Dataset Information

Levodopa Effect on Basal Ganglia Motor Circuit in Parkinson's Disease.

ABSTRACT:

Aims

To investigate the effects of levodopa on the basal ganglia motor circuit (BGMC) in Parkinson's disease (PD).

Methods

Thirty PD patients with asymmetrical bradykinesia and 30 control subjects were scanned using resting-state functional MRI. Functional connectivity of the BGMC was measured and compared before and after levodopa administration in patients with PD. The correlation between improvements in bradykinesia and changes in BGMC connectivity was examined.

Results

In the PD-off state (before medication), the posterior putamen and internal globus pallidus (GPi) had decreased connectivity while the subthalamic nucleus (STN) had enhanced connectivity within the BGMC relative to control subjects. Levodopa administration increased the connectivity of posterior putamen- and GPi-related networks but decreased the connectivity of STN-related networks. Improvements in bradykinesia were correlated with enhanced connectivity of the posterior putamen-cortical motor pathway and with decreased connectivity of the STN-thalamo-cortical motor pathway.

Conclusion

In PD patients with asymmetrical bradykinesia, levodopa can partially normalize the connectivity of the BGMC with a larger effect on the more severely affected side. Moreover, the beneficial effect of levodopa on bradykinesia is associated with normalization of the striato-thalamo-cortical motor and STN-cortical motor pathways. Our findings inform the neural mechanism of levodopa treatment in PD.

SUBMITTER: Gao LL

PROVIDER: S-EPMC6492721 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Publications

Levodopa Effect on Basal Ganglia Motor Circuit in Parkinson's Disease.

Gao Lin-Lin LL Zhang Jia-Rong JR Chan Piu P Wu Tao T

CNS neuroscience & therapeutics 20160924 1

<h4>Aims</h4>To investigate the effects of levodopa on the basal ganglia motor circuit (BGMC) in Parkinson's disease (PD).<h4>Methods</h4>Thirty PD patients with asymmetrical bradykinesia and 30 control subjects were scanned using resting-state functional MRI. Functional connectivity of the BGMC was measured and compared before and after levodopa administration in patients with PD. The correlation between improvements in bradykinesia and changes in BGMC connectivity was examined.<h4>Results</h4> ...[more]

PMID: 27663605

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Project description:Malfunctions in the neural circuitry of the basal ganglia (BG), induced by alterations in the dopaminergic system, are responsible for an array of motor disorders and milder cognitive issues in Parkinson's disease (PD). Recently Baston and Ursino (2015a) presented a new neuroscience mathematical model aimed at exploring the role of basal ganglia in action selection. The model is biologically inspired and reproduces the main BG structures and pathways, modeling explicitly both the dopaminergic and the cholinergic system. The present work aims at interfacing this neurocomputational model with a compartmental model of levodopa, to propose a general model of medicated Parkinson's disease. Levodopa effect on the striatum was simulated with a two-compartment model of pharmacokinetics in plasma joined with a motor effect compartment. The latter is characterized by the levodopa removal rate and by a sigmoidal relationship (Hill law) between concentration and effect. The main parameters of this relationship are saturation, steepness, and the half-maximum concentration. The effect of levodopa is then summed to a term representing the endogenous dopamine effect, and is used as an external input for the neurocomputation model; this allows both the temporal aspects of medication and the individual patient characteristics to be simulated. The frequency of alternate tapping is then used as the outcome of the whole model, to simulate effective clinical scores. Pharmacokinetic-pharmacodynamic modeling was preliminary performed on data of six patients with Parkinson's disease (both "stable" and "wearing-off" responders) after levodopa standardized oral dosing over 4 h. Results show that the model is able to reproduce the temporal profiles of levodopa in plasma and the finger tapping frequency in all patients, discriminating between different patterns of levodopa motor response. The more influential parameters are the Hill coefficient, related with the slope of the effect sigmoidal relationship, the drug concentration at half-maximum effect, and the drug removal rate from the effect compartment. The model can be of value to gain a deeper understanding on the pharmacokinetics and pharmacodynamics of the medication, and on the way dopamine is exploited in the neural circuitry of the basal ganglia in patients at different stages of the disease progression.

Project description:BACKGROUND: In the absence of overt stimuli, the brain shows correlated fluctuations in functionally related brain regions. Approximately ten largely independent resting state networks (RSNs) showing this behaviour have been documented to date. Recent studies have reported the existence of an RSN in the basal ganglia - albeit inconsistently and without the means to interpret its function. Using two large study groups with different resting state conditions and MR protocols, the reproducibility of the network across subjects, behavioural conditions and acquisition parameters is assessed. Independent Component Analysis (ICA), combined with novel analyses of temporal features, is applied to establish the basis of signal fluctuations in the network and its relation to other RSNs. Reference to prior probabilistic diffusion tractography work is used to identify the basal ganglia circuit to which these fluctuations correspond. RESULTS: An RSN is identified in the basal ganglia and thalamus, comprising the pallidum, putamen, subthalamic nucleus and substantia nigra, with a projection also to the supplementary motor area. Participating nuclei and thalamo-cortical connection probabilities allow this network to be identified as the motor control circuit of the basal ganglia. The network was reproducibly identified across subjects, behavioural conditions (fixation, eyes closed), field strength and echo-planar imaging parameters. It shows a frequency peak at 0.025 +/- 0.007 Hz and is most similar in spectral composition to the Default Mode (DM), a network of regions that is more active at rest than during task processing. Frequency features allow the network to be classified as an RSN rather than a physiological artefact. Fluctuations in this RSN are correlated with those in the task-positive fronto-parietal network and anticorrelated with those in the DM, whose hemodynamic response it anticipates. CONCLUSION: Although the basal ganglia RSN has not been reported in most ICA-based studies using a similar methodology, we demonstrate that it is reproducible across subjects, common resting state conditions and imaging parameters, and show that it corresponds with the motor control circuit. This characterisation of the basal ganglia network opens a potential means to investigate the motor-related neuropathologies in which the basal ganglia are involved.

Dataset Information

Levodopa Effect on Basal Ganglia Motor Circuit in Parkinson's Disease.

Aims

Methods

Results

Conclusion

Publications

Levodopa Effect on Basal Ganglia Motor Circuit in Parkinson's Disease.

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