Simulating Idiopathic Parkinson\u27s Disease by In Vitro and Computational Models

In general there is a wide gap between experimental animal results, especially with respect to neuroanatomical data, and computational modeling. In order to be able to investigate the anatomical and functional properties of afferent and efferent connections between the different nuclei of the basal ganglia, similar studies need to be performed as described in this review for the Substantia Nigra. These studies, though very time-consuming, are essential to decide which pathways play important roles in normal functioning and therefore need to be included in modeling studies. In addition, it should be known what neuroanatomical changes take place resulting from the neurodegeneration associated with Parkinson’s disease and how they affect network behavior. For instance, the direct effects of DBS on motor control are of interest, but since DBS has a low threshold to side effects, additional non-motor pathways are expected to be involved. Including these pathways in network models may shed light on the extent and effect of stimulation. Similarly, as PPN stimulation may have a beneficial influence on gait and balance, different pathways are important regarding the different motor symptoms of Parkinson’s disease

Neural model of dopaminergic control of arm movements in Parkinson’s disease bradykinesia

Patients suffering from Parkinson’s disease display a number of symptoms such a resting tremor, bradykinesia, etc. Bradykinesia is the hallmark and most disabling symptom of Parkinson’s disease (PD). Herein, a basal ganglia-cortico-spinal circuit for the control of voluntary arm movements in PD bradykinesia is extended by incorporating DAergic innervation of cells in the cortical and spinal components of the circuit. The resultant model simulates successfully several of the main reported effects of DA depletion on neuronal, electromyographic and movement parameters of PD bradykinesia

Value encoding in the globus pallidus: fMRI reveals an interaction effect between reward and dopamine drive

The external part of the globus pallidus (GPe) is a core nucleus of the basal ganglia (BG) whose activity is disrupted under conditions of low dopamine release, as in Parkinson's disease. Current models assume decreased dopamine release in the dorsal striatum results in deactivation of dorsal GPe, which in turn affects motor expression via a regulatory effect on other nuclei of the BG. However, recent studies in healthy and pathological animal models have reported neural dynamics that do not match with this view of the GPe as a relay in the BG circuit. Thus, the computational role of the GPe in the BG is still to be determined. We previously proposed a neural model that revisits the functions of the nuclei of the BG, and this model predicts that GPe encodes values which are amplified under a condition of low striatal dopaminergic drive. To test this prediction, we used an fMRI paradigm involving a within-subject placebo-controlled design, using the dopamine antagonist risperidone, wherein healthy volunteers performed a motor selection and maintenance task under low and high reward conditions. ROI-based fMRI analysis revealed an interaction between reward and dopamine drive manipulations, with increased BOLD activity in GPe in a high compared to low reward condition, and under risperidone compared to placebo. These results confirm the core prediction of our computational model, and provide a new perspective on neural dynamics in the BG and their effects on motor selection and cognitive disorders

Bradykinesia models of Parkinson’s disease

This entry describes a plethora of experimental observations from PD bradykinesia in humans and animals ranging across neuronal, electromyographic and behavioral levels and discusses related theoretical and computational models developed to reproduce and explain these findings. Some computational models of bradykinesia have focused entirely on the effects of dopamine depletion in the basal ganglio-thalamo-cortical relations, whereas others emphasize dopamine depletion in cortico-spino-muscular interactions. Future models will have to produce a more comprehensive and detailed neural model of basal ganglia-thalamo-cortico-spino-muscular interactions, in order to study more systematically the effects of dopamine depletion in these nuclei and integrate into a ‘unified theory’ all the known neurophysiological, EMG and behavioral observations associated with parkinsonism

Bradykinesia models of Parkinson’s disease

This entry describes a plethora of experimental observations from PD bradykinesia in humans and animals ranging across neuronal, electromyographic and behavioral levels and discusses related theoretical and computational models developed to reproduce and explain these findings. Some computational models of bradykinesia have focused entirely on the effects of dopamine depletion in the basal ganglio-thalamo-cortical relations, whereas others emphasize dopamine depletion in cortico-spino-muscular interactions. Future models will have to produce a more comprehensive and detailed neural model of basal ganglia-thalamo-cortico-spino-muscular interactions, in order to study more systematically the effects of dopamine depletion in these nuclei and integrate into a ‘unified theory’ all the known neurophysiological, EMG and behavioral observations associated with parkinsonism

Electrophysiological activity of basal ganglia under deep brain stimulation in the rat model

