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PubMedDate not supplied

Effects of the activity of the internal globus pallidus-pedunculopontine loop on the transmission of the subthalamic nucleus-external globus pallidus-pacemaker oscillatory activities to the cortex.

Resting tremor is the most specific sign for idiopathic Parkinson' disease. It has been proposed that parkinsonian tremor results from the activity of the central oscillators. One of the hypotheses, which have been proposed about the possible principles underlying such central oscillations, is the subthalamic nucleus (STN)-external globus pallidus (GPe)-pacemaker hypothesis. Activity from the central oscillator is proposed to be transmitted via trans-cortical pathways to the periphery. A computational model of the basal ganglia (BG) is proposed for simulating the effects of the internal globus pallidus (GPi)-pedunculopontine (PPN) loop activity on the transmission of the STN-GPe-pacemaker oscillatory activities to the cortex, based on known anatomy and physiology of the BG. According to the result of the simulation, the GPi-PPN loop activity can suppress the transmission of the STN-GPe-pacemaker oscillatory activities to the cortex. This suppressive effect is controlled by various factors such as the strength of the synaptic connection from the PPN to the GPi, the strength of the synaptic connection from the GPi to the PPN, the spontaneous tonic activities of the GPi and PPN, the direct excitatory projections from the STN to the PPN, the frequency of the STN oscillatory burst activity, the duration of the STN burst, and the maximum T-type calcium channel conductance in the type-I PPN neurons.

Animals↗

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↗

PubMed1997

Subthalamic ablation reverses changes in basal ganglia oxidative metabolism and motor response to apomorphine induced by nigrostriatal lesion in rats.

In Parkinson's disease, the functional architecture of the basal ganglia nuclei undergoes profound alterations, one of the most important of which is overactivity of the basal ganglia output nuclei. This phenomenon seems to be intimately related to pathological overactivity of the subthalamic nucleus, which directly modulates the basal ganglia output through its glutamatergic projections. In this study, we investigated the effects of unilateral subthalamic nucleus lesions on the activities of succinate dehydrogenase and cytochrome oxidase, two markers of neuronal activity, in rats with prior unilateral lesions of the nigrostriatal tract. We also explored the effect of subthalamic nucleus lesions on the rotational response to systemic apomorphine. Rats with unilateral lesions of the nigrostriatal tract showed ipsilateral increases in enzyme activity in the basal ganglia output nuclei, entopeduncular nucleus and substantia nigra pars reticulata. Selective subthalamic nucleus destruction completely reversed this phenomenon. In addition, subthalamic nucleus lesions abolished the rotational response to apomorphine. These results confirm that overactivity of the subthalamic nucleus plays a pivotal role in the functional alterations of basal ganglia associated with Parkinson's disease. They also shed further light on the neural mechanisms through which manipulations of subthalamic activity can ameliorate Parkinson's disease symptoms.

Animals↗

PubMed1985

Bilateral corticosubthalamic nucleus projections: an electrophysiological study in rats with chronic cerebral lesions.

The present study sought to determine the distribution of the cortical areas giving rise to the corticosubthalamic nucleus projections, using extracellular stimulating and recording techniques in rats with and without chronic lesions. In acute rats, cortical stimulation induced a powerful excitation in 87% of the subthalamic nucleus cells recorded. This response was obtained from stimulation over a large extent of the cortex since nearly all the ipsilateral cortex and the rostral two-thirds of the contralateral side was found to influence the activity of the subthalamic nucleus neurones. An excitatory response quite similar to that induced by cortical stimulation was recorded in the subthalamic nucleus after striatal or internal capsule stimulations. Therefore in order to eliminate the possibility of recording a polysynaptic excitation, similar experiments were performed in rats bearing various chronic lesions. With either ipsilateral or contralateral cortical stimulations, there was no major consequence of these lesions on the type or characteristics of the response recorded or on the percentage of responding cells. The cortical origin of the excitation of the subthalamic neurones was further supported by the results of experiments performed in chronically decorticated rats. It is concluded that (1) the subthalamic nucleus receives an excitatory cortical input, (2) this control comes from ipsilateral and contralateral cortical areas and (3) it only involves direct corticosubthalamic nucleus fibres. The subthalamic nucleus is, together with the striatum, the only basal ganglia nucleus known to receive afferents from extensive regions of the cortex. By its two main afferents (cortex and external segment of the pallidum), the subthalamic nucleus is in a position to compare direct cortical informations with cortical informations processed at the striatopallidal complex level.

