons disease and in monkeys rendered parkinsonian by MPTP intoxication. The expression of the messenger RNA coding for the 67 kDa isoform of glutamic acid decarboxylase (GAD67 mRNA), studied by quantitative in situ hybridization, was used as an index of the GABAergic activity of the striatal neurons. A significant increase in GAD67 mRNA expression, generalized to all GABAergic neurons, was observed in MPTP‐treated monkeys compared to control monkeys in the putamen and caudate nucleus (+44 and +67% respectively), but not in the ventral striatum. L‐Dopa therapy significantly reduced GAD67 mRNA expression in the putamen and caudate nucleus to levels similar to those found in control monkeys. However, the return to normal of GAD67 mRNA expression was not homogeneous across all neurons since it was followed by an increase of labelling in one subpopulation of GABAergic neurons and a decrease in another. These data suggest that in MPTP‐treated monkeys the degeneration of nigrostriatal dopaminergic neurons results in a generalized increase in GABAergic activity in all the GABAergic neurons of the striatum, which is partially reversed by L‐dopa therapy. As the expression of GAD67 mRNA is less intense in the ventral than in the dorsal striatum, this increase in striatal GABAergic activity may be related to the severity of nigrostriatal denervation. In parkinsonian patients who had been chronically treated with L‐dopa, GAD67 mRNA expression was significantly decreased in all GABAergic neurons, in the caudate nucleus (by 44%), putamen (by 43.5%) and ventral striatum (by 26%). The opposite variation of GAD67 mRNA in patients with Parkinsons disease, compared with MPTP‐treated monkeys, might be explained by the combination of chronic nigrostriatal denervation and long‐term L‐dopa therapy.

Cabergoline in Parkinson's disease Long‐term follow‐up

We treated 36 patients with motor fluctuations and dyskinesias on chronic levodopa therapy with cabergoline (CBG) once a day for a mean period of 14.2 ± 5.8 months. There was a significant increase in the “on” hours and a reduction in “off-period” dystonia. Ten patients continued to show a marked improvement after 28.3 months of treatment (mean dose, 11.3 ± 4.5 mg). In 23 patients, increased dyskinesias (daily CBG dose, 11 ± 4.3 mg) had complicated the positive effect after 17.2 ± 4.8 months. Three patients (daily CBG dose, 14.3 mg) were therapeutic failures, and administration of CBG was stopped. Side effects leading to CBG discontinuation were visual hallucinations (n = 5), heart failure (n = 5), and nausea and vomiting (n = 1). Plasma CBG levels, measured in seven patients taking 3, 5, or 7 mg daily (po), showed fairly stable concentrations throughout the 24 hours. We concluded that CBG is an efficient dopamine agonist that can provide continuous dopaminergic stimulation when taken orally once a day.

What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity.

One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in patients with Parkinsons disease (PD) and in animal models such as the rat with 6-hydroxydopamine (6-OHDA)-induced lesion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, all of which are associated with severe striatal dopamine depletion. Neuronal hyper-synchronization in the beta (or any other) band is not present despite the presence of bradykinetic features in the rat and monkey models, suggesting that increased beta band power may arise when nigro-striatal lesion is advanced and that it is not an essential feature of the early parkinsonian state. Similar observations and conclusions have been previously made for increased neuronal firing rate in the subthalamic and globus pallidus pars interna nuclei. Accordingly, it is suggested that early parkinsonism may be associated with dynamic changes in basal ganglia output activity leading to reduced movement facilitation that may be an earlier feature of the parkinsonian state.