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PubMedDate not supplied

[Possible mechanisms of involvement of the subthalamic nucleus and structures interconnected with this nucleus in movement disorders evoked by dopamine depletion].

A possible mechanism of involvement of the subthalamic nucleus (STN) in movement disorders evoked by dopamine deficit is suggested. Multifunctional role of the STN is based on following reasons. Various STN cells participate in the cortico-basal ganglia-thalamocortical loop and in the basal ganglia-pedunculopontine-basal ganglia loop. Complexity of neural circuits is determined by functional heterogeneity of neurons in the nuclei, reciprocally connected with the STN, as well as by opposite modulation of activity of these neurons by dopamine due to activation of different types of pre- and postsynaptic receptors. Dopamine influences activity of STN neurons directly, through pre- and postsynaptic receptors. It is assumed that high-frequency stimulation of the STN can reduce or eliminate Parkinsonian symptoms not only owing to inhibition of activity of GABAergic neurons in the output basal ganglia nuclei, projected into the thalamus or pedunculopontine nucleus, but also due to excitation of glutamatergic or cholinergic neurons in the output nuclei, and due to potentiation of excitatory inputs to preserved dopaminergic neurons and subsequent rise in dopamine concentration.

Animals↗

PubMed2000

Unrelated course of subthalamic nucleus and globus pallidus neuronal activities across vigilance states in the rat.

The pallido-subthalamic pathway powerfully controls the output of the basal ganglia circuitry and has been implicated in movement disorders observed in Parkinson's disease (PD). To investigate the normal functioning of this pathway across the sleep-wake cycle, single-unit activities of subthalamic nucleus (STN) and globus pallidus (GP) neurons were examined, together with cortical electroencephalogram and nuchal muscular activity, in non-anaesthetized head-restrained rats. STN neurons shifted from a random discharge in wakefulness (W) to a bursting pattern in slow wave sleep (SWS), without any change in their mean firing rate. This burst discharge occurred in the 1-2 Hz range, but was not correlated with cortical slow wave activity. In contrast, GP neurons, with a mean firing rate higher in W than in SWS, exhibited a relatively regular discharge whatever the state of vigilance. During paradoxical sleep, both STN and GP neurons increased markedly their mean firing rate relative to W and SWS. Our results are not in agreement with the classical 'direct/indirect' model of the basal ganglia organization, as an inverse relationship between STN and GP activities is not observed under normal physiological conditions. Actually, because the STN discharge pattern appears dependent on coincident cortical activity, this nucleus can hardly be viewed as a relay along the indirect pathway, but might rather be considered as an input stage conveying corticothalamic information to the basal ganglia.

Animals↗

PubMed2005

Subthalamic nucleus lesions enhance the psychomotor-activating, incentive motivational, and neurobiological effects of cocaine.

The subthalamic nucleus (STN) is traditionally thought to be involved in motor control, and dysfunction of the STN is thought to contribute to movement disorders. Here, we show that the STN also plays an important role in motivational processes and the response to drugs of abuse. Specifically, bilateral STN lesions produced a dose-dependent increase in the psychomotor-activating effects of cocaine, the rate at which animals acquired cocaine self-administration, and the motivation for cocaine assessed using a progressive ratio schedule. Furthermore, bilateral STN lesions enhanced the ability of cocaine to induce gene expression in the nucleus accumbens and caudate-putamen, two structures known to be involved in mediating the psychomotor-activating and incentive motivational effects of drugs of abuse. These findings suggest that engagement of the STN serves to dampen the psychomotor-activating and incentive motivational effects of drugs of abuse. Thus, the STN may serve as a novel target for therapeutic interventions aimed at treating drug dependence.

Animals↗

PubMed2002

Intraoperative micro- and macrostimulation of the subthalamic nucleus in Parkinson's disease.

