Thalamic Neuronal Activity in Dopamine-Depleted Primates: Evidence for a Loss of Functional Segregation within Basal Ganglia Circuits

Pessiglione, Mathias; Guehl, Dominique; Rolland, Anne‐Sophie; François, Chantal; Hirsch, Étienne C.; Tremblay, Léon

doi:10.1523/jneurosci.4056-04.2005

Cited by 152 publications

(152 citation statements)

References 46 publications

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“…DA depletion induces loss of functional segregation in the BG and in their target structure (Filion et al, 1988;Mink, 1996;Boraud et al, 2000;Pessiglione et al, 2005). We suggest that these pathologies stem from a reduction of the feedback in the direct pathways when DA is depleted, which moves the BG network out of the symmetry-breaking regimen.…”

Section: Discussionmentioning

confidence: 86%

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: Discussionmentioning

confidence: 86%

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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“…Moreover, the majority of TCNs preserved a random discharge pattern and the number of bursty TCNs remained small across the disease conditions, whereas the number of regular TCNs decreased (random, bursty, and regular pattern: 471 vs. 527, 51 vs. 32, and 70 vs. 41 TCNs, respectively, normal vs. PD conditions), consistently with the trend reported in ref. 78. On the other hand, the loss of dopamine had an effect on the oscillations of the TCN discharge pattern: 224 out of 600 TCNs had a significant change in the interspike interval (ISI) histogram (t test, P < 0:05), with an enhanced bimodal distribution of the ISIs in PD conditions and peaks around 3 ms and 30 ms ( In our model under PD conditions, 130-Hz STN DBS affected the GPi PANs by inducing more regular firing patterns, higher average firing rates, and lower burstiness ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic mechanisms of high-frequency stimulation in Parkinson’s disease and neural restoration via loop-based reinforcement

Santaniello¹,

McCarthy

Montgomery³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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High-frequency deep brain stimulation (HFS) is clinically recognized to treat parkinsonian movement disorders, but its mechanisms remain elusive. Current hypotheses suggest that the therapeutic merit of HFS stems from increasing the regularity of the firing patterns in the basal ganglia (BG). Although this is consistent with experiments in humans and animal models of Parkinsonism, it is unclear how the pattern regularization would originate from HFS. To address this question, we built a computational model of the cortico-BG-thalamo-cortical loop in normal and parkinsonian conditions. We simulated the effects of subthalamic deep brain stimulation both proximally to the stimulation site and distally through orthodromic and antidromic mechanisms for several stimulation frequencies and, correspondingly, we studied the evolution of the firing patterns in the loop. The model closely reproduced experimental evidence for each structure in the loop and showed that neither the proximal effects nor the distal effects individually account for the observed pattern changes, whereas the combined impact of these effects increases with the stimulation frequency and becomes significant for HFS. Perturbations evoked proximally and distally propagate along the loop, rendezvous in the striatum, and, for HFS, positively overlap (reinforcement), thus causing larger poststimulus activation and more regular patterns in striatum. Reinforcement is maximal for the clinically relevant 130-Hz stimulation and restores a more normal activity in the nuclei downstream. These results suggest that reinforcement may be pivotal to achieve pattern regularization and restore the neural activity in the nuclei downstream and may stem from frequency-selective resonant properties of the loop.igh-frequency (i.e., above 100 Hz) deep brain stimulation (HFS) of the basal ganglia (BG) and thalamus is clinically recognized to treat movement disorders in Parkinson's disease (PD) (1-4), but its therapeutic mechanisms remain unclear (5, 6).Early hypotheses about HFS were derived from the rate-based model of the BG function (7,8) and postulated the disruption of the output of the BG-thalamic system via either the inactivation of neurons in the stimulated site (target) (9-15), which would provide an effect similar to a surgical lesion, or the abnormal excitation of axons projecting out of the target (16-19), which would disrupt the neuronal activity in the structures downstream, including any pathophysiological activity (20).More recently, an ever-growing number of experiments in PD humans and animal models of Parkinsonism has indicated that HFS affects the firing patterns of the neurons rather than the mean firing rate both in the target and the structures downstream (18,19,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and it replaces repetitive low-frequency (i.e., ≤50 Hz) bursting patterns with regularized (i.e., more tonic) patterns at higher frequencies (25,26). It has been proposed that increased pattern regularity of neurons in the target may be therapeutic (...

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“…9 GPi activity (a, b), STN activity (c, d), and angular velocity (e, f), resulting from simulation of the parkinsonian model (DA=0.7) including DBS mechanism 2 (excitation of afferent axons), and 3 (partial synaptic failure), respectively. In addition, the curves for the intact model (control) and the parkinsonian model (DA=0.8) are included in each graph Pessiglione et al 2005;Calabresi et al 2000). Loss of segregation resulting from an enlargement of the receptive fields of striatal neurons is illustrated in Fig.…”

Section: Discussionmentioning

confidence: 99%

Increased bradykinesia in Parkinson’s disease with increased movement complexity: elbow flexion–extension movements

2008

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The present research investigates factors contributing to bradykinesia in the control of simple and complex voluntary limb movement in Parkinson's disease (PD) patients. The functional scheme of the basal ganglia (BG)-thalamocortical circuit was described by a mathematical model based on the mean firing rates of BG nuclei. PD was simulated as a reduction in dopamine levels, and a loss of functional segregation between two competing motor modules. In order to compare model simulations with performed movements, flexion and extension at the elbow joint is taken as a test case. Results indicated that loss of segregation contributed to bradykinesia due to interference between competing modules and a reduced ability to suppress unwanted movements. Additionally, excessive neurotransmitter depletion is predicted as a possible mechanism for the increased difficulty in performing complex movements. The simulation results showed that the model is in qualitative agreement with the results from movement experiments on PD patients and healthy subjects. Furthermore, based on changes in the firing rate of BG nuclei, the model demonstrated that the effective mechanism of Deep Brain Stimulation (DBS) in STN may result from stimulation induced inhibition of STN, partial synaptic failure of efferent projections, or excitation of inhibitory afferent axons even though the underlying methods of action may be quite different for the different mechanisms.

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Thalamic Neuronal Activity in Dopamine-Depleted Primates: Evidence for a Loss of Functional Segregation within Basal Ganglia Circuits

Cited by 152 publications

References 46 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

Therapeutic mechanisms of high-frequency stimulation in Parkinson’s disease and neural restoration via loop-based reinforcement

Increased bradykinesia in Parkinson’s disease with increased movement complexity: elbow flexion–extension movements

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