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PubMed1988

Two separate neuronal populations of the rat subthalamic nucleus project to the basal ganglia and pedunculopontine tegmental region.

Employing a retrograde fluorescent double labeling technique, we compared the localization of subthalamic nucleus (STN) cells projecting to the striatum and nucleus tegmenti pedunculopontinus pars compacta (TPC), with that of STN cells sending axon collaterals to both the globus pallidus and substantia nigra in the rat. The STN-striatal projections were mostly the third branches of massive STN-pallidal and STN-nigral collateral projection neurons, whereas only very rarely did the STN-TPC projections contribute to these collateral projections. The TPC projecting STN cells, giving rise to an independent output of the nucleus, were located mainly in its thin lateral strip region. The STN may integrate the somatic motor information from various cortical/subcortical brain areas (including the motor cortex, striatum, globus pallidus, thalamus and TPC), and disperse it predominantly to the pallidal complex, substantia nigra and striatum by way of axon collaterals, and to a lesser degree to the TPC through separate fibers. Thus, the STN might be in a strategic position to exert a prominent control over the basal ganglia-related somatic motor functions.

Amidines↗

PubMed1990

Connections of the subthalamic nucleus with ventral striatopallidal parts of the basal ganglia in the rat.

The present study was undertaken to establish the precise anatomical relationship of the subthalamic nucleus (STh) with limbic lobe-afferented parts of the basal ganglia in the rat. The anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L), injected in the STh, the globus pallidus, the ventral pallidum, the ventral striatum, and the parafascicular thalamic nucleus, and the retrograde tracers Fluoro-Gold (FG) and cholera toxin B (CTb), injected in the globus pallidus, the ventral pallidum, the ventral striatum, and the ventral mesencephalon, were used for this purpose. The results of these tracing experiments confirm the general notion of reciprocal connections between the STh and pallidal areas. Thus the dorsomedial part of the STh is connected with the subcommisural ventral pallidum, whereas a more ventral and lateral part of the medial STh is related to the medial globus pallidus. The lateral hypothalamic area, directly adjacent to the STh, containing neurons with a morphology quite similar to those in the STh, projects to parts of the ventral pallidum related to the olfactory tubercle. The reciprocal projection from this pallidal area to subthalamic regions appears to be very sparse. The medial STh sends strong projections to the medial part of the entopeduncular nucleus and the adjacent lateral hypothalamic area. Sparser projections from the medial STh reach the rostral and medial part of the caudate-putamen and the nucleus accumbens. The nucleus accumbens sends a very sparse projection back to the medial STh. The projections of the medial STh to the ventral mesencephalon appear also to be topographically organized. The lateral hypothalamus and a few cells in the most medial part of the STh project to the ventral tegmental area, whereas progressively more lateral parts of the ventral mesencephalon, in particular the substantia nigra, receive input from successively more lateral and caudal parts of the STh. In addition, a number of STh fibers reach the midbrain extrapyramidal area. The lateral part of the parafascicular thalamic nucleus projects to the lateral part of the STh, whereas parafascicular neurons medial to the fasciculus retroflexus project to the dorsomedial portion of the STh. The medial part of the STh and the adjacent lateral hypothalamus are intimately connected with limbic parts of the basal ganglia in a way similar and parallel to the connections of the lateral STh with motor-related parts of the basal ganglia. These findings suggest a role for the STh in nonmotor functions of the basal ganglia.

Animals↗

PubMed2003

Multiple sequential image-fusion and direct MRI localisation of the subthalamic nucleus for deep brain stimulation.

AIM: Deep brain stimulation (DBS) is the treatment of choice for advanced Parkinson's disease. The target co-ordinates are traditionally calculated in relation to the intercommissural distance. Anterior (AC) and posterior commissures (PC) may be visualised by the means of ventriculography, CT or MRI. METHODS: We have studied the efficacy of direct visualisation of the subthalamic-red nucleus complex on MRI, the advantage of fusion of stereotactic CT and MR images (Multiple Sequences Image Fusion - MuSIF). These methods are combined with double check of indirect calculation of the target co-ordinates based on AC-PC line, as well as the corrispondence to the stereotactic electronic atlas. RESULTS: Subthalamic nucleus (STN) was well recognisable in fused images in all 22 sides. At 3 months from surgery it was possible to reduce 76% of L-dopa equivalent daily dose. Dyskine-sias reduced to 50% and motor fluctuation up to 45%. CONCLUSION: In our experience MuSIF offers very high rate of accuracy in calculation of target co-ordinates. Direct visualisation of STN in MR and MuSIF are reliable and facilitate the accuracy of identification of target co-ordinates. Intraoperative neurophysiological recording increases the accuracy of microelectrode position.

