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Biomedical subjects

Andreas Kupsch

Publications and source records attributed to Andreas Kupsch.

At least 19 recordsLinked to original sources
PubMed2004

The effects of electrode material, charge density and stimulation duration on the safety of high-frequency stimulation of the subthalamic nucleus in rats.

High-frequency stimulation (HFS) of deep brain structures is a powerful therapeutic tool for the treatment of various movement disorders in patients. However, the pathophysiological mechanisms of this therapeutic approach on basal ganglia network function are still largely unknown. Hitherto, experimental studies have focused on short-term stimulation. Since patients receive HFS for many years, animal studies which reproduce the conditions of long-term stimulation will be necessary to accurately investigate the effects of HFS. However, stimulation parameters of acute HFS cannot be easily transferred to long-term conditions. Accordingly, for this purpose we studied the influence of different charge densities (0, 3, 6.5, 13 and 26 microC/cm2/phase) and duration (4 h or 3 days) of subthalamic nucleus (STN)-HFS using stainless-steel and platinum-iridium (Pt/Ir) electrodes on neuronal tissue damage in rats. Our data demonstrate the advantage of Pt/Ir over stainless-steel electrodes when used in short-term HFS (frequency 130 Hz, pulse width 60 micros) and indicate that HFS using Pt/Ir-electrodes pulsed with 3 microC/cm2/phase over 3 days did not produce any relevant tissue damage in the STN.

Animals↗
PubMed2004

High-frequency stimulation of the entopeduncular nucleus improves dystonia in dtsz hamsters.

High-frequency stimulation (HFS) of the internal pallidum (GPi) has been reported to improve generalized dystonia in patients. Currently, dystonia is thought to be associated with disturbed neuronal activity of GPi neurons. Similar findings have been observed in the dtsz hamster, a model of idiopathic paroxysmal non-kinesiogenic dystonia. For this reason, we investigated the effect of bilateral HFS of the entopeduncular nucleus (EPN, rodent homologue of GPi) on the severity of dystonia. Bilateral EPN-HFS resulted in a reversible decrease of dystonia severity up to 50% when compared to both pre- and post-HFS scores, and controls. Our results underline the pathophysiological role of the EPN in the dtsz hamster and suggest the suitability of this model to further investigate mechanisms of HFS in dystonia.

Animals↗
PubMed2004

Motor cortex inhibition induced by acoustic stimulation.

The influence of the brainstem motor system on cerebral motor areas may play an important role in motor control in health and disease. A new approach to investigate this interaction in man is combining acoustic stimulation activating the startle system with transcranial magnetic stimulation (TMS) over the motor cortex. However, it is unclear whether the inhibition of TMS responses following acoustic stimulation occurs at the level of the motor cortex through reticulo-cortical projections or subcortically, perhaps through reticulo-spinal projections. We compared the influence of acoustic stimulation on motor effects elicited by TMS over motor cortical areas to those evoked with subcortical electrical stimulation (SES) through depth electrodes in five patients treated with deep brain stimulation for Parkinson's disease. SES bypasses the motor cortex, demonstrating any interaction with acoustic stimuli at the subcortical level. EMG was recorded from the contralateral biceps brachii muscle. Acoustic stimulation was delivered binaurally through headphones and used as a conditioning stimulus at an interstimulus interval of 50 ms. When TMS was used as the test stimulus, the area and amplitude of the conditioned motor response was significantly inhibited (area: 57.5+/-12.9%, amplitude: 47.9+/-7.4%, as percentage of unconditioned response) whereas facilitation occurred with SES (area: 110.1+/-4.3%, amplitude: 116.9+/-6.9%). We conclude that a startle-evoked activation of reticulo-cortical projections transiently inhibits the motor cortex.

Acoustic Stimulation↗
PubMed2004

Subthalamic stimulation differentially modulates declarative and nondeclarative memory.

