Role of External Pallidal Segment in Primate Parkinsonism: Comparison of the Effects of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism and Lesions of the External Pallidal Segment

Soares, Jesus; Kliem, Michele A.; Betarbet, Ranjita; Greenamyre, J. Timothy; Yamamoto, Bryan K.; Wichmann, Thomas

doi:10.1523/jneurosci.0836-04.2004

Cited by 178 publications

(209 citation statements)

References 54 publications

(56 reference statements)

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“…However, how DA depletion could affect this contribution depends crucially on the degree of segregation between the direct and indirect pathways. Because recent experiments indicate that this is incomplete (Aizman et al, 2000;Wu et al, 2000;Levesque and Parent, 2005), we suggest that the indirect pathway only plays a secondary role in the emergence of pathological oscillations in GPi and impairment of movement, in line with Soares et al (2004).…”

Section: Discussionsupporting

confidence: 62%

“…This value or greater was considered to indicate a significant probability ( p Ͻ 0.05) of synchronized oscillatory activity between two cells. For statistical analysis of the autospectra, the elements of the interspike intervals of each spike train were randomly shuffled, and the power spectrum of the resulting (random) spike train was calculated (Soares et al, 2004). The mean and SD of the resulting power spectra of 20 iterations of shuffled data were computed.…”

Section: Numerical Simulations Of the Detailed Modelmentioning

confidence: 99%

“…Moreover, striatal neurons are involved in both the direct and indirect pathways (Bolam et al, 2000;Wu et al, 2000;Levesque and Parent, 2005), D 1 and D 2 receptors are colocalized on striatal neurons (Aizman et al, 2000), and the effects of DA mediated through D 1 and D 2 receptors are not always opposing (Calabresi et al, 2000;Kerr and Wickens, 2001;Nicola et al, 2004). Last but not least, a recent study concludes that lesions in the external pallidum in the monkey do not induce parkinsonian-like motor symptoms and do not affect the activity pattern in GPi (Soares et al, 2004). This raises additional questions regarding the primary involvement of the indirect pathway in PD symptoms.…”

Section: Introductionmentioning

confidence: 99%

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Competition between Feedback Loops Underlies Normal and Pathological Dynamics in the Basal Ganglia

Leblois¹,

Boraud²,

Meissner³

et al. 2006

J. Neurosci.

294

295

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Experiments performed in normal animals suggest that the basal ganglia (BG) are crucial in motor program selection. BG are also involved in movement disorders. In particular, BG neuronal activity in parkinsonian animals and patients is more oscillatory and more synchronous than in normal individuals.We propose a new model for the function and dysfunction of the motor part of BG. We hypothesize that the striatum, the subthalamic nucleus, the internal pallidum (GPi), the thalamus, and the cortex are involved in closed feedback loops. The direct (cortex-striatumGPi-thalamus-cortex) and the hyperdirect loops (cortex-subthalamic nucleus-GPi-thalamus-cortex), which have different polarities, play a key role in the model. We show that the competition between these two loops provides the BG-cortex system with the ability to perform motor program selection. Under the assumption that dopamine potentiates corticostriatal synaptic transmission, we demonstrate that, in our model, moderate dopamine depletion leads to a complete loss of action selection ability. High depletion can lead to synchronous oscillations. These modifications of the network dynamical state stem from an imbalance between the feedback in the direct and hyperdirect loops when dopamine is depleted.Our model predicts that the loss of selection ability occurs before the appearance of oscillations, suggesting that Parkinson's disease motor impairments are not directly related to abnormal oscillatory activity. Another major prediction of our model is that synchronous oscillations driven by the hyperdirect loop appear in BG after inactivation of the striatum.

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Section: Discussionsupporting

confidence: 62%

Section: Numerical Simulations Of the Detailed Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Competition between Feedback Loops Underlies Normal and Pathological Dynamics in the Basal Ganglia

Leblois¹,

Boraud²,

Meissner³

et al. 2006

J. Neurosci.

294

295

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“…This result suggests that, in the parkinsonian state, DBS acts not as an informational lesion, but as an "information filter" (Rosenbaum et al, 2014) or a desynchronizing force (Wilson et al, 2011). We speculate that DBS may permit the transmission of task-related information through the BG while blocking the transmission of some of the resting pathologic firing characteristics of PD, such as low-frequency oscillations in the STN Levy et al, 2002;Soares et al, 2004;Meissner et al, 2005;Kühn et al, 2008;Moran et al, 2008;McConnell et al, 2012) and GP (Wichmann et al, 1994(Wichmann et al, , 1999Raz et al, 2000;Brown et al, 2004;McCairn and Turner, 2009). A filter or desynchronizing effect of DBS (Wilson et al, 2011;Rosenbaum et al, 2014) could explain the divergent motor (Slavin et al, 2004;Alvarez et al, 2005;Merello et al, 2006;Baraduc et al, 2013) and cognitive (Brown et al, 2003;Carbon and Eidelberg, 2006;) effects that follow lesions of the BG versus stimulation of the same structures.…”