Antiparkinson Agents↗

PubMed1996

MRI in hemiballismus due to subthalamic nucleus hemorrhage: an unusual complication of liver transplantation.

A 60-year-old man developed hemiballismus due to an intracranial hemorrhage involving the subthalamic nucleus 8 weeks after orthotopic liver transplantation. The hemorrhage was thought to be due to alterations in cerebral blood flow following a period of hypotensive shock due to sepsis, in the presence of anticoagulant therapy and thrombocytopenia. This represents a rare neurologic complication of liver transplantation.

Cerebral Hemorrhage↗

PubMed1994

Acute and long-term effects of subthalamic nucleus stimulation in Parkinson's disease.

In animal models of Parkinson's disease (PD), it is postulated that the excessive output from the subthalamic nucleus (STN) plays a critical role. Selective lesions or high frequency electrical stimulation of the STN can alleviate parkinsonian symptoms in MPTP-treated monkeys. We decided to carry out STN stimulation in patients suffering from severe akinetic forms of PD. After approval of the institutional ethical committee, we operated on a parkinsonian patient aged 51, suffering for 8 years from a strongly disabling akinetorigid form of PD, complicated by an on-off effect (Hoehn and Yahr stage 5 in the worst-off motor phase). Stereotactic surgery was done on one side under local anesthesia. The theoretical target was chosen according to stereotactic atlases, based on ventriculographic landmarks such as anterior and posterior commissures (AC and PC). The final position of the chronic electrodes was optimized using electrophysiological recording and stimulation along with clinical assessment and surface EMG of agonist and antagonist muscles of the examined limbs. A spontaneous increase in neuronal activity was recorded in an area located 2-4 mm under the level of the intercommissural plane, 10 mm from the midline, at mid-distance between AC and PC. Within the same place, a 130-Hz stimulation induced acute and reversible akinesia alleviation mainly on the contralateral limbs, comparable to that obtained with dopaminergic drugs. No dyskinesia, such as hemiballism, was induced by introduction of electrodes or by stimulation. Then a long-term quadripolar DBS Medtronic electrode was inserted in this area. Studies of the effects of chronic stimulation were extensively performed to determine the best spatiotemporal and electrical stimulation variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Electric Stimulation Therapy↗

PubMed1999

Effect of stimulation of the subthalamic nucleus on oral control of patients with parkinsonism.

OBJECTIVES: To assess the oral system of parkinsonian patients treated with chronic stimulation of the bilateral subthalamic nucleus (STN) to evaluate precisely the effectiveness of this procedure on the articulatory organs. METHODS: Load sensitive cantilevers were used to sample ramp and hold force contractions generated by the upper lip, lower lip, and tongue. The subject was given the instruction to produce forces as rapidly and as accurately as possible in response to the target signal (ranging from 0.25 to 2 N), which appeared on a screen. Maximal force of each effector organ was also measured. Fourteen healthy control subjects and 10 patients participated in this study. After an overnight fast the patients were evaluated in the morning under two conditions: during bilateral stimulation and 1 hour after stopping STN stimulation. RESULTS: During STN stimulation, dynamic and static control of the articulatory organs were improved: the maximal strength of the articulatory organs, their accuracy to reach the target, and the precision of the hold phase increased. In addition, the reaction time and the rise time of the ramp phase decreased. Patients' speech as assessed by the item 18 of the unified Parkinson's disease rating scale (UPDRS) was greatly improved by electrical stimulation of the STN CONCLUSIONS: Improvement of oral control of the stimulated patients suggests that STN stimulation modulates neuronal structures involved in speech. However, more patients have to be evaluated for a fuller understanding of the effect of this surgical procedure on speech.

