Daniel Harnack

Dopamine depletion increases the power and coherence of β-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat

Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) of untreated patients implanted with stimulation electrodes for the treatment of Parkinsons disease (PD) demonstrate strong coherence with the cortical electroencephalogram over the β‐frequency range (15–30 Hz). However, studies in animal models of PD emphasize increased temporal coupling in cortico‐basal ganglia circuits at substantially lower frequencies, undermining the potential usefulness of these models. Here we show that 6‐hydroxydopamine (6‐OHDA) lesions of midbrain dopamine neurons are associated with significant increases in the power and coherence of β‐frequency oscillatory activity present in LFPs recorded from frontal cortex and STN of awake rats, as compared with the healthy animal. Thus, the pattern of synchronization between population activity in the STN and cortex in the 6‐OHDA‐lesioned rodent model of PD closely parallels that seen in the parkinsonian human. The peak frequency of coherent activity in the β‐frequency range was increased in lesioned animals during periods of spontaneous and sustained movement. Furthermore, administration of the dopamine receptor agonist apomorphine to lesioned animals suppressed β‐frequency oscillations, and increased coherent activity at higher frequencies in the cortex and STN, before producing the rotational behaviour indicative of successful lesion. Taken together, these results support a crucial role for dopamine in the modulation of population activity in cortico‐basal ganglia circuits, whereby dopaminergic mechanisms effectively filter out synchronized, rhythmic activity at β‐frequencies at the systems level, and shift temporal couplings in these circuits to higher frequencies. These changes may be important in regulating movement.

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.

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 Parkinsons 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.

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.

Striatal dopaminergic metabolism is increased by deep brain stimulation of the subthalamic nucleus in 6-hydroxydopamine lesioned rats

Deep brain stimulation of the subthalamic nucleus is an established therapeutic strategy for patients with Parkinsons disease. Although the exact mechanisms of action remain unknown, it is noteworthy that dopaminergic medication can be markedly reduced after neurostimulation of the subthalamic nucleus. Previously, we have shown that deep brain stimulation of the subthalamic nucleus is followed by an increase of striatal extracellular dopamine metabolites in naive rats. In the present study we examined the effects of deep brain stimulation on striatal monoamine metabolism in the intrastriatal 6-hydroxydopamine rat model of Parkinsons disease. Deep brain stimulation of the subthalamic nucleus was followed by a delayed increase of extracellular 3,4-dihydroxyphenylacetic and homovanillic whereas dopamine levels were unchanged in stimulated rats and controls. Our results indicate that deep brain stimulation of the subthalamic nucleus affects significantly striatal dopaminergic metabolism in 6-hydroxydopamine lesioned rats.

Oscillatory local field potentials recorded from the subthalamic nucleus of the alert rat.

Hitherto, high-frequency local field potential oscillations in the upper gamma frequency band (40-80 Hz) have been recorded only from the region of subthalamic nucleus (STN) in parkinsonian patients treated with levodopa. Here we show that local field potentials recorded from the STN in the healthy alert rat also have a spectral peak in the upper gamma band (mean 53 Hz, range 46-70 Hz). The power of this high-frequency oscillatory activity was increased by 30 +/- 4% (+/-SEM) during motor activity compared to periods of alert immobility. It was also increased by 86 +/- 36% by systemic injection of the D2 dopamine receptor agonist quinpirole. The similarities between the high-frequency activities in the STN of the healthy rat and in the levodopa-treated parkinsonian human argue that this oscillatory activity may be physiological in nature and not a consequence of the parkinsonian state.

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 Parkinsons 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 Parkinsons 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 Parkinsons 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.

Deep brain stimulation in dystonia.

Abstract. Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinsons 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 Parkinsons 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.

High frequency stimulation and temporary inactivation of the subthalamic nucleus reduce quinpirole-induced compulsive checking behavior in rats

Obsessive-compulsive disorder (OCD) represents a highly prevalent and impairing psychiatric disorder. Functional and structural imaging studies implicate the involvement of basal ganglia-thalamo-cortical circuits in the pathophysiology of this disorder. In patients remaining resistant to pharmaco- and behavioral therapy, modulation of these circuits may consequently reverse clinical symptoms. High frequency stimulation (HFS) of the subthalamic nucleus (STN), an important station of the basal ganglia-thalamo-cortical circuits, has been reported to reduce obsessive-compulsive symptoms in a few Parkinsons disease patients with comorbid OCD. The present study tested the effects of bilateral HFS of the STN and of bilateral pharmacological inactivation of the STN (via intracranial administration of the GABA agonist muscimol) on checking behavior in the quinpirole rat model of OCD. We demonstrate that both HFS and pharmacological inactivation of the STN reduce quinpirole-induced compulsive checking behavior. We conclude that functional inhibition of the STN can alleviate compulsive checking, and suggest the STN as a potential target structure for HFS in the treatment of OCD.

High-frequency stimulation of the nucleus accumbens core and shell reduces quinpirole-induced compulsive checking in rats

Electrical deep brain stimulation (DBS) is currently studied in the treatment of therapy‐refractory obsessive compulsive disorders (OCDs). The variety of targeted brain areas and the inconsistency in demonstrating anti‐compulsive effects, however, highlight the need for better mapping of brain regions in which stimulation may produce beneficial effects in OCD. Such a goal may be advanced by the assessment of DBS in appropriate animal models of OCD. Currently available data on DBS of the nucleus accumbens (NAc) on OCD‐like behavior in rat models of OCD are contradictory and partly in contrast to clinical data and theoretical hypotheses about how the NAc might be pathophysiologically involved in the manifestation of OCD. Consequently, the present study investigates the effects of DBS of the NAc core and shell in a quinpirole rat model of OCD. The study demonstrates that electrical modulation of NAc core and shell activity via DBS reduces quinpirole‐induced compulsive checking behavior in rats. We therefore conclude that both, the NAc core and shell constitute potential target structures in the treatment of OCD.