Declarative memory has been reported to rely on the medial temporal lobe system, whereas non-declarative memory depends on basal ganglia structures. We investigated the functional role of the subthalamic nucleus (STN), a structure closely connected with the basal ganglia for both types of memory. Via deep brain high frequency stimulation (DBS) we manipulated neural activity of the STN in humans. We found that DBS-STN differentially modulated memory performance: declarative memory was impaired, whereas non-declarative memory was improved in the presence of STN-DBS indicating a specific role of the STN in the activation of memory systems.

Aged↗
PubMed2004

Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance.

Although the basal ganglia play an important role in self-generated movement, their involvement in externally paced voluntary movement is less clear. We recorded local field potentials (LFPs) from the region of the subthalamic nuclei of eight patients with Parkinson's disease during the performance of a warned reaction time task in which an imperative cue instructed the subject to move or not to move. In 'go' trials, LFP activity in the beta frequency band ( approximately 20 Hz) decreased prior to movement, with an onset latency that strongly correlated with mean reaction time across patients. This was followed by a late post-movement increase in beta power. In contrast, in 'nogo' trials the beta power drop following imperative signals was prematurely terminated compared with go trials and reversed into an early beta power increase. These differences were manifest as power increases when go trials were subtracted from nogo trials. In six patients these relative beta power increases in nogo-go difference trials were of shorter latency than the respective reaction time. The findings suggest that, firstly, the subthalamic nucleus is involved in the preparation of externally paced voluntary movements in humans and, secondly, the degree of synchronization of subthalamic nucleus activity in the beta band may be an important determinant of whether motor programming and movement initiation is favoured or suppressed.

Aged↗
PubMed2004

Subthalamic high frequency stimulation induced rotations are differentially mediated by D1 and D2 receptors.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) has clinically emerged as a promising approach in the treatment of Parkinson's disease, epilepsy, dystonia as well as compulsive and possibly other mood disorders. The underlying mechanisms are incompletely understood, but are definitely related to high frequency and likely to involve the dopamine (DA)-system. To further test this hypothesis the present study investigated the modulation of STN-HFS-induced circling by systemic and intracerebral injection of drugs acting on DA receptors in naive freely moving rats. Within this experimental setup, unilateral STN-HFS alone induced intensity-dependent circling. Systemic injections of selective D1- (SCH-23390) and D2-((-)-sulpiride) antagonists as well as the mixed D1 and D2 agonist apomorphine dose-dependently reduced STN-HFS-induced rotational behavior. Intracerebral microinjections of (-)-sulpiride but not SCH-23390 decreased circling when injected intrastriatally and increased the number of rotations when injected intranigrally (pars reticulata (SNr)). These data reveal that STN-HFS-induced contralateral circling is differentially modulated by D1 and D2 receptors. While D2 receptor-mediated effects involve the dorso-/ventrolateral striatum and the SNr, D1 receptors probably exert their actions via brain areas outside the striatum and SNr. These findings suggest the nigrostriatal DA-system to be specifically involved in the mediation of STN-HFS-induced motor effects.

Animals↗
PubMed2004

Ablation of the subthalamic nucleus protects dopaminergic phenotype but not cell survival in a rat model of Parkinson's disease.

Inhibition or ablation of the hyperactive subthalamic nucleus (STN) in Parkinson's disease (PD) does not only reverse motor deficits, silencing the glutamatergic output of the subthalamic nucleus, but has also been implicated to have neuroprotective effects on nigral neurons in animal models of Parkinson's disease. Ablation of the subthalamic nucleus has been shown to increase the number of tyrosinhydroxylase-immunopositive cells and partially restores behavioral deficits in animal models of Parkinson's disease. However, it is unclear whether subthalamic nucleus ablation indeed prevents cell death or whether the effect is due to the rescue of the dopaminergic (DA) phenotype of impaired cells by upregulating tyrosine hydroxylase (TH). We therefore investigated the potential neuroprotective effects of a preceding subthalamic nucleus lesion on 6-hydroxydopamine (6-OHDA)-induced nigral cell death and compared the retrograde tracer fluorogold (FG) as a marker of cell survival with tyrosinhydroxylase immunoreactivity as a marker of the dopaminergic phenotype. In the present study, we show that ablation of the subthalamic nucleus does not affect the number of fluorogold-labeled cells but increases the number of tyrosinhydroxylase-positive neurons in subthalamic nucleus-lesioned hemiparkinsonian animals and leads to partial behavioral recovery of the rats. We conclude that subthalamic nucleus ablation exerts neuroprotective properties on the dopaminergic nigrostriatal pathway against 6-hydroxydopamine toxicity in terms of rescuing the neurotransmitter phenotype in the remaining neurons rather than enhancing the total number of nigral cells.