Studying the clinical effects induced by electrical stimulation of the subthalamic nucleus (STN) area in a parkinsonian patient under local anesthesia is a mandatory step to determine the precise location of the final chronic electrode. Using multiple microelectrodes, preferably in a concentric parallel array allows a precise mapping of the STN region. The most reliable features to determine the suitable target are stimulation-induced dyskinesias and rigidity decrease at a low intensity without adverse effects or only at far higher intensities. New skills are needed to assess all stimulation-induced effects and interpret them in anatomo-functional terms.

Brain Mapping↗

PubMed2005

Unilateral subthalamic nucleus deep brain stimulation contralateral to thalamic stimulation in Parkinson disease.

The effects of unilateral subthalamic nucleus (STN) stimulation contralateral to thalamic stimulation in Parkinson disease (PD) have not been previously reported. We are reporting a patient who developed left arm tremor in 1994, at age 62, as her first PD symptom. She underwent right thalamic DBS surgery in 1999 that resulted in complete resolution of left arm tremor. Her PD symptoms progressed and she developed severe motor fluctuations and disabling dyskinesias. In 2003, she underwent left STN electrode implantation. Left STN stimulation improved contralateral motor scores in the medication OFF state, and allowed for reduced medication doses and less dyskinesia. However, there was no significant improvement in activities of daily living (ADL), motor scores in the medication ON state, gait, or postural stability.

Deep Brain Stimulation↗

PubMed2000

High frequency stimulation of the subthalamic nucleus influences striatal dopaminergic metabolism in the naive rat.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) can partially alleviate motor symptoms in patients with Parkinson's disease (PD). However, the mechanism of action of HFS is incompletely understood. We investigated the effect of HFS (130 Hz) and low frequency stimulation (LFS, 20 Hz) of the STN on striatal dopaminergic transmission and metabolism using in vivo microdialysis in anaesthetized and freely moving rats. While LFS had no effect, HFS of the STN produced a delayed, stable and intensity-dependent increase of extracellular dopamine metabolites. Striatal extracellular levels of dopamine and 5-HIAA were not influenced by HFS or LFS in the present experimental paradigm. We conclude that HFS of the STN influences striatal dopaminergic metabolism in naive, nonlesioned rats.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Subthalamic nucleus stimulation affects a frontotemporal network: a PET study.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an effective strategy in the treatment of motor symptoms in advanced Parkinson's disease. However, clinical studies have shown that DBS can affect verbal fluency. Seven Parkinson's disease patients with bilateral DBS of the STN were studied with positron emission tomography (PET) to investigate the effects of STN stimulation on regional cerebral blood flow during a verbal fluency task. Activation of the right orbitofrontal cortex and verbal fluency-associated activation within a left-sided frontotemporal network were decreased during STN stimulation compared with the OFF state. Our results offer an explanation for the commonest neuropsychological side effect of STN stimulation and show that STN stimulation affects a frontotemporal network during a fluency task.

Aged↗

PubMed2006

Subthalamic nucleus lesions increase impulsive action and decrease impulsive choice - mediation by enhanced incentive motivation?

The subthalamic nucleus (STN) is traditionally thought of as part of a system involved in motor control but recent evidence suggests that it may also play a role in other psychological processes. Here we examined the effects of STN lesions on two measures of impulsivity and found that STN lesions increased 'impulsive action' (produced behavioral disinhibition), as measured by performance on a differential reinforcement of low rates of responding task, but decreased 'impulsive choice' (impulsive decision making), as measured by a delay discounting task. In addition, amphetamine and food restriction increased 'impulsive action' and decreased 'impulsive choice' to a greater extent in STN-lesioned animals than in sham controls. We speculate that these apparently discrepant effects may be because STN lesions enhance the incentive salience assigned to rewards. These findings suggest that the STN may serve as a novel target for the treatment of psychological disorders characterized by deficits in behavioral control, such as drug addiction and attention deficit hyperactivity disorder.