Animals↗

PubMed2004

Death of dopaminergic neurones in the rat substantia nigra can be induced by damage to globus pallidus.

Parkinson's disease is a debilitating disorder that results from the death of dopaminergic neurones in the substantia nigra. Subthalamic nucleus neurones use glutamate as their neurotransmitter and send excitatory projections to the substantia nigra. Changes in both the mean firing rate and firing pattern of neurones of the subthalamic nucleus have been found in patients with this disease. This has led to the suggestion that hyperactivity of the subthalamic nucleus may be involved in the pathology of the dopaminergic neurones. Subthalamic nucleus lesions or treatment with glutamatergic antagonists can be neuroprotective in animal models of Parkinson's disease but until now there has been no direct evidence that hyperactivity of subthalamic nucleus neurones can lead to downstream cell death. Here we show that lesions of the rat globus pallidus (a treatment that has been shown to increase subthalamic nucleus neuronal activity) result in a significant reduction of the number of dopaminergic neurones in the substantia nigra.

Animals↗

PubMed2001

A case of clinically and neuropathologically atypical corticobasal degeneration with widespread iron deposition.

A 65-year-old woman was admitted to our hospital for forgetfulness, depression and eccentric behavior that had been first noticed 2 years prior to admission. She showed memory impairment, perseveration and repeated violent actions, but no limb-kinetic apraxia. She died 12 years after the onset of symptoms. At autopsy, the unfixed brain weighed 820 g. Atrophy was circumscribed in the frontal lobe on both sides. The globus pallidus and the caudate nucleus were markedly atrophic and gold yellow in color, and the substantia nigra was strikingly pale. The cortical area showed neuronal loss and status spongiosus of the second and third cortical layers with ballooned neurons. Marked neuronal loss was observed in the dorsomedial nucleus of the thalamus, Meynert basal nucleus and substantia nigra. With Holzer stain, fibrillary gliosis was found to be severe in the frontal lobe, globus pallidus, subthalamic nucleus, hippocampus, dorsomedial nucleus of thalamus, substantia nigra, pontine tegmentum and inferior olivary nucleus. With Bielschowsky-Hirano stain, neurofibrillary tangles were observed in the cortex, hippocampus, substantia nigra, dentate nucleus, subthalamic nucleus, pontine nucleus, the inferior olivary nucleus, dorsomedial nucleus of the thalamus and, to a lesser extent, the neostriatum. Strikingly numerous argyrophilic and tau-positive threads were present in the cerebral white matter. These neuropathological findings corresponded to corticobasal degeneration, but lesions characteristic of progressive supranuclear palsy were also found. Moreover, widespread iron deposition throughout the central nervous system was the most striking finding of the present case. To our knowledge, such a case has not been reported in the literature to date.

Basal Ganglia↗

PubMed1995

Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. III. The basal forebrain compared with other subcortical areas.