Die Tiefe Hirnstimulation (DBS) des Nucleus subthalamicus (STN) wird seit den 1990er Jahren zur Therapie sämtlicher Leitsymptome des Parkinson Syndroms erfolgreich eingesetzt. Der Wirkmechanismus der Hochfrequenzstimulation (HFS) des STN ist allerdings weiterhin unzureichend verstanden. Umfangreiche elektrophysiologische in vitro und in vivo Studien konnten keine einheitliche Erklärung der DBS-Phänomene liefern. Die experimentelle Datenlage zum Einfluss der HFS des STN auf die neuronale Aktivität der Basalganglien ist oft widersprüchlich. Ziel der vorliegenden Arbeit war die Untersuchung der Auswirkungen der STN- HFS auf die elektrophysiologische Aktivität des externen Globus pallidus (GPe), der Substantia nigra pars reticulata (SNr) und des Nucleus pedunculopontinus (PPN). Hierfür wurden in intakten, Urethan-narkotisierten Ratten extrazelluläre Einzelzellableitungen der drei genannten Basalganglien-Kerne vor und nach der HFS des STN durchgeführt. Im Gegensatz zu früheren Studien, die nur einzelne Basalganglien untersuchten, stellt die hier zur Anwendung kommende gleichzeitige Ableitung mehrerer Kerngebiete eine Weiterentwicklung zur Beurteilung der Modulation der neuronalen Aktivität dar. Die Ergebnisse der vorliegenden Arbeit zeigen, dass die STN-HFS die Aktivität sämtlicher untersuchten Basalganglien-Kerne moduliert. Die STN-Stimulation hemmt die Aktivität des GPe, am ehesten durch stimulationsinduzierte Hemmung der exzitatorischen glutamatergen STN-Efferenzen. Die Mehrheit der SNr- Neurone wurde durch die STN-Stimulation gehemmt, was auf einen ähnlichen monosynaptischen Modulationsmechanismus hindeutet. Eine Minderheit der SNr-Neurone zeigte jedoch nach der STN-Stimulation eine erhöhte Aktivität. Dieser Effekt ist vermutlich polysynaptisch unter Beteiligung der inhibitorischen pallidonigralen Projektion. PPN-Neurone reagierten auf die STN-Stimulation teils mit verringerter, teils mit erhöhter Aktivität, in ähnlichem Anteil. Die Hemmung des PPN wird vermutlich durch eine stimulationsinduzierte Inhibition der exzitatorischen Afferenzen vom STN hervorgerufen, wohingegen die Aktivierung des PPN durch eine Enthemmung über GABAerge Afferenzen von der SNr zu erklären ist. Zusammengenommen zeigen die Ergebnisse dieser Studie, dass die STN-HFS die Aktivität des gesamten Basalganglien-Netzwerks moduliert. Dieses deutet darauf hin, dass die klinische Wirkung der STN-DBS in der Behandlung des Parkinson Syndroms ein komplexes Phänomen darstellt, das über die Wiederherstellung des pathologisch hyperaktiven Basalganglien-Ausgangs hinausgeht.Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates all cardinal symptoms in Parkinson’s disease patients. However, the underlying mechanism of high-frequency stimulation (HFS) of the STN is poorly understood. Extensive electrophysiological in vitro and in vivo research has failed to deliver a uniform explanation of the DBS phenomena. The data concerning the influence of STN stimulation on the neuronal activity of the basal ganglia are often contradictory. The current study was performed in intact, urethane-anesthetized rats. It explores the effects of high-frequency STN stimulation on the electrophysiological activity of the external globus pallidus (GPe), the substantia nigra pars reticulata (SNr), and the pedunculopontine nucleus (PPN). To assess the modulation of neuronal activity by stimulation, extracellular single-cell recordings were performed before and after HFS of the STN, in up to three basal ganglia nuclei simultaneously, which provides a significant advantage over previous studies exploring the modulation of a single basal ganglia nucleus. The results of the present work show that HFS of the STN modulates the activity of all examined basal ganglia nuclei. STN stimulation inhibits GPe activity, most likely due to stimulation-induced inhibition of the excitatory glutamatergic projections from the STN. The majority of the SNr neurons were inhibited by STN stimulation, suggesting a similar monosynaptic modulatory mechanism. However, a minority of SNr neurons displayed increased activity after STN stimulation. This effect is most likely polysynaptic, involving the inhibitory pallidonigral projection. PPN neurons were found to respond to STN stimulation both by decreased and increased activity in the same proportion. Inhibition of the PPN is probably caused by stimulation-induced inhibition of the excitatory projections from the STN, whereas excitation of the PPN occurs most likely due to disinhibition via GABAergic projections from the SNr. Taken together, the results of this study demonstrate that HFS of the STN modulates the activity of the whole basal ganglia network, suggesting that the clinical effect of STN-DBS in the treatment of Parkinson’s disease represents a complex phenomenon that extends beyond the restoration of the pathological hyperactive basal ganglia output