Animals↗
PubMed2004

High frequency stimulation of the entopeduncular nucleus has no effect on striatal dopaminergic transmission.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is thought to be superior to stimulation of the internal pallidum (GPi) in alleviating symptoms of Parkinson's disease (PD). However, preliminary controlled studies comparing the effectiveness of both targets have not found significant differences in the improvement of parkinsonian symptoms, but have shown that STN stimulation allows a dramatic decrease in dopaminergic medication. We have previously shown that STN-HFS increases striatal extracellular dopamine (DA) metabolites, but not DA, in both naive and 6-hydroxydopamine (6-OHDA)-lesioned rats, whereas stimulation of the entopeduncular nucleus (EP), the rodent equivalent of the internal pallidum, does not affect DA or metabolite levels. Intriguingly, STN-HFS increases striatal DA release after inhibition of DA reuptake or metabolism, suggesting that this observation may have been obscured in non-drug treated animals by rapid and effective DA reuptake. Since STN-HFS further enhances DA metabolism after DA reuptake inhibition or depletion it has been proposed that STN-HFS increases both, striatal DA release and metabolism, independently. Therefore, the present study assesses the impact of EP-HFS on striatal DA release and metabolism in normal rats after inhibition of DA reuptake or metabolism, using microdialysis. In summary, our data demonstrate that, contrary to STN stimulation, EP-HFS has no effect on striatal DA release and metabolism. Thus, the present study provides a partial explanation for the reported clinical differences, and experimental evidence for differential mechanisms of action between HFS of the internal pallidum and the STN, that are most likely related to differences in functional anatomy.

Animals↗
PubMed2004

Levodopa therapy with entacapone in daily clinical practice: results of a post-marketing surveillance study.

The catechol-O-methyl transferase inhibitor entacapone is given in combination with levodopa/dopa decarboxylase inhibitor for Parkinson's disease (PD) patients experiencing end-of-dose wearing-off. This 4-week post-marketing surveillance study was undertaken to assess patients' responses to levodopa combined with entacapone in a real clinical practice setting. Overall, 466 patients with idiopathic PD treated with levodopa and experiencing symptoms of wearing-off were recruited. Both physicians and patients recorded the response to therapy, including improvements and side-effects. Following initiation of entacapone treatment, the average daily levodopa dose was reduced from 510 to 453 mg. Physician assessment of entacapone efficacy was judged to be "very good" or "good" in 77.6% of the patients, and tolerability was considered to be "very good" or "good" in 92.4% of patients, with only 12 patients (2.6%) withdrawing from the study. Compared with baseline, there was a decrease in the mean duration of daily 'off' time from 3.0 to 1.3 h per day during the treatment period. Adverse events were in line with those previously reported, with diarrhoea being the most frequent event. The percentage of patients suffering from dyskinesia decreased from 46 to 34%, and of those patients still suffering from dyskinesia, the average daily duration of dyskinesia was reduced from 2.2 to 1.7 h. The use of adjunct dopamine agonists decreased from 67 to 59%. At study end, the percentage of patients who rated their quality of life (QoL) as "very good" or "good" increased from 12.1 to 51.7% and the percentage of patients who rated their QoL as "bad" or "very bad" decreased from 40 to 10.7%. In summary, the results of this survey conducted in real clinical practice support the findings of previous clinical trials demonstrating the efficacy and tolerability of entacapone, as well as the benefits of improved QoL, for patients achieved with entacapone.