Female↗

PubMed1999

Magnetic resonance imaging-based stereotactic localization of the globus pallidus and subthalamic nucleus.

OBJECTIVE: To optimize the accuracy of initial stereotactic targeting for movement disorders surgery, we performed stereotactic localization of the internal segment of the globus pallidus (GPi) and subthalamic nucleus (STN) using magnetic resonance imaging protocols in which the borders of these nuclei were directly visualized. METHODS: Fifty-one consecutive cases using the pallidal target and six using the subthalamic target were studied. Localization of these nuclei was performed using the Leksell stereotactic head frame and inversion recovery sequences (GPi) or T2-weighted spin echo sequences (STN). Targeting accuracy and individual variation in the spatial coordinates of these structures were independently measured by identification of nuclear boundaries during multiple microelectrode penetrations. RESULTS: The lateral and vertical coordinates of an atlas-defined point in the GPi, with respect to the line between the anterior and posterior commissures, was highly variable. Initial targeting the GPi based on direct visualization of the target boundaries (external medullary lamina and optic tract) resulted in greater precision than would be expected using fixed anterior and posterior commissure-based coordinates. Initial targeting the STN using magnetic resonance imaging was sufficiently precise to place the initial microelectrode penetration within STN in all six cases. CONCLUSION: Magnetic resonance imaging-based initial stereotactic targeting of the GPi, based on direct visualization of the target boundaries, is useful to improve target accuracy over that of purely indirect anterior and posterior commissure-based targeting methods. Initial targeting of the STN was reliably accomplished by direct visualization. However, there remains sufficient variability that the final target location in both GPi and STN required electrophysiological mapping in all cases.

Brain Mapping↗

PubMed1983

Direct projections from the centre median-parafascicular complex to the subthalamic nucleus in the cat and rat.

Single injections of a mixture of L-[3H] leucine and L-[3H] proline were made into the centre median-parafascicular complex (CM-Pf) of the cat. The ipsilateral subthalamic nucleus (STN) was most heavily labeled at its rostral pole and moderately in the ventral and ventromedial portions of its rostral third. At middle subthalamic levels, label was more sparse and disappeared over the caudal third of the nucleus. Labeled fibers appeared to outline the borders of the STN throughout its rostral half. Control injections of isotope into several other thalamic and mesodiencephalic regions produced no terminal labeling in the cat STN. After horseradish peroxidase (HRP) injections into the cat STN, a small number of the CM-Pf neurons were labeled retrogradely. The labeled neurons were scattered diffusely in the CM-Pf and were not obviously distinguishable from other unlabeled neurons in the nucleus. Single injections of L-[3H] leucine were made into the CM-Pf of the rat. Anterograde labeling was seen in the rostral half of the ipsilateral STN. Heavy labeling was present throughout the most rostral STN, became less prominent more caudally, and was absent from the caudal half of the STN. HRP injections in the rat CM-Pf produced a distribution of anterograde labeling in the STN similar to the isotope injections. It was concluded that a small number of scattered CM-Pf neurons project primarily to rostral region of the STN. Thus, the CM-Pf is in a unique position to regulate the basal ganglia by way of a newly established thalamosubthalamic pathway as well as a widespread, conspicuous thalamostriate pathway in those two mammalian species.

Animals↗

PubMed1998

Postural effects of unilateral blockade of glutamatergic neurotransmission in the subthalamic nucleus on haloperidol-induced akinesia in rats.

The present study examined the postural effects of the local application of glutamatergic antagonists unilaterally into the subthalamic nucleus (STN), on haloperidol-induced akinesia in rats. After intracerebral injections of MK-801, a selective antagonist of N-methyl-D-aspartate (NMDA) receptor, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) disodium, a selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist, or vehicle, unilaterally into the STN, haloperidol was administered systemically and the elicited behaviors were assessed quantitatively. In rats which received injections of MK-801 or CNQX, but not vehicle, unilaterally into the STN, the administration of haloperidol induced contraversive dystonic posturing. The severity of the deviated posturing was dose-dependent. The present findings revealed that the overactivity of the STN under conditions of dopamine blockade is suppressed by interruptions of glutamatergic inputs, mediated via both NMDA or AMPA receptors, to the STN. Therefore, the present study may provide functional evidence in support of a recently proposed hypothesis, that not only disinhibition from the inhibitory globus pallidus efferents but also excitatory glutamatergic inputs to the STN actually contribute to the overactivity of the STN under dopamine-depleted conditions.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1997

The subthalamic nucleus in Parkinson's disease and progressive supranuclear palsy.