Amphetamine↗

PubMedDate not supplied

High frequency stimulation of the subthalamic nucleus eliminates pathological thalamic rhythmicity in a computational model.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) has recently been recognized as an important form of intervention for alleviating motor symptoms associated with Parkinson's disease, but the mechanism underlying its effectiveness remains unknown. Using a computational model, this paper considers the hypothesis that DBS works by replacing pathologically rhythmic basal ganglia output with tonic, high frequency firing. In our simulations of parkinsonian conditions, rhythmic inhibition from GPi to the thalamus compromises the ability of thalamocortical relay (TC) cells to respond to depolarizing inputs, such as sensorimotor signals. High frequency stimulation of STN regularizes GPi firing, and this restores TC responsiveness, despite the increased frequency and amplitude of GPi inhibition to thalamus that result. We provide a mathematical phase plane analysis of the mechanisms that determine TC relay capabilities in normal, parkinsonian, and DBS states in a reduced model. This analysis highlights the differences in deinactivation of the low-threshold calcium T -current that we observe in TC cells in these different conditions. Alternative scenarios involving convergence of thalamic signals in the cortex are also discussed, and predictions associated with these results, including the occurrence of rhythmic rebound bursts in certain TC cells in parkinsonian states and their drastic reduction by DBS, are stated. These results demonstrate how DBS could work by increasing firing rates of target cells, rather than shutting them down.

Action Potentials↗

PubMed2004

[Manipulation of mental competence: an ethical problem in case of electrical stimulation of the subthalamic nucleus for severe Parkinson's disease].

Three years after the implantation of electrodes in the subthalamic nucleus (STN) and the start of deep brain stimulation (DBS) for advanced Parkinson's disease, a 62-year-old man was admitted because of a stimulation-related manic state that did not respond to treatment with a mood stabiliser and that led to chaotic behaviour, megalomania, serious financial debts and mental incompetence. Although adjustment of the stimulation parameters resulted in a normophoric state with a return of insight and capacity to judge, this was only at the cost of a serious exacerbation of his motor symptoms that left the patient bedridden. There was no therapeutic margin between the two states. Ultimately, there seemed to be only two alternatives: to admit the patient to a nursing home because of serious invalidity, but mentally in good condition, or to admit the patient to a chronic psychiatric ward because of a manic state, but with acceptable motor capacity and ADL functions. Thorough ethical evaluation followed. When not being stimulated, the patient was considered competent to decide about his own treatment; in this condition the patient chose for the second option. In accordance with his own wishes he was therefore legally committed to a chronic ward in the regional psychiatric hospital. The current ethical views on mental competence do not consider the potential influence of modern methods of treatment such as STN-DBS on this capacity.

Bipolar Disorder↗

PubMed2004

Subthalamic nucleus stimulation induces deficits in decoding emotional facial expressions in Parkinson's disease.

BACKGROUND: Bilateral subthalamic nucleus (STN) stimulation is recognised as a treatment for parkinsonian patients with severe levodopa related motor complications. Although adverse effects are infrequent, some behavioural disturbances have been reported. OBJECTIVE: To investigate the consequences of STN stimulation on emotional information processing in Parkinson's disease by assessing the performance of an emotional facial expression (EFE) decoding task in a group of patients before and after surgery. METHODS: 12 non-demented patients with Parkinson's disease were studied. They were assessed one month before surgery and three months after. Their ability to decode EFEs was assessed using a standardised quantitative task. Overall cognitive function, executive function, visuospatial perception, depression, and anxiety were also measured. Twelve healthy controls were matched for age, sex, and duration of education. RESULTS: Before surgery, the patients showed no impairment in EFE decoding compared with the controls. Their overall cognitive status was preserved but they had a moderate dysexecutive syndrome. Three months after surgery, they had significant impairment of EFE decoding. This was not related to their overall cognitive status or to depression/anxiety scores. Visuospatial perception was not impaired. There was no change in the extent of the dysexecutive syndrome except for a reduction in phonemic word fluency. CONCLUSIONS: Bilateral STN stimulation disturbs negative emotional information processing in Parkinson's disease. The impairment appears specific and unrelated to certain secondary variables. This behavioural complication of STN may have implications for the patient's social life.

Affect↗

PubMed2000

Multisecond oscillations in the subthalamic nucleus: effects of apomorphine and dopamine cell lesion.