Adult↗
PubMed2003

Comparison of motor effects following subcortical electrical stimulation through electrodes in the globus pallidus internus and cortical transcranial magnetic stimulation.

Current concepts of transcranial magnetic stimulation (TMS) over the primary motor cortex are still under debate as to whether inhibitory motor effects are exclusively of cortical origin. To further elucidate a potential subcortical influence on motor effects, we combined TMS and unilateral subcortical electrical stimulation (SES) of the corticospinal tract. SES was performed through implanted depth electrodes in eight patients treated with deep brain stimulation (DBS) for severe dystonia. Chronaxie, conduction velocity (CV) of the stimulated fibres and poststimulus time histograms of single motor unit recordings were calculated to provide evidence of an activation of large diameter myelinated fibres by SES. Excitatory and inhibitory motor effects recorded bilaterally from the first dorsal interosseus muscle were measured after SES and focal TMS of the motor cortex. This allowed us to compare motor effects of subcortical (direct) and cortical (mainly indirect) activation of corticospinal neurons. SES activated a fast conducting monosynaptic pathway to the alpha motoneuron. Motor responses elicited by SES had significantly shorter onset latency and shorter duration of the contralateral silent period compared to TMS induced motor effects. Spinal excitability as assessed by H-reflex was significantly reduced during the silent period after SES. No ipsilateral motor effects could be elicited by SES while TMS was followed by an ipsilateral inhibition. The results suggest that SES activated the corticospinal neurons at the level of the internal capsule. Comparison of SES and TMS induced motor effects reveals that the first part of the TMS induced contralateral silent period should be of spinal origin while its later part is due to cortical inhibitory mechanisms. Furthermore, the present results suggest that the ipsilateral inhibition is predominantly mediated via transcallosal pathways.

Adolescent↗
PubMed2003

Patterning of globus pallidus local field potentials differs between Parkinson's disease and dystonia.

Here we test the hypothesis that there are distinct temporal patterns of synchronized neuronal activity in the pallidum that characterize untreated and treated parkinsonism and dystonia. To this end we recorded local field potentials (LFPs) from the caudal and rostral contact pairs of macroelectrodes implanted into the pallidum of patients for the treatment of Parkinson's disease (12 cases recorded on and off medication, 17 macroelectrodes) and dystonia (10 cases, 19 macroelectrodes). Percentage LFP power in the 11-30 Hz band was decreased and that in the 4-10 Hz band increased across both contact pairs in treated Parkinson's disease compared with untreated Parkinson's disease. Dystonic patients had even less 11-30 Hz power and greater 4-10 Hz power compared with untreated or treated Parkinson's disease patients. The change in the 4-10 Hz band in patients with dystonia was particularly manifest in the more rostral contact pair, presumed to be within or bridging the globus pallidus externus. We conclude that untreated and treated Parkinson's disease and dystonia are characterized by different spatiotemporal patterns of activity in the human pallidum.

Adult↗
PubMed2003

Behavioural cues are associated with modulations of synchronous oscillations in the human subthalamic nucleus.

The speed with which one reacts to an imperative signal depends on the extent to which preceding cues predict that command. When reliable warning cues are available, the processing of the imperative stimulus can be favoured and responses partially pre-prepared, leading to shorter reaction times. Here we seek evidence for involvement of the human basal ganglia in the exploitation of behaviourally relevant predictive cues. To this end, local field potentials (LFPs) were recorded in the region of the subthalamic nuclei of parkinsonian patients during the performance of a pre-cued reaction task in which the cue either predicted or failed to predict the demands of the imperative signal. We demonstrate that LFP activity in the beta frequency band ( approximately 20 Hz) is modulated by the behavioural relevance of the external cue. The findings suggest that, first, the subthalamic nucleus is involved in mediating or facilitating the response advantage derived from predictive cues in humans and, secondly, variations in synchronous neuronal activity in the beta band may contribute to this function in the subthalamic nucleus.

Aged↗
PubMed2003

Absorption and extinction correction in quantitative DAFS analysis.