The distribution of the reticular neuronal type in the human brain and its involvement in both degeneration and dendritic reorganisation under the conditions of ageing, Korsakoff's disease (KD), Alzheimer's disease (AD), and Parkinson's disease (PD) was comparatively investigated after Golgi impregnation. Reticular neurones are distributed throughout different areas along the brain axis. The cholinergic basal forebrain nuclei, i.e., the basal nucleus of Meynert, the nucleus of the diagonal band, and the medial septal nucleus form the most rostral part of this network of "open nuclei," which is collectively referred to as the "reticular core." Reticular neurones of the following areas were quantitatively investigated by a computer-based three-dimensional analysis: caudate nucleus, globus pallidus, medial septal nucleus, nucleus of the vertical limb of the diagonal band, basal nucleus, medial amygdaloid nucleus, reticular thalamic nucleus, lateral hypothalamic area, subthalamic nucleus, substantia nigra, locus coeruleus, pedunculopontine tegmental nucleus, and raphe magnus nucleus. There are three major findings. First, neurones that were found to be susceptible to degeneration in AD were largely part of the same neuronal populations prone to degeneration during ageing, in KD and PD. Thus, areas could be classified according to their overall degree of vulnerability under the present degenerative conditions as being highly vulnerable (basal forebrain nuclei, caudate nucleus, locus coeruleus), moderately vulnerable (medial amygdaloid nucleus, raphe magnus nucleus, lateral hypothalamic area, substantia nigra, pedunculopontine tegmental nucleus), or marginally vulnerable (globus pallidus, subthalamic nucleus, reticular thalamic nucleus). Second, neuronal populations that are particularly vulnerable to degenerative changes show a high degree of structural plasticity. Third, the degree of this dendritic plasticity is inversely related to the complexity of dendritic arborisation of the neurone. It is concluded that the sparsely ramified reticular type of neurone forms a pool of pluripotent neurones that have retained their plastic capacity throughout life, which makes them vulnerable to a variety of perturbations.

Adult↗

PubMed1993

Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys.

In Parkinson's disease the loss of dopaminergic neurons in the substantia nigra is associated with global disorganization of basal ganglia activity and, in particular, with increased activity of the excitatory glutamatergic neurons of the subthalamic nucleus. Recent experimental studies have shown that parkinsonian symptoms can be alleviated by selective lesioning of the subthalamic nucleus in monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We measured the effect of high-frequency stimulation of the subthalamic nucleus in two unilaterally MPTP-treated monkeys in order to determine whether it was possible to obtain reversible, gradual and controllable functional impairment of this structure. Clinical, mechanographic and electromyographic results demonstrate that this technique can alleviate parkinsonian rigidity and bradykinesia without causing dyskinesia or hemiballismus. This study supports the hypothesis that the subthalamic nucleus and its excitatory projections have an important role in the mechanisms sustaining the expression of parkinsonian motor changes, and suggests that high-frequency stimulation of the subthalamic nucleus could be included in treatment for parkinsonism.

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

PubMed2001

Segregation and convergence of information flow through the cortico-subthalamic pathways.

Cortico-basal ganglia circuits are organized in parallel channels. Information flow from functionally distinct cortical areas remains segregated within the striatum and through its direct projections to basal ganglia output structures. Whether such a segregation is maintained in trans-subthalamic circuits is still questioned. The effects of electrical stimulation of prefrontal, motor, and auditory cortex were analyzed in the subthalamic nucleus as well as in the striatum of anesthetized rats. In the striatum, cells (n = 300) presenting an excitatory response to stimulation of these cortical areas were located in distinct striatal territories, and none of the cells responded to two cortical stimulation sites. In the subthalamic nucleus, both prefrontal and motor cortex stimulations induced early and late excitatory responses as a result of activation of the direct cortico-subthalamic pathway and of the indirect cortico-striato-pallido-subthalamic pathway, respectively. Stimulation of the auditory cortex, which does not send direct projection to the subthalamic nucleus, induced only late excitatory responses. Among the subthalamic responding cells (n = 441), a few received both prefrontal and motor cortex (n = 19) or prefrontal and auditory cortex (n = 10) excitatory inputs, whereas a larger number of cells were activated from both motor and auditory cortices (n = 48). The data indicate that the segregation of cortical information flow originating from prefrontal, motor, and auditory cortices that occurred in the striatum is only partly maintained in the subthalamic nucleus. It can be proposed that the existence of specific patterns of convergence of information flow from these functionally distinct cortical areas in the subthalamic nucleus allows interactions between parallel channels.

Action Potentials↗

PubMed1990

[A case of hemiballism successfully treated by sulpiride, caused by lesions of the striatum].