Section: Discussionmentioning

confidence: 96%

Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus

et al. 2015

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Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) has largely replaced ablative therapies for Parkinson's disease.Because of the similar efficacies of the two treatments, it has been proposed that DBS acts by creating an "informational lesion," whereby pathologic neuronal firing patterns are replaced by low-entropy, stimulus-entrained firing patterns. The informational lesion hypothesis, in its current form, states that DBS blocks the transmission of all information from the basal ganglia, including both pathologic firing patterns and normal, task-related modulations in activity. We tested this prediction in two healthy rhesus macaques by recording single-unit spiking activity from the globus pallidus (232 neurons) while the animals completed choice reaction time reaching movements with and without STN-DBS. Despite strong effects of DBS on the activity of most pallidal cells, reach-related modulations in firing rate were equally prevalent in the DBS-on and DBS-off states. This remained true even when the analysis was restricted to cells affected significantly by DBS. In addition, the overall form and timing of perimovement modulations in firing rate were preserved between DBS-on and DBS-off states in the majority of neurons (66%). Active movement and DBS had largely additive effects on the firing rate of most neurons, indicating an orthogonal relationship in which both inputs contribute independently to the overall firing rate of pallidal neurons. These findings suggest that STN-DBS does not act as an indiscriminate informational lesion but rather as a filter that permits task-related modulations in activity while, presumably, eliminating the pathological firing associated with parkinsonism.

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“…Indeed, as new experimental data are acquired, adjustments must be made to the conceptual and computational basal ganglia models. For example, Soares et al (2004) showed that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced parkinsonism in rhesus monkeys reduced GPe activity (and thus increased STN and GPi activity) as predicted. However, ablation of the GPe did not induce parkinsonian symptoms.…”

mentioning

confidence: 92%

Emergent Basal Ganglia Pathology within Computational Models

Voytek

2006

J. Neurosci.

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Editor's Note: These short reviews of a recent paper in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to mimic the journal clubs that exist in your own departments or institutions. For more information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml. Emergent Basal Ganglia Pathology within Computational Models Bradley VoytekHelen Wills Neuroscience Institute, University of California, Berkeley, California 94720-3190Review of Leblois et al. (http://www.jneurosci.org/cgi/content/full/26/13/3567) Advances in neurobiology and increased computational capabilities have paved the way for more realistic neuronal network models. For a model to be complete, it must account for known neuroanatomy, network electrophysiology, pharmacology, pathophysiology, and behavioral findings. Although the vast interconnectedness of the brain makes the formulation of a complete model computationally restrictive, scaled models of anatomical subsystems have offered new insights into brain function.One particularly attractive system to model is the basal ganglia. The anatomy and electrophysiology of this system of subcortical, prosencephalic nuclei has been well described and is thus ideal for modeling. The basal ganglia consist of four main subnuclei: striatum, globus pallidus [internal segment (GPi) and external segment (GPe)], subthalamic nucleus (STN), and substantia nigra [compact (SNc) and reticular (SNr)]. Movement disorders such as Parkinson's disease (PD) have been traced to basal ganglia dysfunction. Consequently, the basal ganglia are traditionally classified as part of the extrapyramidal motor system.Parkinson's disease is characterized by the loss of dopaminergic innervation of the striatum from the SNc. Early conceptual models (DeLong, 1990) diagrammed a "direct" and "indirect" circuit within the basal ganglia. These parallel circuits diverge according to their nigrostriatal targets; the direct pathway is said to preferentially target striatal D 1 receptors, whereas the indirect pathway is said to preferentially target D 2 receptors. These receptors modulate excitation and inhibition in the circuit, respectively. Ultimately, both pathways project to the cortex via the anterior thalamus (Fig. 1).This simple model proved very useful in describing the motor effects of PD and helped guide treatment. However, recent experimental findings suggest that this model is incomplete. New PD treatments such as deep brain stimulation are difficult to reconcile within the classical model. Similarly, this model inadequately describes the role of the basal ganglia in learning, memory, language, and reward. Finally, there is mounting evidence that the D 1 /D 2 , direct/indirect segregation required by this model does not accurately describe the biology of the system. Indeed, as new experimental data are acquired, adjustments must be made to the conceptual and computational basal ganglia models. For example, Soares et al. (2004) showed that MP...

show abstract

Role of External Pallidal Segment in Primate Parkinsonism: Comparison of the Effects of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism and Lesions of the External Pallidal Segment

Cited by 178 publications

References 54 publications

Competition between Feedback Loops Underlies Normal and Pathological Dynamics in the Basal Ganglia

Competition between Feedback Loops Underlies Normal and Pathological Dynamics in the Basal Ganglia

Movement-Related Discharge in the Macaque Globus Pallidus during High-Frequency Stimulation of the Subthalamic Nucleus

Emergent Basal Ganglia Pathology within Computational Models

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