An approach to X-ray attenuation correction for diffraction anomalous fine-structure (DAFS) measurements is presented, taking into account energy-dependent secondary extinction effects. A numerical model based on the kinematical theory of diffraction is presented. This model is exemplified by DAFS measurements of the Zr 0002 reflection intensities for energies in the vicinity of the Zr K absorption edge of a Co/Zr multilayer exhibiting strong fibre texture. X-ray absorption fine-structure (XAFS) measurements proved to be a necessary auxiliary for DAFS amplitude correction.

Journal Article↗
PubMed2003

Deep brain stimulation in dystonia.

Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinson's disease and essential tremor in the 1990s. DBS evolved from ablative surgery, which was applied with varying results in the 1950s in patients with movement disorders such as Parkinson's disease, essential tremor and dystonia. The present review summarizes the current knowledge on clinical aspects of DBS in dystonia (Dec. 2002). Excellent results have been achieved in dystonic patients carrying a mutation in the DYT1 gene with improvements up to 90 %. Similar results may also be obtained in patients with idiopathic generalized dystonia, myoclonus-dystonia syndrome, and tardive dystonia. Substantial improvement has been observed in patients with focal dystonia (for instance cervical dystonia). Patients with secondary dystonia often display a lesser and more variable degree of improvement. Long-term studies are warranted to assess both motor and neuropsychological sequelae of DBS in dystonia. Furthermore, the optimal target for different dystonic disorders remains to be determined, although the globus pallidus internus has currently emerged as the most promising target for dystonia.

Dystonia↗
PubMed2003

High-frequency stimulation of the subthalamic nucleus enhances striatal dopamine release and metabolism in rats.

High-frequency stimulation of the subthalamic nucleus is believed to exert its main effects via the basal ganglia output structures. Previously, we have shown a concomitant increase in striatal dopamine (DA) metabolites in normal and 6-hydroxydopamine-lesioned rats. The present study was designed to determine whether this increase in striatal DA metabolites reflects enhanced intraneuronal DA turnover or, alternatively, is due to increased DA release with subsequent rapid and efficient reuptake and/or metabolism. Thus, high-frequency stimulation of the subthalamic nucleus was performed in normal rats after inhibition of DA reuptake, metabolism or DA depletion. Extracellular levels of striatal DA and its metabolites were assessed using microdialysis. Our data suggest that subthalamic high-frequency stimulation increases striatal DA release and activates independent striatal DA metabolism. Since such changes could be triggered by modification of either the activity or the gene expression of the rate-limiting enzyme tyrosine hydroxylase, an activity assay and RT-PCR of striatal and nigral samples were performed. Subthalamic stimulation increased striatal tyrosine hydroxylase activity without affecting gene expression. We, therefore, conclude that the application of subthalamic high-frequency stimulation could partially compensate for the DA deficit by inducing increased striatal DA release and metabolism.

Animals↗
PubMed2002

Deep brain stimulation of subthalamic neurons increases striatal dopamine metabolism and induces contralateral circling in freely moving 6-hydroxydopamine-lesioned rats.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates Parkinson's disease (PD) symptoms. Although widely used, the mechanisms of action are still unknown. In an attempt to elucidate those mechanisms, we have previously demonstrated that STN-DBS increases striatal extracellular dopamine (DA) metabolites in anaesthetized rats. PD being a movement disorder, it remains to be determined whether these findings are related to any relevant motor or behavioural changes. Thus, this study investigates concomitant behavioural changes during STN-DBS and extracellular striatal DA metabolites measured using microdialysis in freely moving 6-hydroxydopamine-lesioned rats. STN-DBS induced an increase of striatal DA metabolites in awake, freely moving animals. Furthermore, we observed concomitant contralateral circling behaviour. Taken together, these results suggest that STN-DBS could disinhibit (consequently activate) substantia nigra compacta neurons via inhibition of gamma-aminobutyric acid-ergic substantia nigra reticulata neurons.

3,4-Dihydroxyphenylacetic Acid↗