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PubMed1996

Subthalamic nucleus: a new anticonvulsant site in the brain.

Several brain sites are important for seizure control, including the area tempestas, superior colliculus, thalamus and substantia nigra. These sites are especially sensitive to changes in GABAergic transmission achieved by localized infusions of GABAergic agents. We investigated the effects of the GABAA receptor agonist muscimol (100 ng in a volume of 0.25 microliter) microinfused into the subthalamic nucleus (STN) in the flurothyl seizure model in male adult rats. Both bilateral symmetrical and unilateral STN infusions of muscimol had a significant anticonvulsant effect against flurothyl-induced clonic seizures. Our data suggest that the STN is a part of the network responsible for the control of clonic seizures.

Animals↗
PubMed1994

The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism.

1. The neuronal mechanisms underlying the major motor signs of Parkinson's disease were studied in the basal ganglia of parkinsonian monkeys. Three African green monkeys were systemically treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) until parkinsonian signs, including akinesia, rigidity, and a prominent 4- to 8-Hz tremor, appeared. The activity of neurons in the subthalamic nucleus (STN) and in the internal segment of the globus pallidus (GPi) was recorded before (STN, n = 220 cells; GPi, n = 175 cells) and after MPTP treatment (STN, n = 326 cells; GPi, n = 154 cells). 2. In STN the spontaneous firing rate was significantly increased from 19 +/- 10 (SD) spikes/s before to 26 +/- 15 spikes/s after MPTP treatment. Division of STN neurons recorded after MPTP treatment into cells with rhythmic bursts of discharge occurring at 4-8 Hz (as defined by autocorrelation analysis) and neurons without 4- to 8-Hz periodic activity revealed an even more prominent increase in the firing rate of the 4- to 8-Hz oscillatory neurons. 3. In GPi overall changes in the average firing rate of cells were inconsistent between different animals and behavioral states. However, the average firing rate of the subpopulation of neurons with 4- to 8-Hz periodic oscillatory activity after treatment with MPTP was significantly increased over that of all neurons before MPTP treatment (from 53 to 76 spikes/s, averaged across monkeys). 4. In the normal state the percentage of neurons with burst discharges (as defined by autocorrelation analysis) was 69% and 78% in STN and GPi, respectively. After MPTP treatment the percentage of cells that discharged in bursts was increased to 79% and 89%, respectively. At the same time the average burst duration decreased (from 121 +/- 98 to 81 +/- 99 ms in STN and from 213 +/- 120 to 146 +/- 134 ms in GPi) with no significant change in the average number of spikes per burst. 5. Periodic oscillatory neuronal activity at low frequency, highly correlated with tremor, was detected in a large number of cells in STN and GPi after MPTP treatment (average oscillation frequency 6.0 and 5.1 Hz, respectively). The autocorrelograms of spike trains of these neurons confirm that the periodic oscillatory activity was very stable. The percentage of cells with 4- to 8-Hz periodic activity significantly increased from 2% to 16% in STN and from 0.6% to 25% in GPi with the MPTP treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

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

Behavioral correlates of transneuronal degeneration of substantia nigra reticulata neurons are reversed by ablation of the subthalamic nucleus.

