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Modulatory Effects of Levodopa on Cerebellar Connectivity in Parkinson's Disease.

ABSTRACT: Levodopa has been the mainstay of symptomatic therapy for Parkinson's disease (PD) for the last five decades. However, it is associated with the development of motor fluctuations and dyskinesia, in particular after several years of treatment. The aim of this study was to shed light on the acute brain functional reorganization in response to a single levodopa dose. Functional magnetic resonance imaging (fMRI) was performed after an overnight withdrawal of dopaminergic treatment and 1 h after a single dose of 250 mg levodopa in a group of 24 PD patients. Eigenvector centrality was calculated in both treatment states using resting-state fMRI. This offers a new data-driven and parameter-free approach, similar to Google's PageRank algorithm, revealing brain connectivity alterations due to the effect of levodopa treatment. In all PD patients, levodopa treatment led to an improvement of clinical symptoms as measured with the Unified Parkinson's Disease Rating Scale motor score (UPDRS-III). This therapeutic effect was accompanied with a major connectivity increase between cerebellar brain regions and subcortical areas of the motor system such as the thalamus, putamen, globus pallidus, and brainstem. The degree of interconnectedness of cerebellar regions correlated with the improvement of clinical symptoms due to the administration of levodopa. We observed significant functional cerebellar connectivity reorganization immediately after a single levodopa dose in PD patients. Enhanced general connectivity (eigenvector centrality) was associated with better motor performance as assessed by UPDRS-III score. This underlines the importance of considering cerebellar networks as therapeutic targets in PD.

SUBMITTER: Mueller K

PROVIDER: S-EPMC6443641 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Modulatory Effects of Levodopa on Cerebellar Connectivity in Parkinson's Disease.

Mueller Karsten K Jech Robert R Ballarini Tommaso T Holiga Štefan Š Růžička Filip F Piecha Fabian A FA Möller Harald E HE Vymazal Josef J Růžička Evžen E Schroeter Matthias L ML

Cerebellum (London, England) 20190401 2

Levodopa has been the mainstay of symptomatic therapy for Parkinson's disease (PD) for the last five decades. However, it is associated with the development of motor fluctuations and dyskinesia, in particular after several years of treatment. The aim of this study was to shed light on the acute brain functional reorganization in response to a single levodopa dose. Functional magnetic resonance imaging (fMRI) was performed after an overnight withdrawal of dopaminergic treatment and 1 h after a si ...[more]

PMID: 30298443

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Project description:Levodopa and, later, deep brain stimulation (DBS) have become the mainstays of therapy for motor symptoms associated with Parkinson's disease (PD). Although these therapeutic options lead to similar clinical outcomes, the neural mechanisms underlying their efficacy are different. Therefore, investigating the differential effects of DBS and levodopa on functional brain architecture and associated motor improvement is of paramount interest. Namely, we expected changes in functional brain connectivity patterns when comparing levodopa treatment with DBS. Clinical assessment and functional magnetic resonance imaging (fMRI) was performed before and after implanting electrodes for DBS in the subthalamic nucleus (STN) in 13 PD patients suffering from severe levodopa-induced motor fluctuations and peak-of-dose dyskinesia. All measurements were acquired in a within subject-design with and without levodopa treatment, and with and without DBS. Brain connectivity changes were computed using eigenvector centrality (EC) that offers a data-driven and parameter-free approach-similarly to Google's PageRank algorithm-revealing brain regions that have an increased connectivity to other regions that are highly connected, too. Both levodopa and DBS led to comparable improvement of motor symptoms as measured with the Unified Parkinson's Disease Rating Scale motor score (UPDRS-III). However, this similar therapeutic effect was underpinned by different connectivity modulations within the motor system. In particular, EC revealed a major increase of interconnectedness in the left and right motor cortex when comparing DBS to levodopa. This was accompanied by an increase of connectivity of these motor hubs with the thalamus and cerebellum. We observed, for the first time, significant functional connectivity changes when comparing the effects of STN DBS and oral levodopa administration, revealing different treatment-specific mechanisms linked to clinical benefit in PD. Specifically, in contrast to levodopa treatment, STN DBS was associated with increased connectivity within the cortico-thalamo-cerebellar network. Moreover, given the favorable effects of STN DBS on motor complications, the changes in the patients' clinical profile might also contribute to connectivity changes associated with STN-DBS. Understanding the observed connectivity changes may be essential for enhancing the effectiveness of DBS treatment, and for better defining the pathophysiology of the disrupted motor network in PD.