A case of hemiballism caused by infarction in the left striatum on MRI was reported. Hemiballism is generally associated with lesions in the subthalamic nucleus. However, hemiballism occasionally occurs as a result of lesions outside the subthalamic nucleus. Hemiballism is a benign condition with spontaneous recovery in most cases, but hemiballism caused by lesions outside the subthalamic nucleus is reported to tend to persist for a long term. In our case without involvement of the subthalamic nucleus, hemiballism so far continued for three months since the onset. Successful pharmacological treatments of ballism with haloperidol or phenothiazines were well known. In our case, the treatments of ballism with these drugs were unsuccessful due to drug-induced hepatic dysfunction. Instead of these drugs, ballism was improved by administration of 150 mg of sulpiride per day with no side effects. Sulpiride may be beneficial for persistent hemiballism caused by the extra subthalamic lesions.

Aged↗

PubMed1986

Brain neurotransmitters in dystonia musculorum deformans.

We examined histologically and biochemically the brains of two patients with generalized childhood-onset dystonia musculorum deformans. We found no important histologic changes in the basal ganglia, cerebral cortex, higher brain-stem nuclei, locus ceruleus, or raphe nuclei. Similarly, the activity of choline acetyltransferase and the levels of gamma-aminobutyric acid and glutamic acid in the cerebral cortex and basal ganglia were within the control range. In contrast, the norepinephrine concentrations were markedly and consistently decreased in the lateral and posterior hypothalamus, mamillary body, subthalamic nucleus, and locus ceruleus. The serotonin level was subnormal in the dorsal raphe nucleus, as was the dopamine level in the nucleus accumbens and, in one of the two cases, in the striatum. Elevated concentrations of norepinephrine were found in the septum, thalamus, colliculi, red nucleus, and dorsal raphe nucleus; of serotonin, in the globus pallidus, subthalamic nucleus, and locus ceruleus; and of 5-hydroxyindoleacetic acid, in the globus pallidus, subthalamic nucleus, and nuclei raphe centralis inferior and obscurus. The level of homovanillic acid showed little consistent change in the regions examined. We conclude that some of these monoamine changes, especially the pronounced apparent disturbance of noradrenergic brain mechanisms, may represent a basic neurochemical abnormality in dystonia musculorum deformans and may thus be relevant to the pathoneurophysiology and treatment of this disorder.

Acetyltransferases↗

PubMed1992

Responses of globus pallidus neurons to cortical stimulation: intracellular study in the rat.

The responses of globus pallidus (GP) neurons to stimulation of the sensorimotor cortex, the neostriatum, and the subthalamic nucleus were intracellularly recorded in anesthetized rats. Stimulation of the cortex evoked a sequence of postsynaptic responses including an initial short EPSP, a short IPSP, and a late EPSP with multiple spikes in most of the repetitively firing GP neurons. The response pattern was very similar to those evoked by striatal stimulation, except that the latencies were longer. An acute knife cut placed immediately caudal to the substantia nigra caused no significant change in the responses to cortical and striatal stimulation. Stimulation of the subthalamic nucleus evoked a short latency EPSP overlapped with an IPSP. The polarity of all the IPSPs was reversed by a Cl- injection. A systemic injection of picrotoxin abolished all the IPSPs and unmasked large depolarizations with multiple spikes. An ibotenic acid lesion of the subthalamic nucleus eliminated both the initial short latency and late EPSPs to cortical and striatal stimulation and disclosed a prominent IPSP. Stimulation of the lesioned subthalamic nucleus also evoked large, short latency IPSPs without noticeable EPSPs. These results indicate that (i) the IPSPs evoked by cortical, striatal, and subthalamic stimulation were mediated by a GABAA receptor, (ii) both the initial and late EPSPs to cortical and striatal stimulation involved activation of the subthalamic nucleus but not brainstem nuclei, and (iii) cortically derived signals mediated through the neostriatum (i.e. long latency IPSPs) and the subthalamic nucleus (i.e. short latency EPSPs) converged on most GP neurons.