The subthalamus has become a promising target for the neurosurgical treatment of parkinsonian symptoms. We have used unbiased counting techniques to quantify the neuronal populations of the subthalamic nucleus in patients with idiopathic Parkinson's disease and progressive supranuclear palsy. In addition, the type of calcium binding proteins contained within these subthalamic neurons was established using immunohistochemistry. Most of the 550,000 subthalamic neurons contain either parvalbumin or calretinin calcium binding proteins, and patients with idiopathic Parkinson's disease sustained no damage to this nucleus. This is consistent with current theories of basal ganglia circuitry, which postulate that overstimulation of this excitatory nucleus contributes to the inhibition of the motor thalamus via the activation of inhibitory relays. In contrast, we found that there was substantial cell loss in the subthalamus in progressive supranuclear palsy (45 to 85% neuronal reduction) and that both cell types were equally affected. Extracellular neurofibrillary tangles as well as tau-positive glia were observed in the subthalamus of these cases. As the patients with Parkinson's disease and progressive supranuclear palsy all had overlapping parkinsonian symptoms, the loss of subthalamic stimulation within the basal ganglia of progressive supranuclear palsy cases is puzzling, unless their parkinsonian symptoms were generated by an alternate mechanism.

Aged↗

PubMed2002

Radiosurgery for residual or recurrent nonfunctioning pituitary adenoma.

OBJECT: Nonfunctioning pituitary adenomas comprise approximately 30% of all pituitary tumors. The purpose of this retrospective study is to evaluate the efficacy and role of gamma knife radiosurgery (GKS) in the management of residual or recurrent nonfunctioning pituitary adenomas. METHODS: A review was conducted of the data obtained in 42 patients who underwent adjuvant GKS at the University of Pittsburgh between 1987 and 2001. Prior treatments included transsphenoidal resection, craniotomy and resection, or conventional radiotherapy. Endocrinological, ophthalmological, and radiological responses were evaluated. The duration of follow-up review varied from 6 to 102 months (mean 31.2 months). Fifteen patients were observed for more than 40 months. The mean radiation dose to the tumor margin was 16 Gy. Conformal radiosurgery planning was used to restrict the dose to the optic nerve and chiasm. Tumor control after GKS was achieved in 100% of patients with microadenomas and 97% of patients with macroadenomas. Gamma knife radiosurgery was equally effective in controlling adenomas with cavernous sinus invasion and suprasellar extension. No patient developed a new endocrinological deficiency following GKS. One patient's tumor enlarged with an associated decline in visual function. Another patient experienced a deterioration of visual fields despite a decrease in tumor size. CONCLUSIONS: Gamma knife radiosurgery can achieve tumor control in virtually all residual or recurrent nonfunctioning pituitary adenomas. Dose sparing facilitates tumor management even when the adenoma is close to the optic apparatus or invades the cavernous sinus.

Adenoma↗

PubMed1995

Cholinergic, GABAergic, and glutamate-enriched inputs from the mesopontine tegmentum to the subthalamic nucleus in the rat.