Clinical and preclinical data indicate that the subthalamic nucleus (STN) plays a critical role in mediating the hyper- and hypoactive behavioral states associated with increases and decreases in dopamine receptor stimulation in the basal ganglia. The present study investigates effects of dopamine receptor stimulation on slow multisecond oscillations in firing rates in STN neurons. Extracellular, single-unit recordings were performed in locally anesthetized and immobilized rats which were either intact or had received unilateral 6-OHDA lesions of the medial forebrain bundle. The majority (64%) of spike trains recorded from STN neurons exhibited periodic oscillations in firing rate within the range of 2-60 sec, with an average period of 24 sec. The distribution of these baseline periodicities was not altered by unilateral 6-OHDA lesion, but periods were significantly shortened by systemic administration of the D1/D2 agonist apomorphine. This effect was observed in a greater proportion of neurons recorded from 6-OHDA-lesioned rats as compared to intact rats, was notably diminished in rats systemically anesthetized with chloral hydrate, and did not correlate with drug-induced changes in firing rate. These oscillations are similar to slow periodicities in firing rate recently reported in other basal ganglia nuclei. The possibility that these periodic oscillations in firing rate play a significant role in basal ganglia function was supported by the observation that the time of onset of apomorphine induced alterations in amplitude and periodicity of slow oscillations in STN spike trains is coincident with the onset of behavioral effects of this drug in 6-OHDA-lesioned animals. Synapse 38:38-50, 2000. Published 2000 Wiley-Liss, Inc.

Action Potentials↗

PubMed1991

The role of the subthalamic nucleus in the response of globus pallidus neurons to stimulation of the prelimbic and agranular frontal cortices in rats.

We investigated how the cerebral cortex can influence the globus pallidus by two routes: the larger, net inhibitory route through the neostriatum and the separate, smaller, net excitatory route through the subthalamic nucleus. Stimulation (0.3 and 0.7 mA) of two regions of frontal agranular (motor) cortex and of the medial orbitofrontal cortex centered in the prelimbic cortex typically elicited one or more of the following extracellularly recorded responses in over 50% of tested cells: an initial excitation (approximately 6 ms latency), a short inhibition (15 ms latency) and a late excitation (29 ms latency). Some other cells responded with an excitatory response only (18 ms latency). The excitatory responses largely arise from the subthalamic route. Kainic acid or electrolytic lesion of the subthalamic nucleus eliminated most excitatory responses and greatly prolonged the duration (16 vs 50 ms) of the inhibition. Subthalamic neurons typically showed one or more of the following responses to cortical stimulation: an early excitatory response (4 ms latency), an inhibitory period (9 ms) and a late excitatory response (16 ms). The early response was seen after motor cortex but not prelimbic stimulation. The timing of the globus pallidus and subthalamic responses suggest the operation of a reciprocal inhibitory/excitatory pathway. Two reciprocal interactions were indicated. First, pallidal inhibition may disinhibit the subthalamus and, via a feedback pathway onto the same pallidal cells, act to terminate the neostriatal-induced inhibition. Second, there may be a feedforward pathway from pallidal cells to subthalamic neurons to a different group of pallidal cells. This pathway could act to suppress competing responses. Thus the subthalamus may have three actions: 1) an early direct cortical and 2,3) later reciprocal feedforward and feedback excitatory antagonism of the neostriatal mediated inhibition of globus pallidus.

Animals↗

PubMed2002

Consequences of dopaminergic denervation on the metabolic activity of the cortical neurons projecting to the subthalamic nucleus in the rat.