Animals↗

PubMed2000

Substantia nigra pars reticulata units in 6-hydroxydopamine-lesioned rats: responses to striatal D2 dopamine receptor stimulation and subthalamic lesions.

In order to increase our understanding of Parkinson's disease pathophysiology, we studied the effects of intrastriatally administered selective dopamine receptor agonists on single units from the substantia nigra pars reticulata of 6-hydroxydopamine (6-OHDA)-lesioned rats with or without an additional subthalamic nucleus lesion. Nigral pars reticulata units of 6-OHDA-lesioned rats were classified into two types, showing regular and bursting discharge patterns, respectively ('non-burst' and 'burst' units). Non-burst and burst units showed distinct responses to intrastriatal quinpirole (the former were excited and burst units inhibited). Furthermore, subthalamic nucleus lesions significantly decreased the number of nigral units showing a spontaneous bursting pattern, and reduced the proportion of units that responded to quinpirole. In contrast, subthalamic lesions did not alter the proportion of nigral units that responded to SKF38393, although the lesions changed some response features, e.g. response type and magnitude. Burst analysis showed that quinpirole did not modify the discharge pattern of burst units, whereas SKF38393 produced a shift to regular firing in 62% of the burst units tested. In conjunction, our results support that: (i) the subthalamic nucleus has an important influence on output nuclei firing pattern; (ii) striatal D2 receptors have a strong influence on nigral firing rate, and a less relevant role in controlling firing pattern; (iii) burst and non-burst units differ in their response to selective stimulation of striatal dopamine receptors; (iv) the effects of striatal D2 receptors on nigral units are mainly, though not exclusively, mediated by the subthalamic nucleus; and (v) nigral responses to SKF38393 involve the subthalamic nucleus.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1976

[Morphometric-statistical structure analysis of human striatum, pallidum and nucleus su-thalamicus. III. Nucleus subthalamicus].

1. A morphometric-statistical analysis of the subthalamic nucleus was carried out on 14 hemispheres of 12 normal human brains. 2. The values determined in paraffin embedded sections were corrected for shrinkage which showed considerable interindividual variation. 3. The mean fresh volume of the subthalamic nucleus amounted to 144 mm3 for males and 134 mm3 for females, the difference of 7% not being statistically significant. 4. In the medial part of the subthalamic nucleus the nerve cells were smaller and more closely grouped than in the lateral part which had larger nerve cells. The ratio of the volumes of the two parts was about 1:4 (medial: lateral). 5. The nucleus subthalamicus occupied 0,027% of the volume of the hemisphere. 6. The numerical nerve cell densities -- corrected for shrinkage -- were 1970 +/- 145 nerve cells/mm3 for the lateral part and 2910 +/- 310 nerve cells/mm3 for the medial part, this difference of 48 +/- 4% being highly significant. On the other hand, no difference between sexes could be shown. 7. The mean of the absolute number of nerve cells was 306000 for male and 286000 for females, the difference of 7% not being significant. 8. The volumetric nerve cell densities were found to be 1.58 +/- 0.15 vol% lateral and 1.99 +/- 0.16 vol% medial, the difference of 27% being significant. No differences between sexes were found. 9. The linear dimensions of the nerve cells of the medial part were about 10% smaller than those of the nerve cells of the lateral part. The mean fresh volume of a nerve cell was 8070 mum3 in the lateral portion and 6960 mum3 in the medial portion, the nerve cells of pars lateralis being just as large as the nerve cells of the lateral segment of the pallidum (8100 mum3). 10. The parameters determined showed good correlations with corresponding data of the pallidum. The fresh volume and the absolute numbers of nerve cells of the nucleus subthalamicus were better correlated with the pallidum laterale than with the pallidum mediale.

Biometry↗

PubMed2002

Evidence of thalamic disinhibition in patients with hemichorea: semiquantitative analysis using SPECT.