In order to clarify the origin and to examine the neurochemistry and synaptology of the projection from the mesopontine tegmentum (MTg) to the subthalamic nucleus (STN), rats received discrete deposits of anterograde tracers in different regions of the MTg. Anterogradely labeled fibers were examined in the light and electron microscopes. The distribution of GABA or glutamate immunoreactivity was examined by post-embedding immunocytochemistry. The anterograde tracing demonstrated that the projection to the STN arises from at least three divisions of the MTg: the area defined by the cholinergic neurons of the pedunculopontine region (PPN-Ch 5), the more medial and largely noncholinergic midbrain extrapyramidal area (MEA) and to a lesser extent the laterodorsal tegmental nucleus (LDTg). Post-embedding immunocytochemistry revealed that there are GABA-immunopositive and immunonegative components to this projection and at least a proportion of the GABA-immunonegative component is enriched in glutamate immunoreactivity. The similarity of the morphology, trajectory and synaptology of the anterogradely labeled fibers and the choline acetyltransferase (ChAT)-immunopositive fibers supports the proposal that at least part of the projection is cholinergic. The terminals anterogradely labeled from the MTg and the ChAT-immunoreactive terminals form asymmetrical synapses with the dendrites and spines of subthalamic neurons. Both anterogradely labeled and ChAT-positive terminals make convergent synaptic contacts with GABA-immunoreactive terminals that form symmetrical synaptic contacts and are probably derived from the globus pallidus. Taken together these findings imply that the MTg sends cholinergic, GABAergic and glutamatergic projections to the STN where at least one of the functional roles is to modulate the indirect pathway of information flow through the basal ganglia that is carried via the pallidosubthalamic projection.

Afferent Pathways↗

PubMed1983

A reciprocal axonal connection between the subthalamic nucleus and the neostriatum in the cat.

Injections of wheatgerm agglutinin conjugated to horseradish peroxidase (WGA-HRP) into several small regions of the head and body of the caudate nucleus and the putamen of the cat result in retrograde cell-labeling of neurons in the ipsilateral subthalamic nucleus. A mediolateral but no rostrocaudal or dorsoventral topography is apparent in the subthalamostriatal projection. Anterograde transport of WGA-HRP and autoradiography after [3H]amino acid injection of the caudate suggest also a reciprocal striatosubthalamic projection.

Animals↗

PubMed1998

Globus pallidus lesions depress the excitatory responses to apomorphine but not amphetamine in the subthalamic nucleus of the behaving rat with a 6-OHDA nigra lesion.

The role of the dopaminergic innervation of the basal ganglia on the activity in the subthalamic nucleus (STN) evoked by amphetamine and apomorphine in the behaving rat was examined. The aim was to determine the relationship between that neural activity and the movements evoked by the drugs. Bilateral electrolytic lesions of the globus pallidus (GP), superimposed on the earlier unilateral lesion in substantia nigra (SN) with 6-hydroxydopamine (6-OHDA) affected differently the excitatory responses in the STN evoked by amphetamine and apomorphine and the motor responses to the drugs recorded concurrently. Before the GP lesions, the administration of amphetamine, 5 mg/kg, to the unilaterally deafferented rat induced increased activity in the STN and simultaneously increased movement in the animal. After the GP lesions, the excitatory response to amphetamine in the STN was not different from that seen before the GP lesions. The motor response was also unchanged. In contrast, the GP lesions altered the excitatory response to apomorphine, 3 mg/kg. Before these lesions, the administration of apomorphine to the 6-OHDA lesioned animal evoked a robust and long-lasting excitatory response in the STN and, concurrently, a long-lasting motor response. After the GP lesions, both responses to apomorphine were attenuated. These differential effects of the GP lesions on the unit and motor responses to the two drugs are viewed as representing the effects of the damage in the GP on the dopaminergic innervation contributing to the regulation of activity in the STN. In the 6-OHDA animal, the dopamine afferents innervating the basal ganglia had already been dramatically reduced by 6-OHDA. The GP lesions did not significantly add to the number of these afferents previously eliminated; therefore, the excitatory and motor responses to amphetamine were not changed by the GP lesions. But the GP damage served to eliminate the dopamine receptor in the GP and thus reduced the density of the dopamine receptor in the basal ganglia available for binding to apomorphine. Therefore, the excitatory and motor responses to apomorphine were attenuated after the GP lesions compared to the responses before these lesions.

Amphetamine↗

PubMed1998

Circling behaviour in 6-hydroxydopamine-lesioned rats given pulsed levodopa is reduced more by lesions in the entopeduncular nucleus/substantia nigra pars reticulata than in the subthalamic nucleus.