Parkinsonian symptoms are currently thought to be related to hyperactivity of the subthalamic nucleus (STN). Because the STN is known to receive many inputs including glutamatergic cortical afferent fibers, we sought to determine whether the activity of this pathway is altered after dopaminergic denervation to estimate its contribution to the impairment of STN activity. A precise mapping of the origin of the corticosubthalamic projection was first performed using retrograde and anterograde tracing methods. Cortical neurons projecting to the STN were found to originate in layer V of the motor, anterior cingulate, and dorsal insular cortices, and the most anterior tip of the frontal lobe, leading to different functional corticosubthalamic inputs. The metabolic activity of the neurons projecting to the STN, first identified by retrograde tracing, was then evaluated by in situ hybridization of the first subunit of cytochrome oxidase (COI), a marker of metabolic activity, in unilateral 6-hydroxydopamine-lesioned rats. Measurements of COI mRNA expression showed a 38 and 41.5% decrease after dopaminergic denervation in the neurons projecting to the STN located in the motor and dorsal insular areas, respectively, whereas neuronal activity was mildly changed in neurons of the anterior cingulate cortex. The modified activity of STN neurons in parkinsonism may thus result in part from complex interactions between glutamatergic hyperactive fibers originating in the thalamus and the pedunculopontine nucleus and hypoactive fibers originating in the cerebral cortex.

Animals↗

PubMed2006

Cellular principles underlying normal and pathological activity in the subthalamic nucleus.

The motor symptoms of Parkinson's disease are associated with abnormal, correlated, low frequency, rhythmic burst activity in the subthalamic nucleus and connected nuclei. Research into the mechanisms controlling the pattern of subthalamic activity has intensified because therapies that manipulate the pattern of subthalamic activity, such as deep brain stimulation and levodopa administration, improve motor function in Parkinson's disease. Recent findings suggest that dopamine denervation of the striatum and extrastriatal basal ganglia profoundly alters the transmission and integration of glutamatergic cortical and GABAergic pallidal inputs to subthalamic neurons, leading to pathological activity that resonates throughout the basal ganglia and wider motor system.

Animals↗

PubMed1999

Neuroprotective effect of chronic inactivation of the subthalamic nucleus in a rat model of Parkinson's disease.

Several evidences showed that glutamate can be implicated in the degenerative process of dopaminergic neurons in Parkinson's disease. The treatment with NMDA antagonists have been shown to induce a neuroprotective effect in animal models of this disease. As subthalamic nucleus neurons send direct glutamatergic projections to the substantia nigra, we studied the effects of kainic acid lesion of this nucleus on the degeneration of dopaminergic neurons induced by microinjection of 6-hydroxydopamine in the striatum of rat done one week after the first lesion. Animals were killed 15 days after the injection of 6-hydroxydopamine. Immunohistochemical study showed that lesion of the subthalamic nucleus can prevent the degeneration of substantia nigra dopaminergic somata when carried out one week prior to 6-hydroxydopamine injection in the striatum. Nevertheless neurochemical results showed that this lesion did not antagonize the striatal 6-hydroxydopamine-induced dopamine depletion in the striatum 15 days after 6-hydroxydopamine injection.

Animals↗

PubMed2005

Bilateral subthalamic nucleus deep brain stimulation in a patient with cervical dystonia and essential tremor.

The role of subthalamic nucleus (STN) deep brain stimulation (DBS) is well established in Parkinson's disease, but experience with STN DBS in other movement disorders is limited. We report on a patient with medically refractory cervical dystonia and essential tremor resulting in dystonic head tremor and action tremor of the hands who obtained complete tremor suppression and near resolution of her cervical dystonia with bilateral STN stimulation. The results in this case demonstrate that STN DBS can dramatically improve dystonia and tremor in nonparkinsonian movement disorders.

Adult↗

PubMed2002

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: long-term follow-up.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to be an effective therapy for the treatment of advanced Parkinson's disease (PD). Forty-seven patients were bilaterally implanted for STN DBS and clinically evaluated according to the Core Assessment Program for Intracerebral Transplantations before surgery and 3, 12 and 24 months after surgery. Electrical stimulation led to a significant improvement in motor symptoms and in the quality of life, allowing a significant reduction of dopaminergic drugs with a consequent improvement of drug-induced dyskinesias. Statistical differences were observed between UPDRS parts II, III and IV values and daily levodopa dosage in the pre- and postoperative periods, while no differences were evident between the 3 postoperative conditions.

Aged↗