In rats, acute injury of neurons in the caudate nucleus (CN) and globus pallidus (GP) by local injection of ibotenic acid (IA) or by transient forebrain ischemia has caused transneuronal cell death of neurons in the substantia nigra reticulata (SNr) weeks after the initial injury. Recently transient expression of an immediate early gene c-fos was induced specifically in neurons of the subthalamic nucleus (STN) and SNr at 36-48 h after the IA-lesions, prior to the delayed degeneration of SNr neurons. These cellular and molecular events may alter the level of inhibitory output from the basal ganglia and lead to movement disorders. To test (i) whether movement disorders occur in the early period after unilateral lesions of the CN and GP by IA-injection, and (ii) whether ablation of the STN reverses the early movement disorders, we used a modified version of Porsolt forced swim test in which the lesion-induced asymmetry of motor function becomes apparent as rotation when the animals are forced to swim. Following unilateral IA-lesions of the right CN and GP in rats, rapid contraversive rotation appeared transiently 36-48 h after the lesions, and, in turn, slow ipsiversive rotation appeared at 3-5 days postlesion. Prior ablation of the ipsilateral STN reversed these early movement disorders produced by the unilateral IA-lesions of the CN and GP and instead created persistent contraversive rotation 7-10 days after the lesions. Each phase of the dominant rotation behavior was dependent on asymmetrical limb motor activity; decreased left limb activity caused contraversive rotation, and increased left limb activity caused ipsiversive rotation. Reversal of these early movement disorders suggests that ablation of the STN prevents the transneuronal degeneration of the SNr.

Animals↗
PubMed2006

The relationship of neuronal activity within the sensori-motor region of the subthalamic nucleus to speech.

Microelectrode recordings of human sensori-motor subthalamic neuronal activity during spoken sentence and syllable-repetition tasks provided an opportunity to evaluate the relationship between changes in neuronal activities and specific aspects of these vocal behaviors. Observed patterns of neuronal activity included a build up of activity in anticipation of the start of the utterance, a marked reduction in activity associated with the start of the utterance, and a burst of activity during the course of the sentence between the noun phrase and the verb phrase. Overall, changes of neuronal activity were more robust for the sentence repetition task. These data suggest that the basal ganglia play a role in generating meaningful speech utterances, which may parallel its role in complex sequential limb movements. It is possible that the basal ganglia play a role in generating the syntactical structure of language.

Aged↗
PubMed1997

The connections of the primate subthalamic nucleus: indirect pathways and the open-interconnected scheme of basal ganglia-thalamocortical circuitry.

The current view of basal ganglia organization holds that functionally corresponding subregions of the frontal cortex, basal ganglia and thalamus form several parallel segregated basal ganglia-thalamocortical circuits. In addition, this view states that striatal output reaches the basal ganglia output nuclei (the substantia nigra pars reticulata (SNR) and the internal segment of the globus pallidus (GPi)) via a 'direct' pathway, and via an 'indirect pathway' which traverses the external segment of the globus pallidus (GPe) and the subthalamic nucleus (STN). However, the topographical relationships of GPe and STN, and their topographical relationships with the basal ganglia-thalamocortical circuits are still unclear. The present work reviewed primate data on the topographical organization of STN afferents from GPe, and STN efferents to the pallidum, striatum and SNR, and examined these data with respect to a tripartite (motor, associative and limbic) functional subdivision of the striatum and pallidum. This examination indicated the following. (1) On the basis of its efferent connections, the STN may be divided into a motor and an associative territories, as well as a smaller limbic territory, each projecting to corresponding areas in the pallidum and striatum. (2) Efferents from GPe are in a position to contact subthalamic cells projecting to GPi/SNR, thus providing anatomical support for the existence of indirect pathways. (3) Moreover, given the tripartite division of the striatum, pallidum, and STN, the available data indicate the existence of indirect pathways connecting functionally corresponding subregions of the striatum, pallidum, and STN, as well as indirect pathways connecting functionally non-corresponding subregions. On the basis of the above we suggested that there may be two types of indirect pathways, one which terminates in the same subregion in GPi/SNR as the direct pathway arising from the same striatal subregion, and another which terminates in a different GPi/SNR subregion than the direct pathway arising from the same striatal subregion. We termed the former a 'closed indirect pathway' and the latter an 'open indirect pathway'. The application of these concepts to the surveyed data suggested the existence of three closed indirect pathways, each connecting the corresponding functional (motor, associative, and limbic) regions of the striatum, pallidum, STN, and SNR, as well as of two open indirect pathways, one connecting the associative striatum to the motor subregions of the basal ganglia, and the other connecting the associative striatum to the limbic subregions of the basal ganglia. While the organization of the closed indirect pathways fits the closed segregated arrangement of basal ganglia-thalamocortical circuitry, the organization of the open indirect pathways fits the recently suggested open interconnected scheme of basal ganglia thalamocortical circuitry. The clinical implications of this scheme for Huntington's disease are discussed.