Rats unilaterally lesioned with 6-hydroxydopamine to deplete striatal dopamine received daily injections of levodopa methyl ester in combination with benserazide. Delayed lesions in the subthalamic nucleus (Group 2) or entopeduncular nucleus and substantia nigra par reticulata (Group 3) were made, unilateral to the dopamine depletion. Apomorphine-induced rotation was significantly reduced in Group 2 versus sham-operated controls (P < 0.006) and in Group 3 versus Group 2 (P < 0.03). Results suggest that enhanced apomorphine-induced rotation in this model is mediated through both the striatopallidal and striatonigral pathway.

Adrenergic Agents↗

PubMed2003

Amphetamine-induced c-fos mRNA expression in the caudate-putamen and subthalamic nucleus: interactions between dose, environment, and neuronal phenotype.

When administered in a novel environment relatively low doses of amphetamine induce c-fos mRNA in the subthalamic nucleus (STN) and in preproenkephalin mRNA-containing (ENK+) neurons in the caudate-putamen (CPu). When administered at home, however, low doses of amphetamine do not produce these effects. Environmental novelty also facilitates the behavioral effects of acute and repeated amphetamine, but this is dose-dependent. The purpose of the present experiment therefore was to determine if the effect of context on amphetamine-induced c-fos expression is also dose-dependent. It was found that: (i) No dose of amphetamine tested (1-10 mg/kg) induced c-fos in many ENK+ cells when given at home. (ii) When given in a novel environment low to moderate doses of amphetamine (1-5 mg/kg) induced c-fos in substantial numbers of ENK+ cells, but the highest dose examined (10 mg/kg) did not. (iii) Environmental novelty enhanced the ability of low to moderate doses of amphetamine to induce c-fos in the STN, but the highest dose of amphetamine induced robust c-fos mRNA expression in the STN regardless of context. The results do not support the idea that engaging ENK+ cells, at least as indicated by c-fos mRNA expression, is critical to produce robust behavioral sensitization, but do suggest a possible role for the STN. Furthermore, the results highlight the importance of drug-environment interactions on the neurobiological effects of drugs, and have implications for thinking about the circuits by which context modulates the acute and long-lasting consequences of amphetamine treatment.

Amphetamine↗

PubMed2003

Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD.

OBJECTIVE: To assess whether subthalamic nuclei (STN) stimulation's primary mechanism of action is to drive or inhibit output neurons. METHODS: Cerebral blood flow responses to STN stimulation were measured using PET in 13 patients with Parkinson disease. Patients were scanned with stimulators off and on (six scans each condition). Clinical ratings, EMG, and videotaping of movements were obtained at each scan. Scans with observable tremor or movement were eliminated from analysis. Brain regions where STN stimulation significantly altered blood flow were identified. RESULTS: STN stimulation increased blood flow in midbrain (including STN), globus pallidus, and thalamus, primarily on the left side, but reduced blood flow bilaterally in frontal, parietal, and temporal cortex. CONCLUSIONS: These data suggest that STN stimulation increases firing of STN output neurons, which increases inhibition of thalamocortical projections, ultimately decreasing blood flow in cortical targets. STN stimulation appears to drive, rather than inhibit, STN output neurons.

Action Potentials↗

PubMed1996

Alleviation of experimental hemiparkinsonism by high-frequency stimulation of the subthalamic nucleus in primates: a comparison with L-Dopa treatment.

Experimental studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown that akinesia and rigidity are linked to a hyperactivity of glutamatergic subthalamic nucleus neurons and that the lesion of this nucleus can ameliorate parkinsonian motor signs. In our study, high-frequency stimulation applied at the subthalamic level was performed on two Macaca mulatta monkeys rendered hemiparkinsonian by unilateral infusion of MPTP. Its effects on rigidity and bradykinesia have been quantified. The results exhibit an important alleviation of both symptoms during the application of subthalamic stimulation comparable to that obtained during L-Dopa treatment, but without the appearance of abnormal movements such hemiballism or dyskinesia. Our data show that subthalamic stimulation has a beneficial effect on experimental parkinsonian rigidity and bradykinesia and suggests a new therapy approach for the treatment of Parkinson's disease by using subthalamic high-frequency stimulation instead of L-Dopa treatment.

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