OBJECTIVES: Hemichorea sometimes occurs after lesions that selectively involve the caudate nucleus, putamen, and globus pallidus. Some reports have hypothesised that the loss of subthalamic nucleus control on the internal segment of the globus pallidus, followed by the disinhibition of the thalamus may contribute to chorea. However, the pathophysiology is poorly understood. Therefore, clinicoradiological localisation was evaluated and a comparison of the haemodynamic status of the basal ganglia and thalamus was made. METHODS: Six patients presenting with acute onset of hemichorea were assessed. Neuroimaging studies, including MRI and SPECT examinations in addition to detailed biochemical tests, were performed. A semiquantitative analysis was performed by comparing the ratio of blood flow between patients and normal controls. In addition, the ratio of perfusion asymmetry was calculated as the ratio between each area contralateral to the chorea and that homolateral to the chorea. The comparison was made with a two sample t test. RESULTS: The causes of hemichorea found consisted of four cases of acute stroke, one non-ketotic hyperglycaemia, and one systemic lupus erythematosus. Brain MRI indicated lesion sites in the contralateral putamen, globus pallidus, caudate nucleus, and subthalamic nucleus. A significant decrease in the ratio of blood flow in the basal ganglia contralateral to the chorea and a significant increase in the thalamus was found when comparing the perfusion asymmetries, which were calculated as the ratio of cerebral blood flow (CBF) for each region to that in the homolateral occipital area (p<0.05). CONCLUSION: An alteration in CBF in both the contralateral thalamus and basal ganglia reflect the loss of pallidal inhibitory input from the pallidum to the thalamus. This change in CBF may be one of epiphenomena, which implicates an occurrence of hemichorea in humans.

Adult↗

PubMed2005

Deep-brain stimulation in Parkinson's disease: long-term efficacy and safety - What happened this year?

PURPOSE OF REVIEW: Deep-brain high-frequency stimulation of the thalamus was introduced in 1987 to treat tremor, and was applied in 1993 to the subthalamic nucleus to treat advanced Parkinson's disease. High-frequency stimulation of the subthalamic nucleus has become the surgical therapy of choice. This review concentrates on recent data on long-term results and side-effects, after 12 years of practice using this technique. RECENT FINDINGS: A literature search produced 260 papers from February 2004 to March 2005. The stable efficacy of high-frequency stimulation of the subthalamic nucleus on Parkinson's disease motor symptoms is confirmed. Evidence for a neuroprotective effect is still lacking. There are transient neuropsychological disturbances, but no cognitive impairment over time. Complications are rare and mild, mortality is extremely low and hardware complications are highly variable. SUMMARY: The safety and innocuity of the method legitimizes earlier operations, before impairment of the quality of life. Depression and suicide are related to pre-existing co-morbidities and multifactorial causes that could become contraindications. Neuropsychological effects should be documented, to determine whether they are caused by an alteration of high-frequency stimulation of the subthalamic nucleus, or inappropriate electrode placement. There is an urgent need for the organization of research and reports, and no need to report small series replicating well-established conclusions. Clinical reports should concentrate on unobserved effects in relation to causative parameters, based on the precise location of electrodes, and on clinical reports comparable between teams and on methods to optimize and facilitate the tuning of parameters and postoperative evaluations in order to make this treatment easier to provide for the neurologist.

Deep Brain Stimulation↗

PubMed2000

Parkinsonism, dementia and vertical gaze palsy in a Guamanian with atypical neuroglial degeneration.