Animals↗
PubMed1996

Prevention of transneuronal degeneration of neurons in the substantia nigra reticulata by ablation of the subthalamic nucleus.

Transneuronal degeneration (TND) of neurons in the substantia nigra reticulata (SNR) occurs after initial ischemic or neurotoxin damage to the striatum. The mechanism is incompletely understood. In rats ibotenic acid (IBO) lesion of the caudate nucleus (CN) and the globus pallidus (GP) caused, 3 weeks later, a 47% loss of neurons (P < 0.001) in the SNR. Rats with IBO lesion confined to either the CN or the GP had SNR neuron numbers comparable to control. The volume of the SNR was decreased, as expected, in all groups with striatal lesions. To test whether the subthalamic nucleus (STN) played a role in the demise of SNR neurons, the STN was lesioned 1 week before animals were exposed to CN and GP injury. STN ablation prevented the expected SNR neuron loss. Based on the current information about basal ganglia anatomy, an imbalance between GABAergic and glutamatergic afferents may have caused TND in the SNR. These results suggest that the potential for the release of intrinsic excitotoxicity exists within certain anatomic networks.

Animals↗
PubMed1995

Activation of the subthalamic nucleus and pedunculopontine tegmentum: does it affect dopamine levels in the substantia nigra, nucleus accumbens and striatum?

Parkinson's disease is a neurodegenerative disorder, of which the most prominent morphological feature is the progressive loss of dopaminergic nigrostriatal neurons. Increased glutamatergic transmission in the basal ganglia has been implicated in the pathophysiology of Parkinson's disease (PD). This study investigated whether death of substantia nigra (SN) dopaminergic neurons could be caused by the hyperactivity of afferent pathways resulting in the release of a toxic dose of excitatory amino acids in the SN. Twice-daily unilateral stimulation of the subthalamic nucleus (STN) for 21 days, using two different pulse frequencies and current strengths, significantly increased amphetamine-induced rotation, whereas sham stimulated rats showed significantly reduced rotation. Striatal and SN dopamine (DA) levels were unaffected when compared to naïve and sham stimulated rats. However, levels of the DA metabolite, homovanillic acid (HVA), were significantly higher in the ipsilateral anterior striata of rats that had been stimulated at high frequency (100 Hz) and low current (100 microA) as compared to sham treated animals. Stimulation of the pedunculopontine tegmentum (PPT), using a single kainic acid injection, did not affect DA concentration in the ipsilateral striatum and nucleus accumbens when compared to sham-treated rats. DA levels in the contralateral striatum and nucleus accumbens of lesioned rats were significantly higher than ipsilateral levels. DOPAC/DA ratios were lower in the contralateral striatum and nucleus accumbens, suggesting decreased DA turnover. Glutamic acid decarboxylase activity was significantly higher in the ipsilateral than the contralateral SN. The physical manifestations of PD require a large reduction in caudate and putamen DA levels and no such depletion was measured in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Prefrontal cortex-basal ganglia circuits in the rat: involvement of ventral pallidum and subthalamic nucleus.