Project description:Cognitive and movement processes involved integration of several large-scale brain networks. Central to these integrative processes are connector hubs, brain regions characterized by strong connections with multiple networks. Growing evidence suggests that many neurodegenerative and psychiatric disorders are associated with connector hub dysfunctions. Using a network metric called functional connectivity overlap ratio, we investigated connector hub alterations in Parkinson's disease. Resting-state functional MRI data from 99 patients (male/female = 44/55) and 99 age- and sex-matched healthy controls (male/female = 39/60) participating in our cross-sectional study were used in the analysis. We have identified two sets of connector hubs, mainly located in the sensorimotor cortex and cerebellum, with significant connectivity alterations with multiple resting-state networks. Sensorimotor connector hubs have impaired connections primarily with primary processing (sensorimotor, visual), visuospatial, and basal ganglia networks, whereas cerebellar connector hubs have impaired connections with basal ganglia and executive control networks. These connectivity alterations correlated with patients' motor symptoms. Specifically, values of the functional connectivity overlap ratio of the cerebellar connector hubs were associated with tremor score, whereas that of the sensorimotor connector hubs with postural instability and gait disturbance score, suggesting potential association of each set of connector hubs with the disorder's two predominant forms, the akinesia/rigidity and resting tremor subtypes. In addition, values of the functional connectivity overlap ratio of the sensorimotor connector hubs were highly predictive in classifying patients from controls with an accuracy of 75.76%. These findings suggest that, together with the basal ganglia, cerebellar and sensorimotor connector hubs are significantly involved in Parkinson's disease with their connectivity dysfunction potentially driving the clinical manifestations typically observed in this disorder.

Project description:The cerebellum is associated with the emergence of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), yet the neural mechanism remains obscure. Our aim was to ascertain the role of functional connectivity (FC) patterns of the cerebellar dentate nucleus (DN) in the pathogenesis of peak-dose dyskinesia in PD. Twenty-three peak-dose dyskinetic PD patients, 27 non-dyskinetic PD patients, and 36 healthy controls (HCs) were enrolled and underwent T1-weighted and resting-state functional magnetic resonance imaging (rs-fMRI) scans after dopaminergic medication intake. We selected left and right DN as the regions of interest and then employed voxel-wise FC analysis and voxel-based morphometry analysis (VBM). The correlations between the altered FC pattern and clinical scores were also examined. Finally, receiver operating characteristic (ROC) curve analysis was performed to assess the potential of DN FC measures as a feature of peak-dose dyskinesia in PD. Dyskinetic PD patients showed excessively increased FC between the left DN and right putamen compared with the non-dyskinetic. When compared with controls, dyskinetic PD patients mainly exhibited increased FC between left DN and bilateral putamen, left paracentral lobule, right postcentral gyrus, and supplementary motor area. Additionally, non-dyskinetic PD patients displayed increased FC between left DN and left precentral gyrus and right paracentral lobule compared with controls. Meanwhile, increased FC between DN (left/right) and ipsilateral cerebellum lobule VIII was observed in both PD subgroups. However, no corresponding alteration in gray matter volume (GMV) was found. Further, a positive correlation between the z-FC values of left DN-right putamen and the Unified Dyskinesia Rating Scale (UDysRS) was confirmed in dyskinetic PD patients. Notably, ROC curve analyses revealed that the z-FC values of left DN-right putamen could be a potential neuroimaging feature identifying dyskinetic PD patients. Our findings demonstrated that the excessively strengthened connectivity of DN-putamen might contribute to the pathophysiological mechanisms of peak-dose dyskinesia in PD.

Project description:BackgroundThe primary motor cortex (M1) is a critical node in Parkinson's disease (PD)-related motor circuitry; however, the functional roles of its subregions are poorly understood. In this study, we investigated changes in the functional connectivity patterns of M1 subregions and their relationships to improved clinical symptoms following levodopa administration.MethodsThirty-six PD patients and 37 healthy controls (HCs) were enrolled. A formal levodopa challenge test was conducted in the PD group, and the Unified Parkinson's Disease Rating Scale motor section (UPDRS-III) was assessed before (off state) and 1 h after administration of levodopa (on state). The PD group underwent resting-state functional magnetic resonance imaging in both off and on states, whereas the HC group was scanned once. We used the Human Brainnetome Atlas template to subdivide M1 into twelve regions of interest (ROIs). Functional connectivity (FC) was compared between PD on and off states [paired t-test, voxel-level p < 0.001, cluster-level p < 0.05, Gaussian random field (GRF) correction] and between patients and HC (two-sample t-test voxel-level p < 0.001, cluster-level p < 0.05). Correlations between ΔFC (differences in FC between PD off and on states) and clinical symptom improvements were examined.ResultsThere was decreased FC between the right caudal dorsolateral area 6 and the anterior cingulate gyrus (ACC), the right upper limb region and the left medial dorsal thalamus (mdTHA), as well as increased FC between the left tongue and larynx region and the left medial frontal gyrus. ΔFC between the right caudal dorsolateral area 6 and ACC was positively correlated with improvements in UPDRS-III total scores as well as the rigidity (item 22) and bradykinesia (items 23-26 and 31) subscores. ΔFC between the right upper limb region and left thalamus was positively correlated with improvements in the left upper limb tremor (items 20c and 21b) and postural tremor (item 21b) subscores.ConclusionsOur results reveal novel information regarding the underlying mechanisms in the motor circuits in the M1 and a promising way to explore the internal function of the M1 in PD patients. Notably, M1 is a potential therapeutic target in PD, and the exploration of its subregions provides a basis and a source of new insights for clinical intervention and precise drug treatment.

Dataset Information

Modulatory Effects of Levodopa on Cerebellar Connectivity in Parkinson's Disease.

Publications

Modulatory Effects of Levodopa on Cerebellar Connectivity in Parkinson's Disease.

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