A 58-year-old Chamorro female patient, who died in 1993, was examined clinicopathologically. At the age of 51, she suffered from hemiparkinsonism, then bradykinesia, rigidity without tremor, and dementia. Extrapyramidal symptoms developed, and at the age of 57, vertical gaze palsy was noted. The clinical diagnosis was parkinsonism-dementia complex (PDC) with vertical gaze palsy. The brain showed atrophy in the frontal and temporal lobes, and the atrophy was accentuated in the dentate gyrus, Ammon's horn and parahippocampal gyrus. The basal ganglia, thalamus and midbrain were moderately atrophic. The substantia nigra and locus ceruleus were completely depigmented. Numerous neurofibrillary tangles (NFTs) were seen in the subiculum and amygdaloid nucleus. Many NFTs were evident in the parahippocampal gyrus, lateral occipitotemporal gyrus, insula, Sommer sector, basal nucleus of Meynert, lateral nucleus of the thalamus, subthalamic nucleus and brain stem, and several were observed in the globus pallidus and hypothalamus. The Sommer sector, substantia nigra, locus ceruleus and basal nucleus of Meynert showed severe loss of neurons, and a moderate loss of neurons was exhibited by the globus pallidus. These findings were apparently consistent with those associated with PDC. However, in this patient, severe neuronal loss was seen in the subthalamic nucleus and lateral nucleus of the thalamus, and grumose degeneration, which has not previously been reported in PDC, was seen in the dentate nucleus. In addition, many tufted astrocytes, which have been reported to occur in progressive supranuclear palsy (PSP) and postencephalitic parkinsonism, but scarcely observed in PDC, were present. Furthermore, astrocytic plaques, which have been considered as a specific finding of corticobasal degeneration (CBD), were observed in the cerebral cortex. On the other hand, granular hazy astrocytic inclusions, previously reported to occur in PDC, were not seen. Chromatolytic neurons were not observed. The question thus arises as to whether it is appropriate to consider this patient as having suffered from a combination of PDC, PSP and CBD. From the view points of absence of granular hazy astrocytic inclusions and chromatolytic neurons, and of tufted astrocytes in the neostriatum, it is conceivable that this patient is a case of a new disease entity.

Brain↗

PubMed1990

Topographical and Synaptic Organization of the GABA-Containing Pallidosubthalamic Projection in the Rat.

The anterograde transport of Phaseolus vulgaris-leucoagglutinin (PHA-L) was combined with postembedding immunocytochemistry for gamma-aminobutyric acid (GABA) to study the topography, the synaptic organization and the neurotransmitter content of the pallidosubthalamic projection in the rat. After injections of PHA-L in different parts of the globus pallidus a rich plexus of anterogradely labelled fibres and terminals was found in the ipsilateral subthalamic nucleus. The immunoreactive elements were distributed according to a mediolateral and rostrocaudal topography. Injections of PHA-L restricted to the lateral two-thirds of the globus pallidus gave rise to a massive anterograde labelling confined to the lateral half of the subthalamic nucleus. On the other hand, injections of PHA-L strictly confined to the medial part of the globus pallidus resulted in anterograde labelling that occupied the ventromedial pole of the subthalamic nucleus. In some cases a few retrogradely labelled cells were found in the subthalamic nucleus after PHA-L injections in the globus pallidus. The perikarya and the primary dendrites of these labelled cells were sometimes surrounded by anterogradely labelled terminals suggesting a close reciprocal connection between the globus pallidus and the subthalamic nucleus. Electron microscopic analysis of the PHA-L-labelled terminals revealed that they contain many mitochondria, numerous small round or slightly pleomorphic vesicles and occasionally one or two large dense core vesicles. They form symmetrical synaptic contacts predominantly with the proximal dendrites (39%) and less frequently with the perikarya (31%) and the distal dendrites (30%) of the subthalamic cells. Quantitative measurements showed that the pallidosubthalamic varicosities have a diameter ranging from 0.7 to 4.5 microm and a mean cross-sectional area of 0.79 +/- 0.26 microm2 (Mean +/- SD). Postembedding immunocytochemistry for GABA revealed that the PHA-L-immunoreactive pallidosubthalamic axon terminals display GABA immunoreactivity. The results of our study demonstrate that the pallidosubthalamic projection is organized according to a mediolateral and rostrocaudal topography and that the proximal dendrites of the subthalamic cells are the major targets of the GABA-immunoreactive pallidosubthalamic terminals. This suggests that the globus pallidus exerts a powerful control over the subthalamic cells through an inhibitory GABAergic pathway.

Journal Article↗