The core of the nucleus accumbens (NAcc core) is the principal input structure to the basal ganglia circuitry for the prelimbic and medial orbital areas (PL/MO) of the prefrontal cortex. As is now well recognized in the rat, the main basal ganglia output of this prefrontal channel is the dorsomedial part of the substantia nigra pars reticulata (SNR) and not the ventral pallidum as previously suggested. There is evidence suggesting that the ventral pallidum is rather involved with the subthalamic nucleus (STN) in an indirect NAcc-SNR pathway. Indeed, we have recently shown that the NAcc core sends an inhibitory input to the lateral ventral pallidum (VPl), which projects to the medial STN. In the present study, we injected biocytin into the medial STN, at a site where neurons presented an inhibitory response to VPl stimulation. This produced anterogradely labelled fibres in the medial SNR and in the VPl. Furthermore, the stimulation of the VPl induced an inhibition in a majority of the STN cells identified, by the antidromic activation method, as projecting to SNR (76.6%) and/or back to the VPl (72.7%). In conclusion, these data further demonstrate the existence of an indirect striato-nigral pathway in the PL/MO channel and indicate that VPl is involved in an inhibitory feedback circuit, which modulates the discharge of medial STN. These results indicate that the medial STN is implicated in the limbic/cognitive functions of the basal ganglia.

Animals↗
PubMed1995

Deafferentiation-induced c-fos gene expression in subthalamic nucleus and substantia nigra reticulata is reduced by non-NMDA receptor antagonist.

Molecular events underlying the mechanism by which brain injury elicits delayed transneuronal degeneration of neurons remote from the site of initial injury are not well understood. In rats, acute injury of the caudate nucleus (CN) and globus pallidus (GP) by local injection of excitotoxic ibotenic acid (IA) or by transient forebrain ischemia resulted in delayed cell death of neurons in the substantia nigra reticulata (SNr). To elucidate the involvement of glutamate receptor mediated hyperactivity of neurons produced by loss of inhibitory inputs in this delayed degeneration of SNr neurons, the region-specific expression of an immediate early gene, c-fos, and the effect of glutamate receptor antagonists on the c-fos expression were examined by using immunocytochemical and in situ hybridization analysis. Following unilateral IA-injection into the CN and GP, a robust expression of c-fos mRNA and Fos protein was induced specifically in neurons of both subthalamic nucleus (STN) and SNr deafferented by the IA-lesions 36 h after IA-injection. The delayed expression of Fos-protein in SNr neurons lasted for 48 h longer than that in STN neurons. Following unilateral IA-injection confined to the CN, an intense but short-term expression of Fos-protein was exhibited only in neurons of the deafferented SNr. c-fos mRNA and Fos protein were not expressed in neurons of the substantia nigra compacta at any time points examined. The induction of c-fos mRNA and Fos protein in neurons of the STN and SNr following IA-lesions of the CN and GP was reduced markedly by non-NMDA receptor antagonist (GYKI52466), but not by NMDA receptor antagonist (MK-801). The region-specific c-fos expression implies that deprivation of inhibitory afferents (disinhibition) due to destruction of presynaptic neurons can induce increased activity of postsynaptic neurons. The effect of GYKI52466 on the c-fos gene expression in neurons of the deafferented STN and SNr suggests that activation of non-NMDA receptors may be involved in a pathophysiological cascade for the transneuronal degeneration of SNr neurons.

Afferent Pathways↗
PubMed2006

Expectation and the placebo effect in Parkinson's disease patients with subthalamic nucleus deep brain stimulation.

To determine whether the degree to which a patient with Parkinson's disease expects therapeutic benefit from subthalamic nucleus-deep brain stimulation (STN-DBS) influences the magnitude of his or her improved motor response, 10 patients with idiopathic Parkinson's and bilateral STN-DBS were tested after a 12-hour period off medication and stimulation. Four consecutive UPDRS III scores were performed in the following conditions: (a) stimulation OFF, patient aware; (b) stimulation OFF, patient blind; (c) stimulation ON, patient aware; and (d) stimulation ON, patient blind. Statistical significance (P = 0.0001) was observed when comparing main effect ON versus OFF (mean ON: 32.55; mean OFF: 49.15). When the stimulation was OFF, patients aware of this condition had higher UPDRS motor scores than when they were blinded (mean: 50.7 vs. 47.6). With the stimulation ON, UPDRS motor scores were lower when the patients were aware of the stimulation compared with when they were blinded (mean: 30.6 vs. 34.5). The interaction between these levels was significant (P = 0.049). This variation was important for bradykinesia and was not significant for tremor and rigidity. The authors conclude that the information about the condition of the stimulation enhanced the final clinical effect in opposite directions. The results presented support the role of expectation and placebo effects in STN-DBS in Parkinson's disease patients.

Adult↗
PubMed2001

Acute effects of bilateral subthalamic nucleus stimulation on clinical and kinematic parameters in Parkinson's disease.

After implantation with subthalamic stimulators, nine patients with advanced Parkinson's disease were studied on the task of tracing out, as accurately as possible, the four corners of a square with the dominant hand. The task was performed in four treatment conditions: on stimulation-off medication, off stimulation-off medication, off stimulation-on medication, and on stimulation-on medication. Movement times and peak velocities improved significantly only in the on stimulation-on medication condition compared to off stimulation-off medication. The improvement in clinical parameters with stimulation only (relative to off stimulation off medication) was of borderline significance, while consistent and significant clinical improvement was only obtained with addition of medication (on medication-on stimulation). This study provides quantitative evidence of the effect of subthalamic stimulation on kinematic measures in Parkinson's disease (PD) and suggests that combined treatment (medication and stimulation) is superior to either treatment alone.

Aged↗
PubMed2006

Deep brain stimulation of the subthalamic nucleus as adjunct treatment for refractory epilepsy.

PURPOSE: We studied the efficacy and safety of bilateral subthalamic deep brain stimulation (DBS) for refractory partial-onset epilepsy in two cases. METHODS: This was an open treatment pilot study for subjects who had failed numerous medications and had seizure injuries. Seizure counts and adverse events were collected during a 3-4 month baseline, and for 26-32 months after DBS surgery, with AEDs held constant. RESULTS: Case 1, age 45, with bitemporal seizures, had about half the seizure frequency but still fell with injuries. Case 2, age 46, with left frontal encephalomalacia, had a frequency reduction of about one-third, but a more meaningful reduction of seizure severity and injuries. CONCLUSIONS: Subthalamic DBS partly reduced partial-onset seizures, but the quality of life was more affected by seizure-related injuries.

Accidental Falls↗
PubMed2002

Bilateral subthalamic nucleus stimulation and quality of life in advanced Parkinson's disease.

We examined the impact of the subthalamic nuclei (STN) deep brain stimulation (DBS) on the health-related quality of life (QoL) of patients with advanced Parkinson's disease (PD). Seventeen consecutive patients with refractory motor fluctuations and dyskinesia were included in the study (mean age, 60.9 +/- 7.7 years [range, 43-74 years]; disease duration, 16.4 +/- 8.5 years [range, 7-38 years]; mean off-medication Hoehn and Yahr stage, 4.23 +/- 0.66 [range, 2.5-5]). Each patient's assessment was carried out using common rating scales, following the Core Assessment Program for Intracerebral Transplantation (CAPIT) protocol. Dyskinesia and emotional state were evaluated through the Abnormal Involuntary Movement Scale (AIMS) and the Hospital Anxiety and Depression Scale (HAD). QoL was assessed by means of the Parkinson's Disease Questionnaire Spanish version (PDQ-39). Significant benefit was obtained in the motor manifestations and complications of disease, as well as in the functional state and mood (P < 0.001). Some QoL dimensions (mobility and activities of daily living) and the PDQ-39 Summary Index (PDQ-39SI) showed a significant improvement (P < 0.001). Benefit was modest (P < 0.05) for three other domains (emotional well-being, stigma, bodily discomfort) and nil for the rest. There was no correlation between the change obtained in the QoL (PDQ-39SI) and in the other variables. As measured by the PDQ-39, STN-DBS significantly improves important aspects of QoL in patients with advanced PD.

Adult↗